Nivolumab for unresectable cutaneous epithelial malignancies: An open-label, single-arm, multi-centre, phase II trial (NMSC-PD1)

Nivolumab for unresectable cutaneous epithelial malignancies: An open-label, single-arm, multi-centre, phase II trial (NMSC-PD1) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Nivolumab for unresectable cutaneous epithelial malignancies: An open-label, single-arm, multi-centre, phase II trial (NMSC-PD1) Yoshio Nakamura, Naoya Yamazaki, Kenjiro Namikawa, Hiroshi Uchi, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8709454/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Mar, 2026 Read the published version in BMC Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Background Data in East Asian patients and in other epithelial skin cancers, including extramammary Paget’s disease (EMPD) and adnexal carcinomas, are scarce. Therefore, we conducted a phase II trial of nivolumab in Japanese patients with advanced non-melanoma skin cancers (NMSCs). Patients and methods: This multicentre, open-label, single-arm phase II study enrolled adults (≥ 20 years) with histologically confirmed unresectable or recurrent epithelial cutaneous malignancies, Eastern Cooperative Oncology Group performance status 0–1, and at least one measurable lesion (RECIST v1.1). Nivolumab 480 mg was administered intravenously every 4 weeks for up to 26 cycles. The primary endpoint was overall response rate (ORR), assessed by blinded independent central review (BICR; RECIST v1.1). Secondary endpoints included progression-free survival, overall survival, and safety. Results Thirty-one patients were enrolled (20 cSCC, 4 EMPD, 2 BCC, 5 other NMSCs); median age was 73 years (range 58–86), and 71% were male. ORR by BICR was 22.6% (7/31), and the disease control rate was 54.8% (17/31). Responses were durable, with a median duration of 21.3 months. In the cSCC cohort, median tumour mutational burden (TMB) was 9.0 mut/Mb, lower than in Western series; among three patients with TMB ≥ 30 mut/Mb, two achieved objective responses. Common adverse events included pyrexia, hypothyroidism, adrenal insufficiency, and pruritus. Conclusions Nivolumab showed durable antitumour activity with manageable toxicity in Japanese patients with advanced NMSCs, including rare non-cSCC. The lower ORR compared with Western trials may reflect intrinsic biological differences and support biomarker-driven, region-specific immunotherapy. Clinical trial registration: jRCT2031190048 (jRCT; https://jrct.niph.go.jp/ ), registered on 2 July 2019. Non-melanoma skin cancer nivolumab programmed death-1 squamous cell carcinoma epithelial skin malignancy Figures Figure 1 Figure 2 Introduction Cutaneous epithelial malignancies comprise a heterogeneous group of non-melanoma skin cancers (NMSCs) that arise from keratinocytes or skin adnexal structures. The two most common forms are cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) [ 1 , 2 ]. Other histological subtypes include accessory gland carcinomas (e.g., eccrine and sebaceous carcinomas), primary cutaneous apocrine carcinoma, and extramammary Paget’s disease (EMPD). Although these tumours differ in epidemiology, biological characteristics, and prognosis, advanced cases are associated with a poor prognosis, and treatment options are limited [ 3 – 5 ]. cSCC is the second most common skin cancer worldwide. Its incidence rate is high in European populations, with age-adjusted rates typically ranging from 20 to 80 cases per 100,000 individuals [ 6 ]. Although in most cases, tumours are localised and curable with surgical resection, 2–5% of patients develop metastases [ 7 , 8 ]. Additionally, the prognosis for advanced disease is poor, with a historical median overall survival (OS) of < 2 years [ 9 ]. Recently, immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1), such as cemiplimab and pembrolizumab, have demonstrated substantial and reliable antitumour activity in advanced cSCC [ 10 – 13 ]. Cemiplimab received regulatory approval in the United States and European Union for advanced cSCC treatment in 2018, and pembrolizumab was subsequently approved. The incidence of cSCC in East Asian populations is considerably lower, ranging from 1.0 to 3.4 per 100,000 individuals [ 14 – 16 ]. Mortality rates are also lower than those in Western populations, and data on advanced diseases are limited. This low incidence has contributed to the lack of region-specific drug development. Thus, there are currently no effective systemic therapy options for advanced cSCC in Japan, and PD-1 blockade has not been formally evaluated in population-specific prospective clinical trials. Despite the absence of direct evidence, the extreme rarity of cutaneous epithelial malignancies other than cSCC (non-SCC NMSCs) has resulted in their management being informed by treatment principles developedestablished for cSCC. Locally advanced BCC is extremely rare, accounting for only approximately 0.8% of all BCC cases in a retrospective cohort study based on a large commercially insured population in the United States [ 17 ]. Metastatic BCC is even rarer, with an estimated incidence of 0.0028% to 0.55% [ 18 , 19 ]. For unresectable or metastatic BCC, Hedgehog pathway inhibitors (HHIs) are the standard first-line therapy in Europe and the United States. Prospective studies of PD-1 inhibitors have been conducted for patients with advanced disease who are resistant or intolerant to HHIs; therefore, the anti–PD-1 antibody cemiplimab has been approved for locally advanced or metastatic BCC following HHI failure or intolerance in Europe and the United States [ 20 , 21 ]. Other metastatic non-cSCC NMSCs, such as adnexal carcinomas and EMPD, are also extremely rare cancers [ 22 – 24 ]. Epidemiological data indicate an incidence of less than 1 per million individuals for most of these tumors, and their clinical behaviour is poorly characterised. Consequently, no prospective trials of PD-1 blockade have been conducted for these tumour types, and their management generally follows the treatment principles established for cSCC. Nevertheless, given that several non-cSCC NMSCs exhibit a relatively high tumour mutational burden (TMB), PD-1 antibody therapy is expected to be clinically beneficial [ 25 ]. Therefore, we aimed to conduct the first phase II, investigator-initiated clinical trial to evaluate the antitumour activity and safety of the anti–PD-1 antibody nivolumab monotherapy for Japanese patients with advanced NMSC, including both cSCC and non-cSCC NMSCs. Materials and methods Study design and patient population This single-arm, open-label, multicentre, phase II trial evaluated the efficacy and safety of nivolumab in patients with advanced cutaneous epithelial malignancies. The study design, eligibility criteria, and ethical approval have been previously reported [26]. Patients were enrolled between July 2019 and July 2021 and were administered nivolumab every 4 weeks for up to 26 cycles. For patients who achieved a response without disease progression, treatment could be extended for a maximum of 2 years. A sample size of 26 cases was determined to achieve at least 80% power given an expected response rate of 25%, a threshold response rate of 5%, and a two-sided significance level of 5%. Considering potential dropouts, the enrolment target was 30 patients. The trial was conducted at eight centres in major cities selected based on Japan's population distribution. This study has been conducted in accordance with the principles outlined in the Declaration of Helsinki, guidelines for the conduct of clinical trials, and the SPIRIT (Standard Protocol Items for Intervention Trials) guidelines. The protocol was approved by the Ethics Review Committee of Keio University Hospital in May 2019, and similar approvals were obtained from all other participating institutions. All patients provided written informed consent prior to participation. Inclusion and exclusion criteria Inclusion criteria 1. Age: 20 years or older. 2. Histologically confirmed incurable, advanced, or recurrent epithelial skin malignancies after surgical treatment and/or radiotherapy. 3. ≥1 measurable lesions based on RECIST 1.1 4. ECOG performance status 0–1. 5. Life expectancy ≥ 90 days 6. Women willing to use double contraception and agree not to breastfeed for at least 5 months after final administration. Men willing to use double contraception for at least 5 months after final administration. 7. Sufficient organ functions: all of the following conditions are fulfilled: White blood cell ≥ 2,000/mm 3 Absolute neutrophil count ≥ 1,500/mm 3 Platelets ≥ 100,000/mm 3 Haemoglobin ≥ 9.0g/dL 8. Any investigational medication other than the study drug. 9. Any anticancer therapies including chemotherapy or biologic therapy other than the study medication, excluding the follows: AST and ALT Total bilirubin, Serum creatinine three times the upper limit of normal two times the upper limit of normal 1.5 mg/dL or creatinine clearance or eGFR ≥ 45 mL/min. Patients received an adequate explanation about the study and provided informed consent. Exclusion criteria 1. History of anaphylaxis to other antibody formulations, severe allergy, chronic or recurrent autoimmune disease, transplantation therapy, recent transient cerebral ischaemic attack or cerebral vascular accident, recent thrombosis, or thromboembolism. 2. History of additional malignancy except for completely resected BCC, carcinoma in situ, intramucosal cancer, superficial bladder cancer, or other cancers that have not recurred for at least 5 years before enrollment. 3. History of pretreatment using anti-PD1/L1/L2, anti-CD137, anti-CTLA-4 inhibitor or any other antibody or drugs intended for T-cell regulation. 4. Active central nervous system metastases 5. Uncontrolled tumour-associated pain 6. Current disease; active autoimmune disease, diverticulitis or symptomatic peptic ulcer disease, pericardial effusion, pleural effusion or ascites requiring sustained treatment, uncontrollable diabetes mellitus, systemic infection requiring treatment, interstitial lung diseases, pulmonary fibrosis, or unstabled radiation pneumonitis, uncontrollable or severe cardiovascular disease. 7. Recent following treatments within 28 days prior to the enrollment; systemic adrenocortical hormone, immunosup- pressant, unapproved drugs, any antineoplastic agent, surgical adhesion of the pleura or pericardium, surgery under general anesthesia, radiotherapy. 8. Received surgery under local or topical anesthesia within 14 days prior to the enrollment. 9. Received any radiopharmaceuticals within 56 days prior to the enrolment. 10. Seropositive for HBsAg, HCV-Ab, or HIV-Ab. 11. Pregnant, breast-feeding or potentially pregnant. 12. History of any condition or therapy that might confound the results of this study. Procedure Nivolumab (480 mg) was administered intravenously in an outpatient setting for 30 min every 4 weeks. The maximum number of doses was 26 (with the total treatment duration not exceeding 2 years). Imaging assessments of tumour lesions were performed every two cycles, immediately before initiating the subsequent cycle. Patients who discontinued treatment due to disease progression or adverse events, or completed 2 years of therapy, underwent a final tumour assessment and subsequently entered a post-treatment follow-up phase. AEs were recorded throughout the treatment period, at any time during each cycle, and for 28 days after the final administration. During the post-treatment follow-up phase, imaging examinations were performed every 8 weeks to assess the tumour status. To determine OS, patients were followed until death, withdrawal of consent, or termination of the study (31 December 2023). TMB and microsatellite instability (MSI) assessment Tumour samples were obtained from enrolled patients when adequate formalin-fixed paraffin-embedded material was available. All samples were collected at the time of diagnostic biopsy or surgical resection prior to study enrolment and drug administration. DNA (≥ 40 ng) was extracted from tumour-rich areas (≥ 30% tumour content) and analysed using the TruSight Oncology 500 (TSO500, Illumina) assay, a hybrid-capture panel covering 523 genes (~ 1.94 Mb) [24]. Libraries with unique molecular identifiers were sequenced on Illumina instruments, and the data were processed using the DRAGEN™ TSO500 pipeline for error correction, variant calling, and biomarker analysis [27, 28]. TMB was calculated as the number of eligible somatic variants per megabase after germline filtering, requiring ≥ 50× coverage and a VAF ≥ 5%. In accordance with regulatory standards, TMB-high was defined as ≥ 10 mutations/Mb [29]. MSI was assessed across approximately 130 homopolymer loci; samples with ≥ 40 evaluable loci were scored, and MSI-high was defined as ≥ 20% unstable loci [27, 30]. Endpoints and assessments The primary endpoint was the overall response rate (ORR), assessed by blinded independent central review (BICR) according to RECIST version 1.1. ORR, according to immune-related RECIST (iRECIST), was evaluated as an exploratory endpoint. Secondary endpoints included investigator-assessed ORR, progression-free survival (PFS), OS, disease control rate (DCR), and adverse events (AEs). PFS was defined as the interval from the first administration of study treatment to documented disease progression or death from any cause. The investigator-assessed ORR was determined locally by treating investigators according to RECIST v1.1, without blinding to treatment allocation. OS was defined as the interval from the first administration to death from any cause. Best overall response (BOR) was defined as the best recorded response (CR, PR, SD, or PD) from the commencement of treatment until disease progression or death, whichever occurred first. Duration of response (DOR) was defined as the time from the first documented response (CR or PR) to disease progression or death. Time to response (TTR) was defined as the time from the first nivolumab administration to the first documented response. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Each efficacy endpoint was analysed separately for all NMSCs, cSCC alone, and other non-cSCC NMSCs. Data collection Demographic, clinical, and pathological data were collected from electronic case report forms and medical records at each participating site. The variables included age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, primary tumour site, disease stage, prior treatments, and laboratory findings. Tumour response was assessed according to RECIST version 1.1 by BICR and investigators. Safety data, including treatment-emergent adverse events, were collected at each visit during treatment and follow-up. All data were verified by the data management team before database lock. Statistical analysis All statistical tests were two-sided, with a significance level of 5%. No adjustments for multiplicity were implemented for comparisons across endpoints or time points (such as baseline and each scheduled tumour assessment every two cycles). Safety analyses were conducted in a descriptive manner and were not unadjusted for multiplicity. The full analysis set (FAS) included all patients who received at least one dose of nivolumab, excluding those with major eligibility violations (e.g., absence of informed consent, enrolment outside the study period, or failure to meet key eligibility criteria). The safety analysis set (SAF) comprised all patients who received at least one dose of nivolumab. Exact 95% confidence intervals (CIs) for ORR and DCR were calculated using the binomial distribution. Survival analyses (PFS and OS) were performed using the Kaplan–Meier method. Median survival times and 95% CIs were estimated using the Brookmeyer–Crowley method, and survival curves were compared using the log-rank test. Patients alive or progression-free at the data cutoff date (31 December 2023) were censored. All AEs were coded according to MedDRA/J, version 24.1, and their incidence rates were tabulated with the exact two-sided 95% CIs calculated from the binomial distribution. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA), and figures were generated using R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS Participant selection A total of 33 patients were screened between 2019 and 2023. Two patients were excluded before study treatment owing to major eligibility violations: one for lack of measurable lesions and one for withdrawal of consent. Accordingly, both the FAS and SAF included 31 patients each. No significant differences in age, sex, or disease stage were observed between the screened and enrolled populations, suggesting that the study cohort was representative of the target population. Patients Patient age ranged from 27 to 83 years, with a median of 70.0 years. The primary sites were the head and neck in 4 cases (12.9%), extremities in 12 (38.7%), back in 6 (19.4%), anogenital region in 6 (19.4%), and other sites in 3 (9.7%). Classification according to sun exposure showed that 8 cases (25.8%) occurred in sun-exposed areas and 23 (74.2%) in non-sun‐exposed areas. Regarding prior treatment, 25 patients (80.6%) had undergone surgery, 7 (22.6%) systemic therapy, and 14 (45.2%) radiotherapy. As regard disease stage, 3 (9.7%) patients had stage III disease and 28 (90.3%) had stage IV disease. The histological subtypes included 20 cSCCs (64.5%), 4 EMPDs (12.9%), 3 eccrine porocarcinomas, 2 BCCs, 1 sweat gland carcinoma, and 1 primary cutaneous mucinous carcinoma. No cases of Merkel cell carcinoma were identified. Patient demographics and baseline characteristics are presented in Table 1 . Table 1 Patient demographics and baseline characteristics All (n = 31) SCC (n = 20) Non-SCC NMSC (n = 11) Median age, years(range) 70.0 (27–83) 70.0 (27–83) 70.0 (55–76) ≥ 70 16 (51.6%) 10 (50.0%) 6 (60.0%) Cancer types Squamous cell carcinoma 20 (64.5%) Basal cell carcinoma 2 (6.5%) Extramammary Paget’s disease 4 (12.9%) Others 5 (16.1%) Sex Female 10 (32.3%) 7 (35.0%) 3 (27.3%) Male 21 (67.7%) 13 (65.0%) 8 (72.7%) ECOG performance status 0 21 (67.7%) 12 (60.0%) 2 (18.2%) 1 10 (32.3%) 8 (40.0%) 9 (81.8%) Primary site Head & Neck 4 (12.9%) 3 (15.0%) 1 (9.1%) Extremities 12 (38.7%) 9 (45.0%) 3 (27.3%) Trunk 6 (19.4%) 3 (15.0%) 3 (27.3%) Anogenital 6 (19.4%) 2 (10.0%) 4 (36.4%) Others 3 (9.7%) 3 (15.0%) 0 (0%) Sun exposure areas Exposed areas 8 (25.8%) 6 (30.0%) 2 (18.2%) Non-exposed areas 23 (74.2%) 14 (70.0%) 9 (81.8%) Previous cancer-related surgery 25 (80.6%) 17 (85.0%) 8 (72.3%) Previous cancer-related systemic therapy 7 (22.6%) 4 (20.0%) 3 (27.3%) Previous cancer-related radiotherapy 14 (45.2%) 10 (50.0%) 4 (36.4%) Stage III 3 (9.7%) 2 (10.0%) 1 (9.1%) IV 28 (90.3%) 18 (90.0%) 10 (90.9%) SCC, squamous cell carcinoma; NMSC, non-melanoma skin cancer; ECOG, Eastern Cooperative Oncology Group Efficacy By BICR, the primary endpoint, ORR, was 22.6% (7/31; 95% CI, 9.6–41.1%) (Table 2 ). ORR was 25.0% (5/20; 95% CI, 8.7–49.1%) in cSCC and 18.2% (2/11; 95% CI, 2.3–51.8%) in non-cSCC NMSC. Responses were observed in one patient each with EMPD and BCC, whereas no responses were observed in other non-cSCC NMSC types. Among the 31 patients, 20 had cSCC, and 11 had non-cSCC NMSC (5 EMPD, 3 BCC, and 3 others). The BOR included two complete responses (CRs; 6.5%) and five partial responses (PRs; 16.1%), whereas stable disease (SD) and progressive disease (PD) were observed in 32.3% and 29.0% of cases, respectively, and 16.1% were not evaluable (NE). In the non-cSCC NMSC subgroup, BOR comprised 1 CR, 1 PR, 4 SD, and 5 PD. The overall median PFS was 4.96 months (95% CI, 1.87–35.68), 5.54 months in cSCC, and 3.75 months in non-cSCC NMSC, with a median OS of 17.77 months (95% CI, 3.94–39.56), 24.08 months in cSCC, and 13.54 months in non-cSCC NMSC (Fig. 1 ). The overall DCR was 54.8%, 55.0% for cSCC, and 54.5% for non-cSCC NMSC. Median DOR and TTR were 21.32 and 9.23 months, respectively (Supplementary Fig. 1). Changes in target lesion size and treatment duration are summarised in Fig. 2 . Table 2 Tumour response assessment as per independent central review All (n = 31) SCC (n = 20) Non-SCC NMSC (n = 11) Objective response (%, 95% CI) 7 (22.6%; 9.6–41.1) 5 (25%; 8.7–49.1) 2 (18.2%; 6.0–61.0) Best overall response Complete response 2 (6.5%) 1 (5.0%) 1 (9.1%) Partial response 5 (16.1%) 4 (20.0%) 1 (9.1%) Stable disease 10 (32.3%) 6 (30.0%) 4 (36.4%) Progressive disease 9 (29.0%) 4 (20.0%) 5 (45.5%) Not evaluated* 5 (16.1%) 5 (25.0%) 0 (0%) Disease control (%, 95% CI) 17 (54.8%, 36.0–72.7) 10 (55.0%, 31.5–76.9) 6 (54.5%, 23.4–83.3) Median progression-free survival, months (95% CI) 5.0 (3.7–7.8) 5.5 (3.7–14.1) 3.7 (2.0–5.7) Median overall survival, months (95% CI) 17.8 (12.3–NR) 24.1 (12.3–NR) 13.5 (5.9–NR) Median duration of response, months (95% CI) 21.3 (3.7–NR) 21.3 (3.7–NR) NR (3.8–NR) Median time to response, months (95% CI) 9.2 (3.6–NR) 9.0 (1.9–NR) NR (1.9–NR) Data are % (95% CI) or n (%), unless otherwise specified NR, not reached * Includes patients who did not undergo imaging studies after treatment initiation, who were determined to have no target lesions by central review, or who underwent imaging studies but were not evaluated. SCC, squamous cell carcinoma; NMSC, non-melanoma skin cancer; CI, confidence interval By investigator assessment, ORR was 32.3% (10/31; 95% CI, 16.7–51.4%), including 35.0% in cSCC and 27.3% in non-cSCC NMSC (5 EMPD, 3 BCC, and 3 others). The overall median PFS was 5.52 months (0.66–35.68), 6.31 months in cSCC, and 5.52 months in non-cSCC NMSC, with a median OS of 17.77, 24.08, and 13.54 months, respectively. Further, the overall DCRs were 64.5%, with 60.0% for cSCC and 72.7% for non-cSCC NMSC. The overall median DOR was 26.61 months and 7.36 months in non-cSCC NMSC. The median TTR was 5.32 months. Median PFS was 4.96 months in all NMSC, with corresponding values of 5.54 months in cSCC and 3.75 months in non-cSCC NMSC. Median OS was 17.77 months overall, 24.08 months in cSCC, and 13.54 months in non‐cSCC NMSC. BICR, blinded independent central review; PFS, progression-free survival; OS, overall survival; NMSC, non-melanoma skin cancer; cSCC, cutaneous squamous cell carcinoma ( a ) Spider plot shows the longitudinal changes in target lesion size for each patient. ( b ) Waterfall plot illustrates the maximum percentage change from baseline in target lesion size for each patient, highlighting responses across histological subtypes. ( c ) Swimmer plot shows treatment duration and time to response, with a median time to response of 9.23 months according to BICR. BICR, blinded independent central review; PFS, progression-free survival; OS, overall survival; NMSC, non-melanoma skin cancer; cSCC, cutaneous squamous cell carcinoma Safety Among 31 patients, AEs were observed in 30 patients (96.8%), with a total of 209 events recorded. Treatment-related AEs (TRAEs) occurred in 18 patients (58.1%), comprising 48 events in total. Four patients (12.9%) discontinued treatment because of AEs. The most prevalent AEs (≥ 3 patients) were hyperthyroidism (12.9%), hypothyroidism (12.9%), pyrexia (9.7%), pruritus (9.7%), and interstitial lung disease (9.7%). Grade ≥ 3 AEs occurred in 21 events in 11 patients (35.5%). Grade ≥ 3 TRAEs occurred in 7 events among 6 patients (19.4%), including hyperthyroidism, hypophysitis, pyrexia, interstitial lung disease, aplastic anaemia, abnormal liver function, and decreased appetite. One patient died of acute respiratory distress syndrome; however, this event was deemed unrelated to the study drug (data not shown). AEs leading to treatment discontinuation occurred in 4 patients (12.9%), of which 2 (6.5%) were TRAEs. Permanent drug withdrawal was reported in 4 patients (12.9%), including 1 (3.2%) because of a TRAE (aplastic anaemia). A comprehensive summary of the AEs is presented in Table 3 . Table 3 Adverse events SOC/HLT N Any grade (%) Grade 3–4 (%) Grade 5 (%) All Adverse Event 31 30 96.8 11 35.5 1 3.2 Endocrine disorders 31 13 41.9 2 6.5 0 0.0 Adrenal cortical hypofunctions 31 5 16.1 0 0.0 0 0.0 Thyroid hypofunction disorders 31 5 16.1 0 0.0 0 0.0 Thyroid hyperfunction disorders 31 4 12.9 1 3.2 0 0.0 Hypothalamic and pituitary disorders NEC 31 1 3.2 1 3.2 0 0.0 General disorders and administration site conditions 31 13 41.9 2 6.5 0 0.0 Febrile disorders 31 7 22.6 1 3.2 0 0.0 Asthenic conditions 31 5 16.1 0 0.0 0 0.0 Edema NEC 31 3 9.7 0 0.0 0 0.0 Pain and discomfort NEC 31 2 6.5 1 3.2 0 0.0 Infections and infestations 31 13 41.9 1 3.2 0 0.0 Bacterial infections NEC 31 4 12.9 0 0.0 0 0.0 Upper respiratory tract infections 31 4 12.9 0 0.0 0 0.0 Coronavirus infections 31 2 6.5 0 0.0 0 0.0 Herpes viral infections 31 2 6.5 0 0.0 0 0.0 Skin structures and soft tissue infections 31 2 6.5 0 0.0 0 0.0 Urinary tract infections 31 2 6.5 1 3.2 0 0.0 Cytomegaloviral infections 31 1 3.2 1 3.2 0 0.0 Skin and subcutaneous tissue disorders 31 13 41.9 0 0.0 0 0.0 Dermatitis and eczema 31 10 32.3 0 0.0 0 0.0 Pruritus NEC 31 5 16.1 0 0.0 0 0.0 Skin and subcutaneous tissue ulcerations 31 2 6.5 0 0.0 0 0.0 Investigations 31 12 38.7 0 0.0 0 0.0 Pituitary analyses anterior 31 4 12.9 0 0.0 0 0.0 Hepatobiliary function diagnostic procedures 31 3 9.7 0 0.0 0 0.0 Physical examination procedures and organ system status 31 3 9.7 0 0.0 0 0.0 Renal function analyses 31 2 6.5 0 0.0 0 0.0 Gastrointestinal disorders 31 11 35.5 1 3.2 0 0.0 Gastrointestinal atonic and hypomotility disorders NEC 31 4 12.9 0 0.0 0 0.0 Gastrointestinal and abdominal pains (excluding oral and throat) 31 3 9.7 0 0.0 0 0.0 Nausea and vomiting symptoms 31 3 9.7 0 0.0 0 0.0 Stomatitis and ulceration 31 1 3.2 1 3.2 0 0.0 Metabolism and nutrition disorders 31 8 25.8 4 12.9 0 0.0 Appetite disorders 31 2 6.5 1 3.2 0 0.0 Calcium metabolism disorders 31 2 6.5 1 3.2 0 0.0 Hyperglycaemic conditions NEC 31 2 6.5 1 3.2 0 0.0 Protein metabolism disorders NEC 31 2 6.5 1 3.2 0 0.0 Musculoskeletal and connective tissue disorders 31 8 25.8 0 0.0 0 0.0 Musculoskeletal and connective tissue pain and discomfort 31 3 9.7 0 0.0 0 0.0 Blood and lymphatic system disorders 31 7 22.6 3 9.7 0 0.0 Anaemia’s NEC 31 4 12.9 1 3.2 0 0.0 Leukopenia NEC 31 2 6.5 0 0.0 0 0.0 Marrow depression and hypoplastic anaemia’s 31 2 6.5 2 6.5 0 0.0 Neoplasms benign, malignant, and unspecified (including cysts and polyps) 31 6 19.4 1 3.2 0 0.0 Oncologic complications and emergencies 31 5 16.1 1 3.2 0 0.0 Nervous system disorders 31 5 16.1 0 0.0 0 0.0 Sensory abnormalities NEC 31 3 9.7 0 0.0 0 0.0 Psychiatric disorders 31 5 16.1 0 0.0 0 0.0 Disturbances in initiating and maintaining sleep 31 3 9.7 0 0.0 0 0.0 Respiratory, thoracic, and mediastinal disorders 31 5 16.1 1 3.2 0 0.0 Parenchymal lung disorders NEC 31 3 9.7 1 3.2 0 0.0 Pulmonary oedemas 31 1 3.2 0 0.0 1 3.2 Injury, poisoning and procedural complications 31 4 12.9 0 0.0 0 0.0 Non-site-specific injuries NEC 31 3 9.7 0 0.0 0 0.0 Skin injuries NEC 31 2 6.5 0 0.0 0 0.0 Renal and urinary disorders 31 3 9.7 0 0.0 0 0.0 Vascular disorders 31 3 9.7 0 0.0 0 0.0 Vascular hypertensive disorders NEC 31 2 6.5 0 0.0 0 0.0 Ear and labyrinth disorders 31 2 6.5 0 0.0 0 0.0 Eye disorders 31 2 6.5 0 0.0 0 0.0 Hepatobiliary disorders 31 2 6.5 1 3.2 0 0.0 Hepatic enzymes and function abnormalities 31 2 6.5 1 3.2 0 0.0 Cardiac disorders 31 1 3.2 0 0.0 0 0.0 Immune system disorders 31 1 3.2 0 0.0 0 0.0 Reproductive system and breast disorders 31 1 3.2 0 0.0 0 0.0 Surgical and medical procedures 31 1 3.2 1 3.2 0 0.0 Fracture treatments (excluding skull and spine) 31 1 3.2 1 3.2 0 0.0 NEC, neuroendocrine carcinoma TMB and MSI In our cohort, genomic profiling was feasible in 23 of the 31 patients (16 with cSCC and 7 with non-cSCC NMSC). Genomic profiling could not be performed in the remaining eight patients because tumour specimens were not available, as not all patients underwent surgical resection or biopsy at the participating institutions. The median TMB was 9.0 mut/Mb (range, 3.1–91.7) in the overall cohort, 9.0 mut/Mb (3.1–91.7) in cSCC, and 8.6 mut/Mb (4.7–21.9) in non-cSCC NMSC. TMB-high (≥ 10 mut/Mb) was observed in 30.4% (7/23) of patients, including 31.3% (5/16) in cSCC and 28.6% (2/7) in non-cSCC NMSC. No statistically significant difference in the distribution of TMB was observed between cSCC and non-cSCC NMSC (Mann–Whitney U test, p = 0.74; data not shown). Among the enrolled patients, only three harboured a TMB of ≥ 30 mutations/Mb. Two patients achieved an objective response by BICR. A 63-year-old man with inguinal primary cSCC and a TMB of 32.8 mutations/Mb achieved a PR, with a PFS of 15.0 months. Another 63-year-old man with head and neck primary cSCC and a TMB of 63.3 mutations/Mb also achieved a PR, with a PFS of 22.9 months. The third patient, a 77-year-old man with head and neck primary cSCC, was considered NE by BICR because no target lesion was identified; nevertheless, this patient maintained disease control with a PFS of 35.2 months until the end of the study. The median MSI was 2.7% (range, 0.88–5.36) overall, 2.12% (0.88–5.15) in cSCC, and 2.97% (1.85–5.36) in non-cSCC NMSC. MSI-high (≥ 20%) was not observed in any patient, and all cases were categorised as MSI-low (Supplementary Table 1). DISCUSSION In this phase II trial, nivolumab showed clinically meaningful activity in advanced cutaneous epithelial malignancies in a Japanese population. The BICR-assessed ORR was 22.6%, and the lower bound of the 95% CI (9.6%) exceeded the prespecified threshold of 5%, thereby rejecting the null hypothesis and confirming efficacy. Importantly, responses were durable: the median DOR exceeded 20 months, and some patients exhibited long-lasting benefit comparable to that reported with anti–PD-1 therapy in other tumour types such as melanoma, NSCLC, and renal cell carcinoma, where median DORs of approximately 24–36 months have been described [ 31 – 33 ]. The safety findings were largely consistent with the established profile of nivolumab. Although the incidence of AEs was slightly higher than that reported in other tumour types—where common treatment-related AEs include fatigue, pruritus, rash, and thyroid dysfunction and grade ≥ 3 events occur in approximately 10–15% of patients [ 34 ]—no new safety signals were observed, supporting an overall benefit–risk balance in this setting. In line with these results, the Ministry of Health, Labour and Welfare of Japan approved nivolumab in 2024 for epithelial cutaneous malignancies in Japanese patients (MHLW press release, March 22, 2024. Available at: https://www.mhlw.go.jp/stf/newpage_37482.html . ) Exploratory analyses did not identify clear clinical predictors of response. The ORR was 25.0% in the cSCC cohort and 18.4% in the non-cSCC NMSC cohort, with no meaningful difference apparent between the groups; however, given the limited sample size—20 cases of cSCC and even fewer cases for each non-cSCC subtype—firm conclusions regarding histology-specific efficacy cannot be drawn. Within the cSCC cohort, efficacy did not differ by prior therapy, primary site (sun-exposed vs. non-sun-exposed), age (< 70 vs. ≥70 years), or sex, and similarly no predictive factors were identified in the non-cSCC NMSC cohort (Supplementary Table 2). Responses were observed in EMPD, whereas no responses were observed in cutaneous adnexal carcinoma or in patients treated beyond second-line therapy, although these observations remain hypothesis-generating given the small numbers. Notably, the observed ORR in this Japanese cohort appeared lower than those reported in pivotal trials conducted predominantly in Western populations, including EMPOWER-CSCC-1 (approximately 47%) [ 10 ] and KEYNOTE-629 (34%) [ 12 ], as well as smaller cohorts in which ORRs exceeding 50% have been reported [ 35 , 36 ]. One plausible explanation is lower tumour antigenicity, potentially influenced by skin phototype and mutational processes that shape TMB. In this study, genomic profiling of 23 cases (16 cSCC and 7 non-cSCC NMSC) revealed a median TMB of 8.6 mutations/Mb in cSCC and 9.0 mutations/Mb in non-cSCC NMSC (range: 3.1–97.1), substantially lower than values reported in large-scale analyses of Western populations (median 45.2 mutations/Mb) [ 37 ]. MSI was low in all cases. In addition, TMB did not differ markedly between cSCC arising in sun-exposed (median 10.9, n = 5) and non-sun-exposed sites (median 8.6, n = 11), suggesting that ultraviolet-induced mutagenesis—often a major contributor to high TMB in fair-skinned Western populations—may play a less prominent role in this cohort. Conversely, two of three cases with TMB ≥ 30 mutations/Mb achieved an objective response, indicating that Japanese patients with high TMB may derive clinical benefit comparable to that observed in Western studies [ 38 ]. Several limitations should be acknowledged. The rarity of the target diseases, particularly the small number of non-cSCC NMSC cases, limits statistical power and constrains interpretation of subgroup findings. Nonetheless, this trial provides the first prospective evidence supporting the efficacy and safety of PD-1 blockade for advanced cutaneous epithelial malignancies, including cSCC and rare non-cSCC NMSCs, in an East Asian population, and these data contributed to regulatory approval in Japan, the first such approval worldwide. The findings also underscore the need for region-specific strategies in Asia, where epidemiology and tumour biology may differ from those in Western countries. Future efforts should focus on biomarker-driven patient selection, integration of PD-1 inhibitors into multimodality regimens, and clinical trials tailored to disease patterns in East Asian populations to optimise outcomes for these rare and often treatment-refractory malignancies. Abbreviations cSCC cutaneous squamous cell carcinoma BCC basal cell carcinoma TMB tumour mutational burden EMPD extramammary Paget’s disease NMSC non-melanoma skin cancer BICR blinded independent central review ORR overall response rate PFS progression-free survival OS overall survival ICI immune checkpoint inhibitor PD-1 programmed death-1 HHI Hedgehog pathway inhibitor MSI microsatellite instability DCR disease control rate AE adverse event BOR best overall response DOR duration of response TTR time to response ECOG Eastern Cooperative Oncology Group FAS full analysis set SAF safety analysis set CI confidence interval Declarations Competing Interests YN (during the past 3 years) received speaking fees from Ono Pharmaceutical and Maruho Co., Ltd. NY (during the past 3 years) received honoraria for invited lectures from Bristol Myers Squibb, Takeda Pharmaceuticals, Incyte Biosciences, Chugai Pharmaceutical, MSD, Novartis, and Ono Pharmaceutical; served on advisory boards for Chugai Pharmaceutical, MSD, and Ono Pharmaceutical; and received institutional research grants from Astellas Amgen Biopharma, Bristol Myers Squibb Japan, Merck Serono, Novartis, Ono Pharmaceutical, Takara Bio, MSD, and GlaxoSmithKline. KN received honoraria from Ono Pharmaceutical, Novartis, Bristol-Myers Squibb, and MSD, and served on an advisory board for Novartis, MSD, Rakuten Medical, and Chugai Pharmaceutical, and received institutional research grants from Novartis, Bristol-Myers Squibb, GlaxoSmithKline, PAREXEL International, Takara Bio, MSD, and Chugai Pharmaceutical.TT (during the past 3 years) received speaking fees from Ono Pharmaceutical.SY (during the past 3 years) received speaking fees from AstraZeneca and Janssen Pharmaceutical K.K.; and received advisory fees from Mochida Pharmaceutical Co., Ltd and SBI Pharmaceuticals Co., Ltd.Taku F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, Minophagen Pharmaceutical, Esai, Sun Pharmaceutical, and Daiichi-Sankyo.AO (during the past 3 years) received speaking fees from Sanofi, Eli Lilly,Abbvie, LEO Pharma, Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, andKyowa Kirin International.Takeru F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, and Kyowa Kirin International; and received an institutional grant from Ono Pharmaceutical.All remaining authors have declared no conflicts of interest. Ethics approval The protocol was approved by the Ethics Review Committee of Keio University Hospital in May 2019, and similar approvals were obtained from all other participating institutions. This study has been conducted in accordance with the principles outlined in the Declaration of Helsinki, guidelines for the conduct of clinical trials, and the SPIRIT (Standard Protocol Items for Intervention Trials) guidelines. Consent to participate All patients provided written informed consent prior to participation. Consent to publish The manuscript contains no images, videos, or other information that could identify individual participants; therefore, consent for publication was not required. Funding This work was supported by Ono Pharmaceutical Co., Ltd. The study drugs were provided free of charge by Ono Pharmaceutical Co., Ltd. The funding source had no direct role in the design of the study protocol or the collection, analysis, and interpretation of data. Author Contribution Conceptualization, Methodology, Protocol development and Funding acquisition were led by Takeru F. Material preparation, data collection and investigation were performed by YN, NY, KN, HU, SM, MM, Taku F, TT, MN, YY, AO, KK, Takayuki F, IH, and Takeru F. Formal analysis was performed by RT and YS. Project administration and safety oversight/pharmacovigilance were performed by TF and YS. Supervision was provided by MA. The first draft of the manuscript was written by YN. KT and Takeru F reviewed and edited the manuscript, and Ryo Takemura and YN prepared the visualizations. All authors commented on previous versions of the manuscript, read, and approved the final manuscript. Acknowledgement We thank all the patients and their families who participated in this clinical trial. We also thank the clinical research coordinators at Keio University Hospital, National Cancer Centre Hospital, National Hospital Organisation Kyushu Cancer Centre, Nagoya University Hospital, Tohoku University Hospital, Niigata Cancer Centre Hospital, Wakayama Medical University Hospital, and Kyoto University Hospital. In addition, we appreciate the review committees and medical experts who were involved in this study. We are grateful to Ono Pharmaceutical for providing the investigational drug nivolumab. In addition, this work was supported by Ono Pharmaceutical Co., Ltd. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. References Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, Coldiron BM. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283–7. https://doi.org/10.1001/archdermatol.2010.19 . 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NY (during the past 3 years) received honoraria for invited lectures from Bristol Myers Squibb, Takeda Pharmaceuticals, Incyte Biosciences, Chugai Pharmaceutical, MSD, Novartis, and Ono Pharmaceutical; served on advisory boards for Chugai Pharmaceutical, MSD, and Ono Pharmaceutical; and received institutional research grants from Astellas Amgen Biopharma, Bristol Myers Squibb Japan, Merck Serono, Novartis, Ono Pharmaceutical, Takara Bio, MSD, and GlaxoSmithKline. KN received honoraria from Ono Pharmaceutical, Novartis, Bristol-Myers Squibb, and MSD, and served on an advisory board for Novartis, MSD, Rakuten Medical, and Chugai Pharmaceutical, and received institutional research grants from Novartis, Bristol-Myers Squibb, GlaxoSmithKline, PAREXEL International, Takara Bio, MSD, and Chugai Pharmaceutical. TT (during the past 3 years) received speaking fees from Ono Pharmaceutical. SY (during the past 3 years) received speaking fees from AstraZeneca and Janssen Pharmaceutical K.K.; and received advisory fees from Mochida Pharmaceutical Co., Ltd and SBI Pharmaceuticals Co., Ltd. Taku F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, Minophagen Pharmaceutical, Esai, Sun Pharmaceutical, and Daiichi-Sankyo. AO (during the past 3 years) received speaking fees from Sanofi, Eli Lilly, Abbvie, LEO Pharma, Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, and Kyowa Kirin International. Takeru F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, and Kyowa Kirin International; and received an institutional grant from Ono Pharmaceutical. All remaining authors have declared no conflicts of interest. Supplementary Files NMSCPD1Supplementarymaterials.pdf Cite Share Download PDF Status: Published Journal Publication published 04 Mar, 2026 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 16 Feb, 2026 Reviews received at journal 10 Feb, 2026 Reviewers agreed at journal 07 Feb, 2026 Reviews received at journal 04 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers invited by journal 02 Feb, 2026 Editor assigned by journal 02 Feb, 2026 Editor invited by journal 02 Feb, 2026 Submission checks completed at journal 30 Jan, 2026 First submitted to journal 30 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8709454","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":584880671,"identity":"4edf33e9-a439-421a-b63d-c9bb2edca7dd","order_by":0,"name":"Yoshio Nakamura","email":"","orcid":"","institution":"Keio University","correspondingAuthor":false,"prefix":"","firstName":"Yoshio","middleName":"","lastName":"Nakamura","suffix":""},{"id":584880672,"identity":"7fddda3d-1db5-403c-88ba-1e46249f87da","order_by":1,"name":"Naoya Yamazaki","email":"","orcid":"","institution":"National Cancer Centre Japan","correspondingAuthor":false,"prefix":"","firstName":"Naoya","middleName":"","lastName":"Yamazaki","suffix":""},{"id":584880673,"identity":"35f20f0e-0f32-4bd8-8be0-840a1898309b","order_by":2,"name":"Kenjiro Namikawa","email":"","orcid":"","institution":"National Cancer Centre Japan","correspondingAuthor":false,"prefix":"","firstName":"Kenjiro","middleName":"","lastName":"Namikawa","suffix":""},{"id":584880675,"identity":"8429a16f-d408-4642-a9bb-be583212821b","order_by":3,"name":"Hiroshi Uchi","email":"","orcid":"","institution":"National Hospital Organization Kyushu Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Uchi","suffix":""},{"id":584880677,"identity":"a6b32d45-8216-473b-a888-661c9115e693","order_by":4,"name":"Shoichiro Mori","email":"","orcid":"","institution":"Nagoya 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Takenouchi","suffix":""},{"id":584880683,"identity":"5e06e496-8d46-407f-a377-abaabd9d28bb","order_by":8,"name":"Mana Nishiguchi","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mana","middleName":"","lastName":"Nishiguchi","suffix":""},{"id":584880685,"identity":"afb5586c-e9b9-4dd1-aaea-b73eedc0c8bd","order_by":9,"name":"Yuki Yamamoto","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Yamamoto","suffix":""},{"id":584880687,"identity":"42b96a8f-6842-4dda-8b36-4a4324c6c8c4","order_by":10,"name":"Atsushi Otsuka","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Otsuka","suffix":""},{"id":584880689,"identity":"f1f3ef37-f9c4-4efc-837f-ea76bf7563b2","order_by":11,"name":"Kenji Kabashima","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Kabashima","suffix":""},{"id":584880691,"identity":"95df32d5-a1f2-4078-95bf-edc6f54a700b","order_by":12,"name":"Takayuki Fusumae","email":"","orcid":"","institution":"Keio University","correspondingAuthor":false,"prefix":"","firstName":"Takayuki","middleName":"","lastName":"Fusumae","suffix":""},{"id":584880692,"identity":"4c684d79-48f7-4022-aeea-2bae5a64ce2e","order_by":13,"name":"Ikuko Hirai","email":"","orcid":"","institution":"Keio 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University","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Amagai","suffix":""},{"id":584880697,"identity":"ded428c8-a7b0-4ff7-ac9a-978ac27bbc19","order_by":17,"name":"Ryo Takemura","email":"","orcid":"","institution":"Keio University","correspondingAuthor":false,"prefix":"","firstName":"Ryo","middleName":"","lastName":"Takemura","suffix":""},{"id":584880698,"identity":"62fa747a-7a6d-485a-97dc-c60770a40fda","order_by":18,"name":"Yasunori Sato","email":"","orcid":"","institution":"Keio University","correspondingAuthor":false,"prefix":"","firstName":"Yasunori","middleName":"","lastName":"Sato","suffix":""},{"id":584880699,"identity":"70e0f35d-97f7-4898-8472-f9f3c09e7110","order_by":19,"name":"Takeru Funakoshi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtUlEQVRIiWNgGAWjYFACNhAhJyfBwNjAwMBDhAYeiBZjY9K1JM4g2ln27McSH1e2GaTPbG9ufMAgc4cIW3jSDhuebTPInc1zsNmAgecZMQ5Lb5NsbPuTO08isU2CgecwEVr4n7f/bAQ6TE7+IbFaJNKOMQK1JEhLMBKr5cazZMmGcwaGM3sSmw0SiPELe3+a4ceGMgN5iePHHz742ENEiKGCxJ4DpGph+EG6llEwCkbBKBj+AACwIzbWkxlN4QAAAABJRU5ErkJggg==","orcid":"","institution":"Keio University","correspondingAuthor":true,"prefix":"","firstName":"Takeru","middleName":"","lastName":"Funakoshi","suffix":""}],"badges":[],"createdAt":"2026-01-27 10:55:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8709454/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8709454/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-026-15829-2","type":"published","date":"2026-03-04T15:57:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":101852076,"identity":"380bbc93-a917-4783-b760-cf391fd405e6","added_by":"auto","created_at":"2026-02-04 10:10:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":234014,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of the probability of progression-free survival and overall survival as assessed by BICR\u003c/p\u003e\n\u003cp\u003eMedian PFS was 4.96 months in all NMSC, with corresponding values of 5.54 months in cSCC and 3.75 months in non‐cSCC NMSC. Median OS was 17.77 months overall, 24.08 months in cSCC, and 13.54 months in non‐cSCC NMSC.\u003c/p\u003e\n\u003cp\u003eBICR, blinded independent central review; PFS, progression-free survival; OS, overall survival; NMSC, non-melanoma skin cancer; cSCC, cutaneous squamous cell carcinoma\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8709454/v1/6189ba4459da4d63c489fd25.png"},{"id":101851979,"identity":"f038f6ee-ed83-452e-ae09-229ef319e766","added_by":"auto","created_at":"2026-02-04 10:10:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":547917,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in target lesion and treatment duration\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Spider plot shows the longitudinal changes in target lesion size for each patient. (\u003cstrong\u003eb\u003c/strong\u003e) Waterfall plot illustrates the maximum percentage change from baseline in target lesion size for each patient, highlighting responses across histological subtypes. (\u003cstrong\u003ec\u003c/strong\u003e) Swimmer plot shows treatment duration and time to response, with a median time to response of 9.23 months according to BICR.\u003c/p\u003e\n\u003cp\u003eBICR, blinded independent central review; PFS, progression-free survival; OS, overall survival; NMSC, non-melanoma skin cancer; cSCC, cutaneous squamous cell carcinoma\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8709454/v1/f6fbeff627c2cf8ff65b054f.png"},{"id":104250652,"identity":"44f3a684-ad01-42d4-897c-fe1913b936d1","added_by":"auto","created_at":"2026-03-09 16:04:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2445077,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8709454/v1/5cb66467-ef46-4f89-bef0-dd2bbbfcd79e.pdf"},{"id":101852103,"identity":"cccda494-8d3e-42f3-952e-e04276b364f4","added_by":"auto","created_at":"2026-02-04 10:11:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":273422,"visible":true,"origin":"","legend":"","description":"","filename":"NMSCPD1Supplementarymaterials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8709454/v1/94a5cc1526039f6cee71ada4.pdf"}],"financialInterests":"Competing interest reported. YN (during the past 3 years) received speaking fees from Ono Pharmaceutical and Maruho Co., Ltd.\nNY (during the past 3 years) received honoraria for invited lectures from Bristol Myers Squibb, Takeda Pharmaceuticals, Incyte Biosciences, Chugai Pharmaceutical, MSD, Novartis, and Ono Pharmaceutical; served on advisory boards for Chugai Pharmaceutical, MSD, and Ono Pharmaceutical; and received institutional research grants from Astellas Amgen Biopharma, Bristol Myers Squibb Japan, Merck Serono, Novartis, Ono Pharmaceutical, Takara Bio, MSD, and GlaxoSmithKline.\nKN received honoraria from Ono Pharmaceutical, Novartis, Bristol-Myers Squibb, and MSD, and served on an advisory board for Novartis, MSD, Rakuten Medical, and Chugai Pharmaceutical, and received institutional research grants from Novartis, Bristol-Myers Squibb, GlaxoSmithKline, PAREXEL International, Takara Bio, MSD, and Chugai Pharmaceutical.\nTT (during the past 3 years) received speaking fees from Ono Pharmaceutical.\nSY (during the past 3 years) received speaking fees from AstraZeneca and Janssen Pharmaceutical K.K.; and received advisory fees from Mochida Pharmaceutical Co., Ltd and SBI Pharmaceuticals Co., Ltd.\nTaku F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, Minophagen Pharmaceutical, Esai, Sun Pharmaceutical, and Daiichi-Sankyo.\nAO (during the past 3 years) received speaking fees from Sanofi, Eli Lilly,\nAbbvie, LEO Pharma, Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, and\nKyowa Kirin International.\nTakeru F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, and Kyowa Kirin International; and received an institutional grant from Ono Pharmaceutical.\nAll remaining authors have declared no conflicts of interest.","formattedTitle":"Nivolumab for unresectable cutaneous epithelial malignancies: An open-label, single-arm, multi-centre, phase II trial (NMSC-PD1)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCutaneous epithelial malignancies comprise a heterogeneous group of non-melanoma skin cancers (NMSCs) that arise from keratinocytes or skin adnexal structures. The two most common forms are cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Other histological subtypes include accessory gland carcinomas (e.g., eccrine and sebaceous carcinomas), primary cutaneous apocrine carcinoma, and extramammary Paget\u0026rsquo;s disease (EMPD). Although these tumours differ in epidemiology, biological characteristics, and prognosis, advanced cases are associated with a poor prognosis, and treatment options are limited [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ecSCC is the second most common skin cancer worldwide. Its incidence rate is high in European populations, with age-adjusted rates typically ranging from 20 to 80 cases per 100,000 individuals [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although in most cases, tumours are localised and curable with surgical resection, 2\u0026ndash;5% of patients develop metastases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, the prognosis for advanced disease is poor, with a historical median overall survival (OS) of \u0026lt;\u0026thinsp;2 years [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recently, immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1), such as cemiplimab and pembrolizumab, have demonstrated substantial and reliable antitumour activity in advanced cSCC [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Cemiplimab received regulatory approval in the United States and European Union for advanced cSCC treatment in 2018, and pembrolizumab was subsequently approved.\u003c/p\u003e \u003cp\u003eThe incidence of cSCC in East Asian populations is considerably lower, ranging from 1.0 to 3.4 per 100,000 individuals [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Mortality rates are also lower than those in Western populations, and data on advanced diseases are limited. This low incidence has contributed to the lack of region-specific drug development. Thus, there are currently no effective systemic therapy options for advanced cSCC in Japan, and PD-1 blockade has not been formally evaluated in population-specific prospective clinical trials.\u003c/p\u003e \u003cp\u003eDespite the absence of direct evidence, the extreme rarity of cutaneous epithelial malignancies other than cSCC (non-SCC NMSCs) has resulted in their management being informed by treatment principles developedestablished for cSCC. Locally advanced BCC is extremely rare, accounting for only approximately 0.8% of all BCC cases in a retrospective cohort study based on a large commercially insured population in the United States [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Metastatic BCC is even rarer, with an estimated incidence of 0.0028% to 0.55% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. For unresectable or metastatic BCC, Hedgehog pathway inhibitors (HHIs) are the standard first-line therapy in Europe and the United States. Prospective studies of PD-1 inhibitors have been conducted for patients with advanced disease who are resistant or intolerant to HHIs; therefore, the anti\u0026ndash;PD-1 antibody cemiplimab has been approved for locally advanced or metastatic BCC following HHI failure or intolerance in Europe and the United States [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOther metastatic non-cSCC NMSCs, such as adnexal carcinomas and EMPD, are also extremely rare cancers [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Epidemiological data indicate an incidence of less than 1 per million individuals for most of these tumors, and their clinical behaviour is poorly characterised. Consequently, no prospective trials of PD-1 blockade have been conducted for these tumour types, and their management generally follows the treatment principles established for cSCC. Nevertheless, given that several non-cSCC NMSCs exhibit a relatively high tumour mutational burden (TMB), PD-1 antibody therapy is expected to be clinically beneficial [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, we aimed to conduct the first phase II, investigator-initiated clinical trial to evaluate the antitumour activity and safety of the anti\u0026ndash;PD-1 antibody nivolumab monotherapy for Japanese patients with advanced NMSC, including both cSCC and non-cSCC NMSCs.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eStudy design and patient population\u003c/h2\u003e\n \u003cp\u003eThis single-arm, open-label, multicentre, phase II trial evaluated the efficacy and safety of nivolumab in patients with advanced cutaneous epithelial malignancies. The study design, eligibility criteria, and ethical approval have been previously reported [26].\u003c/p\u003e\n \u003cp\u003ePatients were enrolled between July 2019 and July 2021 and were administered nivolumab every 4 weeks for up to 26 cycles. For patients who achieved a response without disease progression, treatment could be extended for a maximum of 2 years. A sample size of 26 cases was determined to achieve at least 80% power given an expected response rate of 25%, a threshold response rate of 5%, and a two-sided significance level of 5%. Considering potential dropouts, the enrolment target was 30 patients.\u003c/p\u003e\n \u003cp\u003eThe trial was conducted at eight centres in major cities selected based on Japan\u0026apos;s population distribution. This study has been conducted in accordance with the principles outlined in the Declaration of Helsinki, guidelines for the conduct of clinical trials, and the SPIRIT (Standard Protocol Items for Intervention Trials) guidelines. The protocol was approved by the Ethics Review Committee of Keio University Hospital in May 2019, and similar approvals were obtained from all other participating institutions. All patients provided written informed consent prior to participation.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eInclusion and exclusion criteria\u003c/h3\u003e\n\u003cp\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e1. Age: 20 years or older.\u003c/p\u003e\n\u003cp\u003e2. Histologically confirmed incurable, advanced, or recurrent\u003c/p\u003e\n\u003cp\u003eepithelial skin malignancies after surgical treatment and/or\u003c/p\u003e\n\u003cp\u003eradiotherapy.\u003c/p\u003e\n\u003cp\u003e3. \u0026ge;1 measurable lesions based on RECIST 1.1\u003c/p\u003e\n\u003cp\u003e4. ECOG performance status 0\u0026ndash;1.\u003c/p\u003e\n\u003cp\u003e5. Life expectancy\u0026thinsp;\u0026ge;\u0026thinsp;90 days\u003c/p\u003e\n\u003cp\u003e6. Women willing to use double contraception and agree not to\u003c/p\u003e\n\u003cp\u003ebreastfeed for at least 5 months after final administration. Men willing to use double contraception for at least 5 months\u003c/p\u003e\n\u003cp\u003eafter final administration.\u003c/p\u003e\n\u003cp\u003e7. Sufficient organ functions: all of the following conditions are fulfilled:\u003c/p\u003e\n\u003cp\u003eWhite blood cell\u0026thinsp;\u0026ge;\u0026thinsp;2,000/mm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAbsolute neutrophil count\u0026thinsp;\u0026ge;\u0026thinsp;1,500/mm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003ePlatelets\u0026thinsp;\u0026ge;\u0026thinsp;100,000/mm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eHaemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;9.0g/dL\u003c/p\u003e\n\u003cp\u003e8. Any investigational medication other than the study drug.\u003c/p\u003e\n\u003cp\u003e9. Any anticancer therapies including chemotherapy or biologic therapy other than the study medication, excluding the follows: AST and ALT Total bilirubin, Serum creatinine three times the upper limit of normal two times the upper limit of normal 1.5 mg/dL or creatinine clearance or eGFR\u0026thinsp;\u0026ge;\u0026thinsp;45 mL/min.\u003c/p\u003e\n\u003cp\u003ePatients received an adequate explanation about the study and provided informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eExclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e1. History of anaphylaxis to other antibody formulations, severe allergy, chronic or recurrent autoimmune disease, transplantation therapy, recent transient cerebral ischaemic attack or cerebral vascular accident, recent thrombosis, or thromboembolism.\u003c/p\u003e\n\u003cp\u003e2. History of additional malignancy except for completely resected BCC, carcinoma in situ, intramucosal cancer, superficial bladder cancer, or other cancers that have not recurred for at least 5 years before enrollment.\u003c/p\u003e\n\u003cp\u003e3. History of pretreatment using anti-PD1/L1/L2, anti-CD137, anti-CTLA-4 inhibitor or any other antibody or drugs intended for T-cell regulation.\u003c/p\u003e\n\u003cp\u003e4. Active central nervous system metastases\u003c/p\u003e\n\u003cp\u003e5. Uncontrolled tumour-associated pain\u003c/p\u003e\n\u003cp\u003e6. Current disease; active autoimmune disease, diverticulitis or symptomatic peptic ulcer disease, pericardial effusion, pleural effusion or ascites requiring sustained treatment, uncontrollable diabetes mellitus, systemic infection requiring treatment, interstitial lung diseases, pulmonary fibrosis, or unstabled radiation pneumonitis, uncontrollable or severe cardiovascular disease.\u003c/p\u003e\n\u003cp\u003e7. Recent following treatments within 28 days prior to the enrollment; systemic adrenocortical hormone, immunosup- pressant, unapproved drugs, any antineoplastic agent, surgical adhesion of the pleura or pericardium, surgery under general anesthesia, radiotherapy.\u003c/p\u003e\n\u003cp\u003e8. Received surgery under local or topical anesthesia within 14 days prior to the enrollment.\u003c/p\u003e\n\u003cp\u003e9. Received any radiopharmaceuticals within 56 days prior to the enrolment.\u003c/p\u003e\n\u003cp\u003e10. Seropositive for HBsAg, HCV-Ab, or HIV-Ab.\u003c/p\u003e\n\u003cp\u003e11. Pregnant, breast-feeding or potentially pregnant.\u003c/p\u003e\n\u003cp\u003e12. History of any condition or therapy that might confound the\u003c/p\u003e\n\u003cp\u003eresults of this study.\u003c/p\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eNivolumab (480 mg) was administered intravenously in an outpatient setting for 30 min every 4 weeks. The maximum number of doses was 26 (with the total treatment duration not exceeding 2 years). Imaging assessments of tumour lesions were performed every two cycles, immediately before initiating the subsequent cycle. Patients who discontinued treatment due to disease progression or adverse events, or completed 2 years of therapy, underwent a final tumour assessment and subsequently entered a post-treatment follow-up phase.\u003c/p\u003e\n\u003cp\u003eAEs were recorded throughout the treatment period, at any time during each cycle, and for 28 days after the final administration. During the post-treatment follow-up phase, imaging examinations were performed every 8 weeks to assess the tumour status. To determine OS, patients were followed until death, withdrawal of consent, or termination of the study (31 December 2023).\u003c/p\u003e\n\u003ch3\u003eTMB and microsatellite instability (MSI) assessment\u003c/h3\u003e\n\u003cp\u003eTumour samples were obtained from enrolled patients when adequate formalin-fixed paraffin-embedded material was available. All samples were collected at the time of diagnostic biopsy or surgical resection prior to study enrolment and drug administration. DNA (\u0026ge;\u0026thinsp;40 ng) was extracted from tumour-rich areas (\u0026ge;\u0026thinsp;30% tumour content) and analysed using the TruSight Oncology 500 (TSO500, Illumina) assay, a hybrid-capture panel covering 523 genes (~\u0026thinsp;1.94 Mb) [24]. Libraries with unique molecular identifiers were sequenced on Illumina instruments, and the data were processed using the DRAGEN\u0026trade; TSO500 pipeline for error correction, variant calling, and biomarker analysis [27, 28].\u003c/p\u003e\n\u003cp\u003eTMB was calculated as the number of eligible somatic variants per megabase after germline filtering, requiring\u0026thinsp;\u0026ge;\u0026thinsp;50\u0026times; coverage and a VAF\u0026thinsp;\u0026ge;\u0026thinsp;5%. In accordance with regulatory standards, TMB-high was defined as \u0026ge;\u0026thinsp;10 mutations/Mb [29]. MSI was assessed across approximately 130 homopolymer loci; samples with \u0026ge;\u0026thinsp;40 evaluable loci were scored, and MSI-high was defined as \u0026ge;\u0026thinsp;20% unstable loci [27, 30].\u003c/p\u003e\n\u003ch3\u003eEndpoints and assessments\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was the overall response rate (ORR), assessed by blinded independent central review (BICR) according to RECIST version 1.1. ORR, according to immune-related RECIST (iRECIST), was evaluated as an exploratory endpoint.\u003c/p\u003e\n\u003cp\u003eSecondary endpoints included investigator-assessed ORR, progression-free survival (PFS), OS, disease control rate (DCR), and adverse events (AEs).\u003c/p\u003e\n\u003cp\u003ePFS was defined as the interval from the first administration of study treatment to documented disease progression or death from any cause. The investigator-assessed ORR was determined locally by treating investigators according to RECIST v1.1, without blinding to treatment allocation. OS was defined as the interval from the first administration to death from any cause. Best overall response (BOR) was defined as the best recorded response (CR, PR, SD, or PD) from the commencement of treatment until disease progression or death, whichever occurred first. Duration of response (DOR) was defined as the time from the first documented response (CR or PR) to disease progression or death. Time to response (TTR) was defined as the time from the first nivolumab administration to the first documented response. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Each efficacy endpoint was analysed separately for all NMSCs, cSCC alone, and other non-cSCC NMSCs.\u003c/p\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eData collection\u003c/h2\u003e\n \u003cp\u003eDemographic, clinical, and pathological data were collected from electronic case report forms and medical records at each participating site. The variables included age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, primary tumour site, disease stage, prior treatments, and laboratory findings. Tumour response was assessed according to RECIST version 1.1 by BICR and investigators. Safety data, including treatment-emergent adverse events, were collected at each visit during treatment and follow-up. All data were verified by the data management team before database lock.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eAll statistical tests were two-sided, with a significance level of 5%. No adjustments for multiplicity were implemented for comparisons across endpoints or time points (such as baseline and each scheduled tumour assessment every two cycles). Safety analyses were conducted in a descriptive manner and were not unadjusted for multiplicity. The full analysis set (FAS) included all patients who received at least one dose of nivolumab, excluding those with major eligibility violations (e.g., absence of informed consent, enrolment outside the study period, or failure to meet key eligibility criteria). The safety analysis set (SAF) comprised all patients who received at least one dose of nivolumab. Exact 95% confidence intervals (CIs) for ORR and DCR were calculated using the binomial distribution. Survival analyses (PFS and OS) were performed using the Kaplan\u0026ndash;Meier method. Median survival times and 95% CIs were estimated using the Brookmeyer\u0026ndash;Crowley method, and survival curves were compared using the log-rank test. Patients alive or progression-free at the data cutoff date (31 December 2023) were censored. All AEs were coded according to MedDRA/J, version 24.1, and their incidence rates were tabulated with the exact two-sided 95% CIs calculated from the binomial distribution. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA), and figures were generated using R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eParticipant selection\u003c/h2\u003e \u003cp\u003eA total of 33 patients were screened between 2019 and 2023. Two patients were excluded before study treatment owing to major eligibility violations: one for lack of measurable lesions and one for withdrawal of consent. Accordingly, both the FAS and SAF included 31 patients each. No significant differences in age, sex, or disease stage were observed between the screened and enrolled populations, suggesting that the study cohort was representative of the target population.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePatient age ranged from 27 to 83 years, with a median of 70.0 years. The primary sites were the head and neck in 4 cases (12.9%), extremities in 12 (38.7%), back in 6 (19.4%), anogenital region in 6 (19.4%), and other sites in 3 (9.7%). Classification according to sun exposure showed that 8 cases (25.8%) occurred in sun-exposed areas and 23 (74.2%) in non-sun‐exposed areas. Regarding prior treatment, 25 patients (80.6%) had undergone surgery, 7 (22.6%) systemic therapy, and 14 (45.2%) radiotherapy. As regard disease stage, 3 (9.7%) patients had stage III disease and 28 (90.3%) had stage IV disease.\u003c/p\u003e \u003cp\u003eThe histological subtypes included 20 cSCCs (64.5%), 4 EMPDs (12.9%), 3 eccrine porocarcinomas, 2 BCCs, 1 sweat gland carcinoma, and 1 primary cutaneous mucinous carcinoma. No cases of Merkel cell carcinoma were identified. Patient demographics and baseline characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient demographics and baseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSCC (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-SCC NMSC (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age, years(range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e70.0 (27\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70.0 (27\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.0 (55\u0026ndash;76)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16 (51.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer types\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (64.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasal cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtramammary Paget\u0026rsquo;s disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (12.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (35.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21 (67.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (65.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (72.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG performance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21 (67.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (40.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (81.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHead \u0026amp; Neck\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (12.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtremities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (38.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (45.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrunk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (19.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnogenital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (19.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (36.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (9.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun exposure areas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposed areas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (25.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (30.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-exposed areas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (74.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (70.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (81.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious cancer-related surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25 (80.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (85.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (72.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious cancer-related systemic therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (22.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious cancer-related radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (36.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (9.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (90.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18 (90.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (90.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSCC, squamous cell carcinoma; NMSC, non-melanoma skin cancer; ECOG, Eastern Cooperative Oncology Group\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eBy BICR, the primary endpoint, ORR, was 22.6% (7/31; 95% CI, 9.6\u0026ndash;41.1%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). ORR was 25.0% (5/20; 95% CI, 8.7\u0026ndash;49.1%) in cSCC and 18.2% (2/11; 95% CI, 2.3\u0026ndash;51.8%) in non-cSCC NMSC. Responses were observed in one patient each with EMPD and BCC, whereas no responses were observed in other non-cSCC NMSC types. Among the 31 patients, 20 had cSCC, and 11 had non-cSCC NMSC (5 EMPD, 3 BCC, and 3 others). The BOR included two complete responses (CRs; 6.5%) and five partial responses (PRs; 16.1%), whereas stable disease (SD) and progressive disease (PD) were observed in 32.3% and 29.0% of cases, respectively, and 16.1% were not evaluable (NE). In the non-cSCC NMSC subgroup, BOR comprised 1 CR, 1 PR, 4 SD, and 5 PD. The overall median PFS was 4.96 months (95% CI, 1.87\u0026ndash;35.68), 5.54 months in cSCC, and 3.75 months in non-cSCC NMSC, with a median OS of 17.77 months (95% CI, 3.94\u0026ndash;39.56), 24.08 months in cSCC, and 13.54 months in non-cSCC NMSC (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The overall DCR was 54.8%, 55.0% for cSCC, and 54.5% for non-cSCC NMSC. Median DOR and TTR were 21.32 and 9.23 months, respectively (Supplementary Fig.\u0026nbsp;1). Changes in target lesion size and treatment duration are summarised in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTumour response assessment as per independent central review\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSCC (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-SCC NMSC (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response (%, 95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (22.6%; 9.6\u0026ndash;41.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (25%; 8.7\u0026ndash;49.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (18.2%; 6.0\u0026ndash;61.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBest overall response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (30.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (36.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (29.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (45.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot evaluated*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease control (%, 95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (54.8%, 36.0\u0026ndash;72.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (55.0%, 31.5\u0026ndash;76.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (54.5%, 23.4\u0026ndash;83.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian progression-free survival, months (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.0 (3.7\u0026ndash;7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5 (3.7\u0026ndash;14.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.7 (2.0\u0026ndash;5.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian overall survival, months (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.8 (12.3\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.1 (12.3\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.5 (5.9\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of response, months (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.3 (3.7\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.3 (3.7\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNR (3.8\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time to response, months (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.2 (3.6\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0 (1.9\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNR (1.9\u0026ndash;NR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are % (95% CI) or n (%), unless otherwise specified\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNR, not reached\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* Includes patients who did not undergo imaging studies after treatment initiation, who were determined to have no target lesions by central review, or who underwent imaging studies but were not evaluated.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSCC, squamous cell carcinoma; NMSC, non-melanoma skin cancer; CI, confidence interval\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBy investigator assessment, ORR was 32.3% (10/31; 95% CI, 16.7\u0026ndash;51.4%), including 35.0% in cSCC and 27.3% in non-cSCC NMSC (5 EMPD, 3 BCC, and 3 others). The overall median PFS was 5.52 months (0.66\u0026ndash;35.68), 6.31 months in cSCC, and 5.52 months in non-cSCC NMSC, with a median OS of 17.77, 24.08, and 13.54 months, respectively. Further, the overall DCRs were 64.5%, with 60.0% for cSCC and 72.7% for non-cSCC NMSC. The overall median DOR was 26.61 months and 7.36 months in non-cSCC NMSC. The median TTR was 5.32 months.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMedian PFS was 4.96 months in all NMSC, with corresponding values of 5.54 months in cSCC and 3.75 months in non-cSCC NMSC. Median OS was 17.77 months overall, 24.08 months in cSCC, and 13.54 months in non‐cSCC NMSC.\u003c/p\u003e \u003cp\u003eBICR, blinded independent central review; PFS, progression-free survival; OS, overall survival; NMSC, non-melanoma skin cancer; cSCC, cutaneous squamous cell carcinoma\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e(\u003cb\u003ea\u003c/b\u003e) Spider plot shows the longitudinal changes in target lesion size for each patient. (\u003cb\u003eb\u003c/b\u003e) Waterfall plot illustrates the maximum percentage change from baseline in target lesion size for each patient, highlighting responses across histological subtypes. (\u003cb\u003ec\u003c/b\u003e) Swimmer plot shows treatment duration and time to response, with a median time to response of 9.23 months according to BICR.\u003c/p\u003e \u003cp\u003eBICR, blinded independent central review; PFS, progression-free survival; OS, overall survival; NMSC, non-melanoma skin cancer; cSCC, cutaneous squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eAmong 31 patients, AEs were observed in 30 patients (96.8%), with a total of 209 events recorded. Treatment-related AEs (TRAEs) occurred in 18 patients (58.1%), comprising 48 events in total. Four patients (12.9%) discontinued treatment because of AEs. The most prevalent AEs (\u0026ge;\u0026thinsp;3 patients) were hyperthyroidism (12.9%), hypothyroidism (12.9%), pyrexia (9.7%), pruritus (9.7%), and interstitial lung disease (9.7%). Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs occurred in 21 events in 11 patients (35.5%). Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs occurred in 7 events among 6 patients (19.4%), including hyperthyroidism, hypophysitis, pyrexia, interstitial lung disease, aplastic anaemia, abnormal liver function, and decreased appetite. One patient died of acute respiratory distress syndrome; however, this event was deemed unrelated to the study drug (data not shown). AEs leading to treatment discontinuation occurred in 4 patients (12.9%), of which 2 (6.5%) were TRAEs. Permanent drug withdrawal was reported in 4 patients (12.9%), including 1 (3.2%) because of a TRAE (aplastic anaemia). A comprehensive summary of the AEs is presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSOC/HLT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGrade 5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAll Adverse Event\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e35.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndocrine disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdrenal cortical hypofunctions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThyroid hypofunction disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThyroid hyperfunction disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHypothalamic and pituitary disorders NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGeneral disorders and administration site conditions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFebrile disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsthenic conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEdema NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePain and discomfort NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInfections and infestations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBacterial infections NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpper respiratory tract infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoronavirus infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHerpes viral infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSkin structures and soft tissue infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUrinary tract infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytomegaloviral infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSkin and subcutaneous tissue disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDermatitis and eczema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePruritus NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSkin and subcutaneous tissue ulcerations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInvestigations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePituitary analyses anterior\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatobiliary function diagnostic procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhysical examination procedures and organ system status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal function analyses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGastrointestinal disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal atonic and hypomotility disorders NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal and abdominal pains (excluding oral and throat)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNausea and vomiting symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStomatitis and ulceration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetabolism and nutrition disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAppetite disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCalcium metabolism disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHyperglycaemic conditions NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProtein metabolism disorders NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMusculoskeletal and connective tissue disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue pain and discomfort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlood and lymphatic system disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnaemia\u0026rsquo;s NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeukopenia NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarrow depression and hypoplastic anaemia\u0026rsquo;s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeoplasms benign, malignant, and unspecified (including cysts and polyps)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOncologic complications and emergencies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNervous system disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSensory abnormalities NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePsychiatric disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDisturbances in initiating and maintaining sleep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRespiratory, thoracic, and mediastinal disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParenchymal lung disorders NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePulmonary oedemas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInjury, poisoning and procedural complications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-site-specific injuries NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSkin injuries NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRenal and urinary disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVascular disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVascular hypertensive disorders NEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEar and labyrinth disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEye disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHepatobiliary disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatic enzymes and function abnormalities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCardiac disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImmune system disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReproductive system and breast disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurgical and medical procedures\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFracture treatments (excluding skull and spine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eNEC, neuroendocrine carcinoma\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eTMB and MSI\u003c/h2\u003e \u003cp\u003eIn our cohort, genomic profiling was feasible in 23 of the 31 patients (16 with cSCC and 7 with non-cSCC NMSC). Genomic profiling could not be performed in the remaining eight patients because tumour specimens were not available, as not all patients underwent surgical resection or biopsy at the participating institutions. The median TMB was 9.0 mut/Mb (range, 3.1\u0026ndash;91.7) in the overall cohort, 9.0 mut/Mb (3.1\u0026ndash;91.7) in cSCC, and 8.6 mut/Mb (4.7\u0026ndash;21.9) in non-cSCC NMSC. TMB-high (\u0026ge;\u0026thinsp;10 mut/Mb) was observed in 30.4% (7/23) of patients, including 31.3% (5/16) in cSCC and 28.6% (2/7) in non-cSCC NMSC. No statistically significant difference in the distribution of TMB was observed between cSCC and non-cSCC NMSC (Mann\u0026ndash;Whitney U test, p\u0026thinsp;=\u0026thinsp;0.74; data not shown). Among the enrolled patients, only three harboured a TMB of \u0026ge;\u0026thinsp;30 mutations/Mb. Two patients achieved an objective response by BICR. A 63-year-old man with inguinal primary cSCC and a TMB of 32.8 mutations/Mb achieved a PR, with a PFS of 15.0 months. Another 63-year-old man with head and neck primary cSCC and a TMB of 63.3 mutations/Mb also achieved a PR, with a PFS of 22.9 months. The third patient, a 77-year-old man with head and neck primary cSCC, was considered NE by BICR because no target lesion was identified; nevertheless, this patient maintained disease control with a PFS of 35.2 months until the end of the study.\u003c/p\u003e \u003cp\u003eThe median MSI was 2.7% (range, 0.88\u0026ndash;5.36) overall, 2.12% (0.88\u0026ndash;5.15) in cSCC, and 2.97% (1.85\u0026ndash;5.36) in non-cSCC NMSC. MSI-high (\u0026ge;\u0026thinsp;20%) was not observed in any patient, and all cases were categorised as MSI-low (Supplementary Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this phase II trial, nivolumab showed clinically meaningful activity in advanced cutaneous epithelial malignancies in a Japanese population. The BICR-assessed ORR was 22.6%, and the lower bound of the 95% CI (9.6%) exceeded the prespecified threshold of 5%, thereby rejecting the null hypothesis and confirming efficacy. Importantly, responses were durable: the median DOR exceeded 20 months, and some patients exhibited long-lasting benefit comparable to that reported with anti\u0026ndash;PD-1 therapy in other tumour types such as melanoma, NSCLC, and renal cell carcinoma, where median DORs of approximately 24\u0026ndash;36 months have been described [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe safety findings were largely consistent with the established profile of nivolumab. Although the incidence of AEs was slightly higher than that reported in other tumour types\u0026mdash;where common treatment-related AEs include fatigue, pruritus, rash, and thyroid dysfunction and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 events occur in approximately 10\u0026ndash;15% of patients [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u0026mdash;no new safety signals were observed, supporting an overall benefit\u0026ndash;risk balance in this setting. In line with these results, the Ministry of Health, Labour and Welfare of Japan approved nivolumab in 2024 for epithelial cutaneous malignancies in Japanese patients (MHLW press release, March 22, 2024. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mhlw.go.jp/stf/newpage_37482.html\u003c/span\u003e\u003cspan address=\"https://www.mhlw.go.jp/stf/newpage_37482.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. )\u003c/p\u003e \u003cp\u003eExploratory analyses did not identify clear clinical predictors of response. The ORR was 25.0% in the cSCC cohort and 18.4% in the non-cSCC NMSC cohort, with no meaningful difference apparent between the groups; however, given the limited sample size\u0026mdash;20 cases of cSCC and even fewer cases for each non-cSCC subtype\u0026mdash;firm conclusions regarding histology-specific efficacy cannot be drawn. Within the cSCC cohort, efficacy did not differ by prior therapy, primary site (sun-exposed vs. non-sun-exposed), age (\u0026lt;\u0026thinsp;70 vs. \u0026ge;70 years), or sex, and similarly no predictive factors were identified in the non-cSCC NMSC cohort (Supplementary Table\u0026nbsp;2). Responses were observed in EMPD, whereas no responses were observed in cutaneous adnexal carcinoma or in patients treated beyond second-line therapy, although these observations remain hypothesis-generating given the small numbers.\u003c/p\u003e \u003cp\u003eNotably, the observed ORR in this Japanese cohort appeared lower than those reported in pivotal trials conducted predominantly in Western populations, including EMPOWER-CSCC-1 (approximately 47%) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and KEYNOTE-629 (34%) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], as well as smaller cohorts in which ORRs exceeding 50% have been reported [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. One plausible explanation is lower tumour antigenicity, potentially influenced by skin phototype and mutational processes that shape TMB. In this study, genomic profiling of 23 cases (16 cSCC and 7 non-cSCC NMSC) revealed a median TMB of 8.6 mutations/Mb in cSCC and 9.0 mutations/Mb in non-cSCC NMSC (range: 3.1\u0026ndash;97.1), substantially lower than values reported in large-scale analyses of Western populations (median 45.2 mutations/Mb) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. MSI was low in all cases. In addition, TMB did not differ markedly between cSCC arising in sun-exposed (median 10.9, n\u0026thinsp;=\u0026thinsp;5) and non-sun-exposed sites (median 8.6, n\u0026thinsp;=\u0026thinsp;11), suggesting that ultraviolet-induced mutagenesis\u0026mdash;often a major contributor to high TMB in fair-skinned Western populations\u0026mdash;may play a less prominent role in this cohort. Conversely, two of three cases with TMB\u0026thinsp;\u0026ge;\u0026thinsp;30 mutations/Mb achieved an objective response, indicating that Japanese patients with high TMB may derive clinical benefit comparable to that observed in Western studies [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. The rarity of the target diseases, particularly the small number of non-cSCC NMSC cases, limits statistical power and constrains interpretation of subgroup findings. Nonetheless, this trial provides the first prospective evidence supporting the efficacy and safety of PD-1 blockade for advanced cutaneous epithelial malignancies, including cSCC and rare non-cSCC NMSCs, in an East Asian population, and these data contributed to regulatory approval in Japan, the first such approval worldwide. The findings also underscore the need for region-specific strategies in Asia, where epidemiology and tumour biology may differ from those in Western countries. Future efforts should focus on biomarker-driven patient selection, integration of PD-1 inhibitors into multimodality regimens, and clinical trials tailored to disease patterns in East Asian populations to optimise outcomes for these rare and often treatment-refractory malignancies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecSCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecutaneous squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebasal cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etumour mutational burden\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eextramammary Paget\u0026rsquo;s disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNMSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-melanoma skin cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBICR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eblinded independent central review\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune checkpoint inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed death-1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHHI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHedgehog pathway inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMSI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emicrosatellite instability\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edisease control rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebest overall response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eduration of response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTTR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etime to response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efull analysis set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esafety analysis set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eYN (during the past 3 years) received speaking fees from Ono Pharmaceutical and Maruho Co., Ltd. NY (during the past 3 years) received honoraria for invited lectures from Bristol Myers Squibb, Takeda Pharmaceuticals, Incyte Biosciences, Chugai Pharmaceutical, MSD, Novartis, and Ono Pharmaceutical; served on advisory boards for Chugai Pharmaceutical, MSD, and Ono Pharmaceutical; and received institutional research grants from Astellas Amgen Biopharma, Bristol Myers Squibb Japan, Merck Serono, Novartis, Ono Pharmaceutical, Takara Bio, MSD, and GlaxoSmithKline. KN received honoraria from Ono Pharmaceutical, Novartis, Bristol-Myers Squibb, and MSD, and served on an advisory board for Novartis, MSD, Rakuten Medical, and Chugai Pharmaceutical, and received institutional research grants from Novartis, Bristol-Myers Squibb, GlaxoSmithKline, PAREXEL International, Takara Bio, MSD, and Chugai Pharmaceutical.TT (during the past 3 years) received speaking fees from Ono Pharmaceutical.SY (during the past 3 years) received speaking fees from AstraZeneca and Janssen Pharmaceutical K.K.; and received advisory fees from Mochida Pharmaceutical Co., Ltd and SBI Pharmaceuticals Co., Ltd.Taku F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, Minophagen Pharmaceutical, Esai, Sun Pharmaceutical, and Daiichi-Sankyo.AO (during the past 3 years) received speaking fees from Sanofi, Eli Lilly,Abbvie, LEO Pharma, Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, andKyowa Kirin International.Takeru F (during the past 3 years) received speaking fees from Ono Pharmaceutical, Novartis, BMS, MSD, Maruho, and Kyowa Kirin International; and received an institutional grant from Ono Pharmaceutical.All remaining authors have declared no conflicts of interest.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eThe protocol was approved by the Ethics Review Committee of Keio University Hospital in May 2019, and similar approvals were obtained from all other participating institutions. This study has been conducted in accordance with the principles outlined in the Declaration of Helsinki, guidelines for the conduct of clinical trials, and the SPIRIT (Standard Protocol Items for Intervention Trials) guidelines.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003eAll patients provided written informed consent prior to participation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to publish\u003c/strong\u003e \u003cp\u003e The manuscript contains no images, videos, or other information that could identify individual participants; therefore, consent for publication was not required.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by Ono Pharmaceutical Co., Ltd. The study drugs were provided free of charge by Ono Pharmaceutical Co., Ltd. The funding source had no direct role in the design of the study protocol or the collection, analysis, and interpretation of data.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization, Methodology, Protocol development and Funding acquisition were led by Takeru F. Material preparation, data collection and investigation were performed by YN, NY, KN, HU, SM, MM, Taku F, TT, MN, YY, AO, KK, Takayuki F, IH, and Takeru F. Formal analysis was performed by RT and YS. Project administration and safety oversight/pharmacovigilance were performed by TF and YS. Supervision was provided by MA. The first draft of the manuscript was written by YN. KT and Takeru F reviewed and edited the manuscript, and Ryo Takemura and YN prepared the visualizations. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank all the patients and their families who participated in this clinical trial. We also thank the clinical research coordinators at Keio University Hospital, National Cancer Centre Hospital, National Hospital Organisation Kyushu Cancer Centre, Nagoya University Hospital, Tohoku University Hospital, Niigata Cancer Centre Hospital, Wakayama Medical University Hospital, and Kyoto University Hospital. In addition, we appreciate the review committees and medical experts who were involved in this study. We are grateful to Ono Pharmaceutical for providing the investigational drug nivolumab. In addition, this work was supported by Ono Pharmaceutical Co., Ltd.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, Coldiron BM. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. 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Mol Cancer Ther. 2017;16:2598\u0026ndash;608. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1158/1535-7163\u003c/span\u003e\u003cspan address=\"10.1158/1535-7163\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Non-melanoma skin cancer, nivolumab, programmed death-1, squamous cell carcinoma, epithelial skin malignancy","lastPublishedDoi":"10.21203/rs.3.rs-8709454/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8709454/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eData in East Asian patients and in other epithelial skin cancers, including extramammary Paget\u0026rsquo;s disease (EMPD) and adnexal carcinomas, are scarce. Therefore, we conducted a phase II trial of nivolumab in Japanese patients with advanced non-melanoma skin cancers (NMSCs).\u003c/p\u003e\u003ch2\u003ePatients and methods:\u003c/h2\u003e \u003cp\u003eThis multicentre, open-label, single-arm phase II study enrolled adults (\u0026ge;\u0026thinsp;20 years) with histologically confirmed unresectable or recurrent epithelial cutaneous malignancies, Eastern Cooperative Oncology Group performance status 0\u0026ndash;1, and at least one measurable lesion (RECIST v1.1). Nivolumab 480 mg was administered intravenously every 4 weeks for up to 26 cycles. The primary endpoint was overall response rate (ORR), assessed by blinded independent central review (BICR; RECIST v1.1). Secondary endpoints included progression-free survival, overall survival, and safety.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThirty-one patients were enrolled (20 cSCC, 4 EMPD, 2 BCC, 5 other NMSCs); median age was 73 years (range 58\u0026ndash;86), and 71% were male. ORR by BICR was 22.6% (7/31), and the disease control rate was 54.8% (17/31). Responses were durable, with a median duration of 21.3 months. In the cSCC cohort, median tumour mutational burden (TMB) was 9.0 mut/Mb, lower than in Western series; among three patients with TMB\u0026thinsp;\u0026ge;\u0026thinsp;30 mut/Mb, two achieved objective responses. Common adverse events included pyrexia, hypothyroidism, adrenal insufficiency, and pruritus.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eNivolumab showed durable antitumour activity with manageable toxicity in Japanese patients with advanced NMSCs, including rare non-cSCC. The lower ORR compared with Western trials may reflect intrinsic biological differences and support biomarker-driven, region-specific immunotherapy.\u003c/p\u003e\u003ch2\u003eClinical trial registration:\u003c/h2\u003e \u003cp\u003ejRCT2031190048 (jRCT; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jrct.niph.go.jp/\u003c/span\u003e\u003cspan address=\"https://jrct.niph.go.jp/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), registered on 2 July 2019.\u003c/p\u003e","manuscriptTitle":"Nivolumab for unresectable cutaneous epithelial malignancies: An open-label, single-arm, multi-centre, phase II trial (NMSC-PD1)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-04 10:08:34","doi":"10.21203/rs.3.rs-8709454/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-16T15:19:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-11T00:16:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"310455805566496884778292357693269664915","date":"2026-02-08T00:59:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-04T17:45:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164549462001805307369126528121707749323","date":"2026-02-04T16:27:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-02T09:53:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-02T09:51:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-02T05:34:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-31T01:45:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-01-31T01:40:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5cfc0b6c-c0c4-4cff-9998-12ec14745411","owner":[],"postedDate":"February 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-09T16:01:34+00:00","versionOfRecord":{"articleIdentity":"rs-8709454","link":"https://doi.org/10.1186/s12885-026-15829-2","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2026-03-04 15:57:35","publishedOnDateReadable":"March 4th, 2026"},"versionCreatedAt":"2026-02-04 10:08:34","video":"","vorDoi":"10.1186/s12885-026-15829-2","vorDoiUrl":"https://doi.org/10.1186/s12885-026-15829-2","workflowStages":[]},"version":"v1","identity":"rs-8709454","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8709454","identity":"rs-8709454","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}