Combination of cadonilimab (anti-PD-1 and CTLA-4 bispecific antibody) with chemotherapy in anti-PD-1 resistant recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II clinical trial

Combination of cadonilimab (anti-PD-1 and CTLA-4 bispecific antibody) with chemotherapy in anti-PD-1 resistant recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II clinical trial | 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 Article Combination of cadonilimab (anti-PD-1 and CTLA-4 bispecific antibody) with chemotherapy in anti-PD-1 resistant recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II clinical trial Yanqun Xiang, Yao-Fei Jiang, Wei-Xin Bei, Lin Wang, Nian Lu, Cheng Xu, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4232165/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Treatment options are limited for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) after failure to anti-PD-1 therapy. Cadonilimab (AK104) is a humanized bispecific antibody that targets to PD-1 and CTLA-4. We aimed to evaluate the efficacy and safety of cadonilimab plus TPC chemotherapy (NAB-paclitaxel, cisplatin or lobaplatin, and capecitabine) in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. In this phase II clinical trial (ChiCRT2200067057), 25 patients were enrolled and received cadonilimab plus TPC chemotherapy every three weeks for up to six cycles followed by maintenance treatment of cadonilimab plus capecitabine. Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of progression-free survival, overall survival, duration of response, and safety. This trial met its prespecified primary endpoint of ORR (68%, 95% CI, 48-88), with 3 complete response (12%), 14 partial response (56%), 6 stable disease (24%). Grade ≥3 treatment-related adverse events were occurred in 12 (48%) patients, with the most common being anemia (6[24%]) and neutropenia (6[24%]). This phase II trial shows that cadonilimab in combination with TPC chemotherapy demonstrated satisfactory antitumoral efficacy and manageable toxicities in patients with systemic chemotherapy and anti-PD-1 therapy resistance RM-NPC. Health sciences/Oncology/Cancer/Head and neck cancer Health sciences/Oncology/Cancer/Cancer therapy/Cancer immunotherapy Figures Figure 1 Figure 2 Figure 3 Introduction Nasopharyngeal carcinoma (NPC) is a special type of head and neck tumors due to its distinct geographical, etiological and biological characteristics 1 . It has a high prevalence in South China, Southeast Asia, and North Africa, and is closely linked to Epstein-Barr virus (EBV) infections 1-3 . The incidence of distant metastasis of newly diagnosed NPC patients is approximately 6-15%, and about 20% of non-metastatic NPC experience recurrent or metastasis eventually after definitive treatments 4, 5 . The results from recently studies have established the combination of gemcitabine plus cisplatin and PD-1 inhibitor as the standard first-line regimens for recurrent or metastatic NPC (RM-NPC) patients 6-8 . With objective response rate (ORR) of 69.5% to 87.3% though, the median progression-free survival (PFS) was 9.2 to 21.4 months 6-8 . Under such conditions, most patients will develop disease progression within 1 to 2 years. Recent studies showed that the prognosis of these patients was poor under later line therapy, with an ORR of 22.68% to 34.3% and median PFS of 4.4 to 7.9 months 9-11 . Therefore, novel treatment options are urgently needed to improve the efficacy and prognosis for RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. Cadonilimab (AK104) is humanized bispecific antibody that targets to PD-1 and CTLA-4 12 . Its tetravalent and no Fc binding design contribute to its high binding activity in the tumor microenvironment and improved safety profile 13 . Recent studies have shown encouraging efficacy and manageable toxicity of cadonilimab in several different cancer types 14-16 . Cadonilimab monotherapy has shown an ORR of 26.1% and disease control rate (DCR) of 56.5%, with the median PFS time of 3.71 months in RM-NPC patients who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy 17 . There is no study available to explore the role of cadonilimab in anti-PD-1 resistant RM NPC patients. Our previous study prospectively proven the superiority of TPC regimen (paclitaxel, cisplatin, and capecitabine) versus cisplatin and fluorouracil (PF) as induction treatment for patients with stage IVA NPC in NPC patients 18 . Besides, after achieved disease control from TPC regimen, capecitabine maintenance therapy significantly improved PFS for patients with newly diagnosed metastatic NPC with tolerable toxicities 19 . These results suggest the promising application prospect of TPC regimen in RM-NPC patients. In this phase II trial, we firstly assessed the efficacy and safety of cadonilimab plus TPC chemotherapy as the second or later-line treatment in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. Results Patients Between February 15, 2023 and June 28, 2023, we screened 38 patients and 25 of them were finally enrolled in this study and received at least one cycle of study treatment (ITT and safety set; Fig. 1). One patient refused to continue the treatment after the first cycle of treatment due to personal reasons. The remaining 24 patients had at least one post-treatment tumor assessment and were evaluable for treatment responses (Fig. 2). Baseline characteristics of the enrolled patients are summarized in Table 1. The median age was 44 years (range, 24-60 years). All patients received at least one line of prior systemic therapy for advanced disease, with 3 (12%) received 2 lines and 6 (24%) received ≥ 3 lines. There were 5 (20%) patients previously received two or more different PD-1 inhibitors. Twelve patients (48%) had > 3000 copies/ml plasma EBV DNA level before treatment. The median interval of the last anti-PD-1 therapy to enrollment was 2.03 months (range, 0.7 – 16.03 months). Detail information of previous treatment regimens was shown in supplementary Table S1. Efficacy Of the 10 patients enrolled in the first stage, 7 patients obtained confirmed responses, which achieved the requestion of the first stage and the trial continued to full accrual. In the ITT set (n=25), 17 patients reached a confirmed objective response (ORR 68%, 95% CI, 48 - 88%), with 3 CR (12%), and 14 PR (56%) (Table 2, Fig. 2, Supplementary Fig. S1). Six patients maintained SD, one patient with PD and one patient was not evaluated. Interestingly, 20 patients (20/24, 83.33%) got EBV DNA level decrease ≥ 50% from baseline to the first post-treatment assessment, and 17 patients (17/24, 70.83%) decrease ≥ 90%. Patients with plasma EBV DNA level decrease ≥ 50% from baseline to the first post-treatment assessment had significantly higher ORR than those with plasma EBV DNA level decrease < 50% (17/20 vs. 4/4, p < 0.001). Furthermore, the EBV DNA level decrease, interval of the last administration of immunotherapy to the enrollment, and previous immunotherapy efficacy showed a numerically correlation with ordered response variables (PD, SD, PR to CR) decided by Cochran-Armitage trend test, although there was not a significantly difference (p > 0.05) (Supplementary Fig. S2). To the date cutoff (March 25, 2024), the median follow-up was 10.2 months (range, 4.3 – 13.5 months). The mTTR was 1.7 months (range, 1.2 – 4.9 months). The median DoR was 9.1 months (95% CI, 3.8 – 14.5 months; Fig. 3A). The median PFS was 10.6 months (95% CI, 5.2 – 16.0 months; Fig. 3B). The median OS has not reached, and 12-month OS was 75.6% (Fig. 3C). Intriguingly, we observed that patients with EBV DNA level decrease ≥ 50% from baseline to the first post-treatment assessment had a significantly longer PFS (p=0.006) and OS (p=0.008, Supplementary Fig. S3) than those with plasma EBV DNA level decrease < 50%. However, no significant difference was observed between EBV DNA level at baseline and survival (PFS and OS). Up to the date cutoff, fourteen patients (14/25, 52%) discontinued the study treatment, with thirteen developed disease progression, and one declined further therapy after the first cycle of the study treatment (Fig. 1-2, Supplementary Table S2). Safety In the safety set, twenty-four patients (24/25, 96%) experienced at least one treatment-related AE (TRAE) of any grade. TRAEs with an incidence greater than 50% included hypoesthesia (n=19, 76%), anemia (n=18, 72%), decreased appetite (n=18, 72%), fatigue (n=18, 72%), leukopenia (n=17, 68%), nausea (n=16, 64%), increased thyroid-stimulating hormone (n=13, 52%, Table 3). Grade 3 or 4 TRAEs occurred in 12 patients (48%), the most common of which (the incidence of preferred term ≥ 2%) were anemia (n=6, 24%), neutropenia (n=6, 24%), thrombocytopenia (n=4, 16%), hypoesthesia (n=2, 8%), fatigue (n=2, 8%), leukopenia (n=2, 8%), rash (n=2, 8%), and febrile neutropenia (n=2, 8%). Fourteen patients (14/25, 56%) reported potentially immune-related AEs (irAEs). The most common irAEs (the incidence of preferred term ≥ 10%) include grade 1-2 TSH elevation (n=10, 40%), hypothyroidism (n=8, 32%), musculoskeletal (n=8, 32%), pruritus (n=7, 28%), mucositis (n=6, 24%), and rash (n=4, 16%). Only two patients experienced grade 3 irAEs, one with rash and another with lipase increased. Both of them were managed with supportive measurements and signs/symptoms subsided without sequelae. During induction phase, twenty-one patients completed at least four cycles of TPC chemotherapy (Supplementary Table. S2). Of the other four patients, three progressed and one drop out. Twelve patients (48%) finished all six cycles of the TPC treatment. Dose reduction occurred in 11 (44%) patients, with the reasons of gastrointestinal reaction (n=5), hand-foot syndrome (n=3), and hematologic AEs (n=3). One patient required interruption of the treatment because of fall-induce femoral fracture (Supplementary Table. S2). Nineteen patients received the maintenance treatment, in which two patients (8%) required capecitabine dose reduction and cadonilimab interruption, respectively (Supplementary Table. S2). Fourteen patients are still on the study treatment at the date cutoff. Discussion This is the first trial to prospectively evaluate the efficacy and safety of additional bispecific antibody (anti PD-1/CTLA-4) cadonilimab to TPC chemotherapy in patients with RM-NPC who progressed to at least one line of systemic chemotherapy and anti-PD-1 therapy. In this study, cadonilimab plus TPC chemotherapy exhibited promising anti-tumoral activity, evidenced by favorable ORR, PFS, DoR, and manageable toxicities. Patients who developed immunotherapy resistance have poor prognosis and limited treatment options. Immunotherapy rechallenge has not been much successful in various cancer types 20-23 . Rechallenge strategies include combination mode (such as anti-PD-1 plus anti-CTLA-4 or antiangiogenic therapy) and replacement mode (such as changing ICI types) 24-26 . Our retrospective study demonstrated that immunotherapy plus target therapy with or without chemotherapy showed a relative better survival than chemotherapy only in RM-NPC patients who failed to prior anti-PD-1 therapy, with an ORR of 31.25% and 22.68%, respectively 9 . So far, several clinical trials reported the outcome of immunotherapy rechallenge in patients with RM-NPC which were resistant to anti-PD-1 therapy. Results of the trials showed an ORR of 33.3% with anti-PD-1 camrelizubam plus famitinib and 34.3% with camrelizumab plus apatinib respectively 10, 11 . These data demonstrate that immunotherapy rechallenge indeed exhibits a certain but not yet satisfactory anti-tumoral efficacy. More effectively new medications and combination therapy strategies should be explored for this patient population who developed immunotherapy resistance. Cadonilimab (AK104) is a symmetric tetravalent bispecific antibody that can target both PD-1 and CTLA-4 13 . It was reported that the preferential retention of cadonilimab may improve the drug retention and bring better antitumor efficacy and safety 13 . Cadonilimab has been shown promising antitumor efficacy either used as monotherapy or combination therapy. Cadonilimab monotherapy can reach an ORR of 26.1% in RM-NPC patients 17 and 13.4% to 32.3 % in other advanced solid tumors 14, 15 , respectively. Whereas the combination of cadonilimab and lenvatinib in advanced hepatocellular carcinoma at the first-line setting showed an ORR of 36% and median PFS of 9 months in COMPASSION-08 study 16 . Besides, the safety profile of cadonilimab was proved to be relatively better than the combination of anti-PD-1 and anti-CTLA-4 therapy, with the incidence of grade ≥ 3 TRAEs being 6.7 to 28% versus 18-37% 14, 15, 17, 27-30 . With our previous studies elaborated the anti-tumor activity of TPC regimen, here, we performed this study to rechallenge using cadonilimab in combination with TPC in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. In this trial, we observed unexpected and extraordinary ORR of 68% (3 CR (12%) and14 PR (56%)) in patients with RM-NPC who progressed to at least one line of systemic chemotherapy and anti-PD-1 therapy, which was doubled numerically compared to previous reports (ORR: 31.3-34.3%) 9-11 . The median DoR of this study was 9.1 month, which was much higher than previously reported numbers (2.9 – 4.2 months) 10, 11 . The median PFS was 10.6 months, which was also much longer than previously reported median PFS of 4.5 – 7.2 months 10, 11 . These results strongly suggest that the additional cadonilimab to TPC chemotherapy showed robust and durable antitumoral efficacy in patients with immunotherapy resistant RM-NPC. A recent study reported that patients may regain sensitivity to immunotherapy after prolonged suspension of ICIs 10 . In this study, we also found that the patients with longer interval from the last administration of immunotherapy to the enrollment had a numerically higher ORR. Measurement of plasma EBV-DNA level at baseline and dynamic changes were proved to be a useful biomarker for outcomes and monitoring disease progression 31-33 . In this study, the combination therapy achieved 83.33% patients with ≥ 50% decrease and 70.83% patients with ≥ 90% decrease in plasma EBV DNA level. Noteworthily, we found that patients with plasma EBV DNA level decrease ≥ 50% from baseline to the first post-treatment assessment had a significantly higher ORR, longer PFS and OS than those with plasma EBV DNA level decrease < 50%. These results were consistent with data from CAPTAIN study 33 , which hint the value of plasma EBV DNA changes as a reliable clinical efficacy predictor for immunotherapy rechallenge for patients with RM-NPC who progressed to anti-PD-1 therapy. Since almost all NPCs in endemic area are associated with EBV infection 34 , whether the clinical outcomes of immunotherapy rechallenge with cadonilimab plus TPC chemotherapy could be extrapolated to the non-endemic regions still needs further investigation. The safety profiles of cadonilimab plus TPC chemotherapy in RM-NPC were consistent with previous reports derived from the same patient population or patients with other cancers 10, 11, 14-17 . With chemotherapy addition in our study, however, TRAEs were still comparable to that of the other common regimens with grade ≥ 3 TRAE of 58.6%-94% in RM-NPC 6, 7, 11 . In this study, grade ≥ 3 TRAE were reported in 12 patients (48%) which was similar to that reported in a retrospectively study that patients with RM-NPC who progressed to anti-PD-1 therapy received camrelizumab plus famitinib (44.4%) 10 . The main grade ≥ 3 TRAEs were anemia, hypoesthesia, fatigue, thrombocytopenia, rash, neutropenia, which was also consistent with previous reported safety profile 17, 19 . The irAEs in this study were similar to previous reported cadonilimab-related AEs, including hypothyroidism, musculoskeletal, pruritus, and rash 14, 15, 26 . These results suggests that the combination of cadonilimab and TPC chemotherapy did not results in any unexpected grade 3 or 4 TRAEs or irAEs in this trial, and the combination regimen is well tolerated. Several limitations exist in this study. Firstly, although there is a notable numerical improvement of antitumoral efficacy of the study regimen compared with previous exploration in the same population, this was a single-arm study without control group, thus these promising results need to be validated in a large-scale prospective controlled trial. Secondly, the sample size was relatively small which may reduce the certainty of the reported efficacy and limit the exploration of predictive factors. Third, we did not attempt to explore the underlying molecular mechanisms, which is also valuable to understand exceptional clinical outcome in this study. In conclusion, here, this study’s findings suggest that cadonilimab in combination with TPC chemotherapy exhibited unprecedented and extraordinary antitumoral efficacy and manageable toxicities in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. This regimen provides a potential effective treatment option for RM-NPC patients in the era of immunotherapy. Further randomized controlled clinical trial is warranted to validate the clinical benefit of this combination regimen. Methods Study design and participants This was an open-label, single-arm, phase II study conducted at Sun Yat-Sen University Cancer Center. The study was performed in accordance with the Declaration of Helsinki and the International Standards of Good Clinical Practice. All protocols and amendments were approved by the Ethics Committee of Sun Yat-Sen University Cancer Center. The trial was registered at Chinese Ethics Committee of Registering Clinical Trials (ChiCRT2200067057). All participants were informed of the trial and provided written consent. Patients with histologically confirmed differentiated or undifferentiated non-keratinizing RM-NPC, that is refractory to at least one-line prior chemotherapy and anti-PD-1 systemic therapy and unfit for radical local treatment, were enrolled. Other main eligibility criteria for this study included age 18-70 years, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, a life expectancy of at least 3 months, at least one measurable lesion assessed with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V.1.1), and adequate organ function. The major exclusion criteria included patients who receive TPC chemotherapy within 6 months before enrollment, patients who received the last radiotherapy or antineoplastic treatment within 3 weeks before enrollment, patients who experienced active tuberculosis or autoimmune disease, other uncontrolled malignancies, active hepatitis B or hepatitis C virus infection, and patients who were pregnant or breast feeding. The full eligibility criteria are available in the study protocol (available in the study protocol). All patients provided informed consent. Procedures After screening, the eligible subjects received cadonilimab in combination with TPC regimen (NAB-paclitaxel, cisplatin/lobaplatin, and capecitabine) every 3 weeks for a maximum of 6 cycles as induction treatment, following by cadonilimab and capecitabine every 3 weeks as maintenance treatment until documented progressive disease (PD), death, intolerable toxicity, withdrawal of consent, or finishing scheduled 24-month treatment. Cadonilimab was intravenously given at dose of 10 mg/kg on day 1. The TPC regimen included NAB-paclitaxel administered at a dose of 200 mg/m 2 on day 1, cisplatin at a dose of 60 mg/m 2 on day 1, and capecitabine at a dose of 1000 mg/m 2 , taken orally twice a day on days 1 to 14, for each cycle. For those with cisplatin intolerance, cisplatin was replaced with lobaplatin at a dose of 30 mg/m 2 on day 1. Dose modifications of cadonilimab were not permitted. Details about criteria of discontinuation of cadonilimab and step-wise strategies of dose adjustment of other drugs are provided in the study protocol. Assessments After the treatment initiated, tumor response was evaluated according to the RECIST V.1.1 base on the imaging examination at baseline, every two cycles during induction phase, every three cycles during maintenance therapy phase, and three months thereafter until PD, withdrawal of informed consents, death, initiation of other anti-tumor therapies, study discontinuation, whichever occurs first. Safety evaluation was evaluated in every cycle throughout the treatment period and 30 days after treatment discontinuation (90 days for immune-related AEs), and were graded according to the National Cancer Institute Common Terminology for Adverse Events Version 5.0 (NCI CTCAE V5.0). Outcomes The primary endpoint was ORR, which was defined as the proportion of patients with complete response (CR) or partial response (PR) according to RECIST V.1.1. The secondary endpoints include PFS, defined as the time from treatment initiation to disease progression or death from any cause, whichever occurs first; overall survival (OS), defined as the time from treatment initiation until death; duration of response (DoR), defined as the time from the first evidence of response to disease progression or death; median time to response (mTTR), defined as the median time from treatment initiation to response and safety. Statistical analysis This study was based on Simon’s optimal two-stage design, with one-sided type I error rate of 5% and power of 80%. The null hypothesis ORR was 20% and target ORR was 45%. In the first stage, 10 patients will be accrued. If there are 2 or fewer responders in these 10 patients, enrollment will discontinue. Otherwise, 12 additional patients will be accrued for a total of 22 patients. If there were more than 7 patients with PR or CR, then the treatment regimen was considered a success. With an estimated 10% shedding rate, a total of 25 patients should be finally included. Efficacy analysis was performed in the intention-to-treat (ITT) population. Safety analyses were performed in patients who received at least one cycle of study treatment. ORR was calculated using the Clopper Pearson method and estimated 95% confidence intervals (CIs). Time to event endpoints (DoR, PFS, and OS) were analyzed using the Kaplan-Meier method. Clinical outcomes, demographic characteristics, and AEs were performed using proportions, frequencies, medians, and interquartile ranges (IQRs). We used R software V 4.3.0 to perform all statistical tests. A p value less than 0.05 was considered statistically significant. Declarations Data availability De-identified participant data will be made available to qualified researchers upon request, starting 24 months after the completion of the study, including follow-up. Researchers interested in accessing the data should submit a methodologically sound research proposal to the corresponding author, Y.-Q.X., via email at [email protected] . To obtain access, a data access agreement must be signed. Acknowledgements This study was supported by the National Natural Science Foundation of China (No. 62220106006, and No. 82203755), the Guangdong Basic and Applied Basic Research Foundation (No. 2021B1515120013). We thank the patients and their families for their willingness to participate in this trial, and the medical, nursing, and research staff at the study centers. Author contributions Drs Y-F Jiang, Y-Q Xiang, G-Y Liu and C Xie had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Y-F Jiang, W-X Bei, L Wang, N Lu, and C Xu contributed equally to this study. Drs Y-Q Xiang, G-Y Liu, and C Xie were joint senior authors. Conception and design: Y-Q Xiang, G-Y Liu, C Xie. Provision of study materials or patients: Y-F Jiang, L Wang, H Liang, L-R Ke. Data collection and assemble: Y-F Jiang, W-X Bei, C Xu, N Lu, L-R Ke, Y-F Ye, T Fang, S-Q He, S-H Ding, Q Liu, C-R Zhang, X-G Wang, W-X Xia, C Zhao. Data analysis and interpretation: Y-F Jiang, W-X Bei, C Xu, N Lu, Y-F Ye, C Xie, Y-Q Xiang. Manuscript writing: Y-F Jiang, L Wang, W-X Bei, C Xu, N Lu, C Xie, G-Y Liu, Y-Q Xiang. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors. Supervision: Y-Q Xiang, G-Y Liu, and C Xie. 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Nat Commun. 14 , 2781 (2023). Yau, T. et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 6 , e204564 (2020). Baas, P. et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 397 , 375-386 (2021). Hellmann, M.D. et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 18 , 31-41 (2017). Xu, J.-Y. et al. Association of Plasma Epstein-Barr Virus DNA With Outcomes for Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma Receiving Anti-Programmed Cell Death 1 Immunotherapy. JAMA Netw Open. 5 , e220587 (2022). Wang, F.-H. et al. Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02). J Clin Oncol. 39 , 704-712 (2021). Yang, Y. et al. Efficacy, safety, and biomarker analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN study). J Immunother Cancer. 9 (2021). Hau, P.M. et al. Targeting Epstein-Barr Virus in Nasopharyngeal Carcinoma. Front Oncol. 10 , 600 (2020). Tables Table 1 Characteristics of the Patients at Baseline Characteristic Value (N = 25) Age, years, median (range) 44 (24-60) Gender, no. (%) Female 4 (16) Male 21 (84) ECOG* performance-status score, no. (%) 0 19 (76) 1 6 (24) Initial stage†, no. (%) II-III 9 (36) IVa 10 (40) IVb 6 (24) Location of recurrences/metastases, no. (%) Local recurrence 2 (8) Regional lymph nodes 3 (12) Liver 12 (48) Lung 10 (40) Distant lymph nodes 13 (52) Bone and soft tissue 15 (60) EBV DNA copy number, no. (%) ≤ 3000 copies/mL 13 (52) > 3000 copies/mL 12 (48) Time from initial cancer diagnosis to study enrollment, months, median (range) 25.43 (6.2-105.43) Prior radiotherapy, no. (%) Yes 22 (88) None 3 (12) Prior therapy lines for advanced disease, no. (%) 1 16 (64) 2 3 (12) ≥3 6 (24) ICI-free interval, months, median (range) 2.03 (0.7-16.03) No. of types of prior ICI, no. (%) 1 20 (80) 2 4 (16) 3 1 (4) The initial stage of all enrolled patients was referred to the TNM staging system of American Joint Committee on Cancer, 8 th edition. * Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher scores indicating greater disability. † The initial stage of all enrolled patients was referred to the TNM staging system of American Joint Committee on Cancer, 8 th edition. Abbreviations: EBV, Epstein-Barr virus; ICI, immune checkpoint inhibitor. Table 2 Antitumor activity Response evaluation Value (N = 25) Objective response rate, no. (%) 17 (68) 95% Cl 0.48-0.88 Disease control rate, no. (%) 23 (92) 95% Cl 0.81-1.03 Best overall response, no. (%) Complete response 3 (12) Partial response 14 (56) Stable disease 6 (24) Progressive disease 1 (4) Unevaluable 1 (4) Table 3 Treatment related Adverse events Event N = 25 Any TRAE, No. (%) Grade 1-2 Grade 3 Grade 4 Hypoesthesia 17 (68) 2 (8) 0 Decreased appetite 17 (68) 1 (4) 0 Fatigue 16 (64) 2 (8) 0 Nausea 15 (60) 1 (4) 0 Leukopenia 15 (60) 0 2 (8) Blood thyroid-stimulating hormone increased 13 (52) 0 0 Anemia 12 (48) 6 (24) 0 Creatine phosphokinase elevation 12 (48) 0 0 Musculoskeletal pain 12 (48) 0 0 Hypomagnesemia 10 (40) 1 (4) 0 Hyperuricemia 10 (40) 0 0 Constipation 10 (40) 0 0 Pruritus 10 (40) 0 0 Dizziness 9 (36) 0 0 Insomnia 9 (36) 0 0 Vomiting 9 (36) 0 0 Abdominal pain 9 (36) 0 0 Mucositis 8 (32) 0 0 Hypothyroidism 8 (32) 0 0 Hypoalbuminemia 7 (28) 0 0 Hypokalemia 6 (24) 1 (4) 0 Cough 6 (24) 0 0 Thrombocytopenia 5 (20) 2 (8) 2 (8) Hypocalcemia 5 (20) 1 (4) 0 Hand-foot syndrome 5 (20) 0 0 Headache 5 (20) 0 0 Hiccups 5 (20) 0 0 Diarrhea 5 (20) 0 0 Serum creatinine elevation 5 (20) 0 0 Rash 4 (16) 2 (8) 0 Neutropenia 3 (12) 2 (8) 4 (12) Weight loss 3 (12) 0 0 Hyponatraemia 2 (8) 0 0 Fever 2 (8) 0 0 Lipase increased 1 (4) 1 (4) 0 Febrile neutropenia 0 2 (8) 0 Total bilirubin elevation 1 (4) 0 0 Amylase increased 1 (4) 0 0 Hypertension 1 (4) 0 0 Colonitis 1 (4) 0 0 ALT elevation 1 (4) 0 0 AST elevation 0 1 (4) 0 Potential irAEs, No. (%) .. .. .. TSH elevation 10 (40) 0 0 Hypothyroidism 8 (32) 0 0 Musculoskeletal pain 8 (32) 0 0 Pruritus 7 (28) 0 0 Mucositis oral 6 (24) 0 0 Rash 3 (12) 1 (4) 0 Lipase increased 1 (4) 1 (4) 0 Hypertension 1 (4) 0 0 Colonitis 1 (4) 0 0 Amylase increased 1 (4) 0 0 Abbreviations: TRAEs, treatment-related adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; irAEs, immune-related adverse events; TSH, thyroid stimulating hormone. Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformationfile1.pdf SupplementaryInformationfile2.pdf Supplementary data Cite Share Download PDF Status: Posted Version 1 posted 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-4232165","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":288912171,"identity":"560430af-ce1e-4abe-8bef-1f1f8f33f698","order_by":0,"name":"Yanqun 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16:00:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4232165/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4232165/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54596148,"identity":"d8bb9704-d34d-4c9e-974b-3e86970aff33","added_by":"auto","created_at":"2024-04-12 19:00:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":108794,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrial profiles.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4232165/v1/66d74ad1f1296657d8dbef95.png"},{"id":54596141,"identity":"9652f929-ef0a-46f2-8b0e-bb1bc3d2fc43","added_by":"auto","created_at":"2024-04-12 19:00:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":140162,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAntitumor activity. A\u003c/strong\u003e Best percentage change from baseline in target lesion (n = 24). \u003cstrong\u003eB\u003c/strong\u003e Swimmer plot (n = 25). Abbreviation: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4232165/v1/696bc70e9f7c6635735ff94b.png"},{"id":54596144,"identity":"3657178f-1401-4862-8218-ed78d29f6083","added_by":"auto","created_at":"2024-04-12 19:00:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":161406,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier plots of survival outcomes. A\u003c/strong\u003eDuration of response (DoR) was assessed in responders (n = 17). \u003cstrong\u003eB and C\u003c/strong\u003eProgression-free survival (PFS) and overall survival (OS) in the intertion-to-treat population (n = 25). NR, Not reached; NE, Not evaluable.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-4232165/v1/6edeff2ddd6403e00680bfda.png"},{"id":56651136,"identity":"271c9994-ecce-4234-b949-11cf1abc025e","added_by":"auto","created_at":"2024-05-17 08:43:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1067749,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4232165/v1/8a88ee48-f6a4-4c13-8a15-28010937ed65.pdf"},{"id":54596162,"identity":"2d348f35-3031-45da-9953-6e6760d216b0","added_by":"auto","created_at":"2024-04-12 19:00:29","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":458299,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryInformationfile1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4232165/v1/0ffbe63ed0a697edbe81ae23.pdf"},{"id":54596143,"identity":"4327ddcd-6fbb-481e-afa6-599edc23e50e","added_by":"auto","created_at":"2024-04-12 19:00:22","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":689808,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary data\u003c/p\u003e","description":"","filename":"SupplementaryInformationfile2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4232165/v1/af09b39ce572e328e708a4b9.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Combination of cadonilimab (anti-PD-1 and CTLA-4 bispecific antibody) with chemotherapy in anti-PD-1 resistant recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II clinical trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNasopharyngeal carcinoma (NPC) is a special type of head and neck tumors due to its distinct geographical, etiological and biological characteristics\u003csup\u003e1\u003c/sup\u003e. It has a high prevalence in South China, Southeast Asia, and North Africa, and is closely linked to Epstein-Barr virus (EBV) infections\u003csup\u003e1-3\u003c/sup\u003e. The incidence of distant metastasis of newly diagnosed NPC patients is approximately 6-15%, and about 20% of non-metastatic NPC experience recurrent or metastasis eventually after definitive treatments\u003csup\u003e4, 5\u003c/sup\u003e. The results from recently studies have established the combination of gemcitabine plus cisplatin and PD-1 inhibitor as the standard first-line regimens for recurrent or metastatic NPC (RM-NPC) patients\u003csup\u003e6-8\u003c/sup\u003e. With objective response rate (ORR) of 69.5% to 87.3% though, the median progression-free survival (PFS) was 9.2 to 21.4 months\u003csup\u003e6-8\u003c/sup\u003e. Under such conditions, most patients will develop disease progression within 1 to 2 years.\u0026nbsp;Recent studies showed that the prognosis of these patients was poor under later line therapy, with an ORR of 22.68% to 34.3% and median PFS of 4.4 to 7.9 months\u003csup\u003e9-11\u003c/sup\u003e. Therefore, novel treatment options are urgently needed to improve the efficacy and prognosis for RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCadonilimab (AK104) is humanized bispecific antibody that targets to PD-1 and CTLA-4\u003csup\u003e12\u003c/sup\u003e. Its tetravalent and no Fc binding design contribute to its high binding activity in the tumor microenvironment and improved safety profile\u003csup\u003e13\u003c/sup\u003e. Recent studies have shown encouraging efficacy and manageable toxicity of cadonilimab in several different cancer types\u003csup\u003e14-16\u003c/sup\u003e. Cadonilimab monotherapy has shown an ORR of 26.1% and disease control rate (DCR) of 56.5%, with the median PFS time of 3.71 months in RM-NPC patients who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy\u003csup\u003e17\u003c/sup\u003e. There is no study available to explore the role of cadonilimab in anti-PD-1 resistant RM NPC patients.\u003c/p\u003e\n\u003cp\u003eOur previous study prospectively proven the superiority of TPC regimen (paclitaxel, cisplatin, and capecitabine) versus cisplatin and fluorouracil (PF) as induction treatment for patients with stage IVA NPC in NPC patients\u003csup\u003e18\u003c/sup\u003e. Besides, after achieved disease control from TPC regimen, capecitabine maintenance therapy significantly improved PFS for patients with newly diagnosed metastatic NPC with tolerable toxicities\u003csup\u003e19\u003c/sup\u003e. These results suggest the promising application prospect of TPC regimen in RM-NPC patients.\u003c/p\u003e\n\u003cp\u003eIn this phase II\u0026nbsp;trial, we firstly assessed the efficacy and safety of cadonilimab plus TPC chemotherapy as the second or later-line treatment in\u0026nbsp;patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween February 15, 2023 and June 28, 2023, we screened 38 patients and 25 of them were finally enrolled in this study and received at least one cycle of study treatment (ITT and safety set; Fig. 1). One patient refused to continue the treatment after the first cycle of treatment due to personal reasons. The remaining 24 patients had at least one post-treatment tumor assessment and were evaluable for treatment responses (Fig. 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBaseline characteristics of the enrolled patients are summarized in Table 1. The median age was 44 years (range, 24-60 years). All patients received at least one line of prior systemic therapy for advanced disease, with 3 (12%) received 2 lines and 6 (24%) received \u0026ge; 3 lines. There were 5 (20%) patients previously received two or more different PD-1 inhibitors. Twelve patients (48%) had \u0026gt; 3000 copies/ml plasma EBV DNA level before treatment. The median interval of the last anti-PD-1 therapy to enrollment was 2.03 months (range, 0.7 \u0026ndash; 16.03 months). Detail information of previous treatment regimens was shown in supplementary Table S1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 10 patients enrolled in the first stage, 7 patients obtained confirmed responses, which achieved the requestion of the first stage and the trial continued to full accrual. In the ITT set (n=25), 17 patients reached a confirmed objective response (ORR 68%, 95% CI, 48 - 88%), with 3 CR (12%), and 14 PR (56%) (Table 2, Fig. 2, Supplementary Fig. S1). Six patients maintained SD, one patient with PD and one patient was not evaluated. Interestingly, 20 patients (20/24, 83.33%) got EBV DNA level decrease \u0026ge; 50% from baseline to the first post-treatment assessment, and 17 patients (17/24, 70.83%) decrease \u0026ge; 90%. Patients with plasma EBV DNA level decrease \u0026ge; 50% from baseline to the first post-treatment assessment had significantly higher ORR than those with plasma EBV DNA level decrease \u0026lt; 50% (17/20 vs. 4/4, p \u0026lt; 0.001). Furthermore, the EBV DNA level decrease, interval of the last administration of immunotherapy to the enrollment, and previous immunotherapy efficacy showed a numerically correlation with ordered response variables (PD, SD, PR to CR) decided by Cochran-Armitage trend test, although there was not a significantly difference (p \u0026gt; 0.05) (Supplementary Fig. S2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo the date cutoff (March 25, 2024), the median follow-up was 10.2 months (range, 4.3 \u0026ndash; 13.5 months). The mTTR was 1.7 months (range, 1.2 \u0026ndash; 4.9 months). The median DoR was 9.1 months (95% CI, 3.8 \u0026ndash; 14.5 months; Fig. 3A). The median PFS was 10.6 months (95% CI, 5.2 \u0026ndash; 16.0 months; Fig. 3B). The median OS has not reached, and 12-month OS was 75.6% (Fig. 3C). Intriguingly, we observed that patients with EBV DNA level decrease \u0026ge; 50% from baseline to the first post-treatment assessment had a significantly longer PFS (p=0.006) and OS (p=0.008, Supplementary Fig. S3) than those with plasma EBV DNA level decrease \u0026lt; 50%. However, no significant difference was observed between EBV DNA level at baseline and survival (PFS and OS). Up to the date cutoff, fourteen patients (14/25, 52%) discontinued the study treatment, with thirteen developed disease progression, and one declined further therapy after the first cycle of the study treatment (Fig. 1-2, Supplementary Table S2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the safety set, twenty-four patients (24/25, 96%) experienced at least one treatment-related AE (TRAE) of any grade. TRAEs with an incidence greater than 50% included hypoesthesia (n=19, 76%), anemia (n=18, 72%), decreased appetite (n=18, 72%), fatigue (n=18, 72%), leukopenia (n=17, 68%), nausea (n=16, 64%), increased thyroid-stimulating hormone (n=13, 52%, Table 3).\u0026nbsp;Grade 3 or 4 TRAEs occurred in 12 patients (48%), the most common of which (the incidence of preferred term \u0026ge; 2%) were anemia (n=6, 24%), neutropenia (n=6, 24%), thrombocytopenia (n=4, 16%), hypoesthesia (n=2, 8%), fatigue (n=2, 8%), leukopenia (n=2, 8%), rash (n=2, 8%), and febrile neutropenia (n=2, 8%). Fourteen patients (14/25, 56%) reported potentially immune-related AEs (irAEs). The most common irAEs (the incidence of preferred term \u0026ge; 10%) include grade 1-2 TSH elevation (n=10, 40%), hypothyroidism (n=8, 32%), musculoskeletal (n=8, 32%), pruritus (n=7, 28%), mucositis (n=6, 24%), and rash (n=4, 16%). \u0026nbsp;Only two patients experienced grade 3 irAEs, one with rash and another with lipase increased. Both of them were managed with supportive measurements and signs/symptoms subsided without sequelae.\u003c/p\u003e\n\u003cp\u003eDuring induction phase, twenty-one patients completed at least four cycles of TPC chemotherapy (Supplementary Table. S2). Of the other four patients, three progressed and one drop out. Twelve patients (48%) finished all six cycles of the TPC treatment. Dose reduction occurred in 11 (44%) patients, with the reasons of gastrointestinal reaction (n=5), hand-foot syndrome (n=3), and hematologic AEs (n=3). One patient required interruption of the treatment because of fall-induce femoral fracture (Supplementary Table. S2). Nineteen patients received the maintenance treatment, in which two patients (8%) required capecitabine dose reduction and cadonilimab interruption, respectively (Supplementary Table. S2). Fourteen patients are still on the study treatment at the date cutoff.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first trial to prospectively evaluate the efficacy and safety of additional bispecific antibody (anti PD-1/CTLA-4) cadonilimab to TPC chemotherapy in patients with RM-NPC who progressed to at least one line of systemic chemotherapy and anti-PD-1 therapy. In this study, cadonilimab plus TPC chemotherapy\u0026nbsp;exhibited promising anti-tumoral activity, evidenced by favorable ORR, PFS, DoR, and manageable toxicities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients who developed immunotherapy resistance have poor prognosis and limited treatment options. Immunotherapy rechallenge has not been much successful in various cancer types\u003csup\u003e20-23\u003c/sup\u003e. Rechallenge strategies include combination mode (such as anti-PD-1 plus anti-CTLA-4 or antiangiogenic therapy) and replacement mode (such as changing ICI types)\u003csup\u003e24-26\u003c/sup\u003e. Our retrospective study demonstrated that immunotherapy plus target therapy with or without chemotherapy showed a relative better survival than chemotherapy only in RM-NPC patients who failed to prior anti-PD-1 therapy, with an ORR of 31.25% and 22.68%, respectively\u003csup\u003e9\u003c/sup\u003e. So far, several clinical trials reported the outcome of immunotherapy rechallenge in patients with RM-NPC which were resistant to anti-PD-1 therapy. Results of the trials showed an ORR of 33.3% with anti-PD-1 camrelizubam plus famitinib and 34.3% with camrelizumab plus apatinib respectively\u003csup\u003e10, 11\u003c/sup\u003e. These data demonstrate that immunotherapy rechallenge indeed exhibits a certain but not yet satisfactory anti-tumoral efficacy. More effectively new medications and combination therapy strategies should be explored for this patient population who developed immunotherapy resistance.\u003c/p\u003e\n\u003cp\u003eCadonilimab (AK104) is a symmetric tetravalent bispecific antibody that can target both PD-1 and CTLA-4\u003csup\u003e13\u003c/sup\u003e. It was reported that the preferential retention of cadonilimab may improve the drug retention and bring better antitumor efficacy and safety\u003csup\u003e13\u003c/sup\u003e. Cadonilimab has been shown promising antitumor efficacy either used as monotherapy or combination therapy. Cadonilimab monotherapy can reach an ORR of 26.1% in RM-NPC patients\u0026nbsp;\u003csup\u003e17\u003c/sup\u003e and 13.4% to 32.3 % in other advanced solid tumors\u003csup\u003e14, 15\u003c/sup\u003e, respectively. Whereas the combination of cadonilimab and lenvatinib in advanced hepatocellular carcinoma at the first-line setting showed an ORR of 36% and median PFS of 9 months in COMPASSION-08 study\u003csup\u003e16\u003c/sup\u003e. Besides, the safety profile of cadonilimab was proved to be relatively better than the combination of anti-PD-1 and anti-CTLA-4 therapy, with the incidence of grade \u0026ge; 3 TRAEs being 6.7 to 28% versus 18-37%\u003csup\u003e14, 15, 17, 27-30\u003c/sup\u003e. With our previous studies elaborated the anti-tumor activity of TPC regimen, here, we performed this study to rechallenge using cadonilimab in combination with TPC in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy.\u003c/p\u003e\n\u003cp\u003eIn this trial, we observed unexpected and extraordinary ORR of 68% (3 CR (12%) and14 PR (56%)) in patients with RM-NPC who progressed to at least one line of systemic chemotherapy and anti-PD-1 therapy, which was doubled numerically compared to previous reports (ORR: 31.3-34.3%)\u003csup\u003e9-11\u003c/sup\u003e. The median DoR of this study was 9.1 month, which was much higher than previously reported numbers (2.9 \u0026ndash; 4.2 months)\u003csup\u003e10, 11\u003c/sup\u003e. The median PFS was 10.6 months, which was also much longer than previously reported median PFS of 4.5 \u0026ndash; 7.2 months\u003csup\u003e10, 11\u003c/sup\u003e. These results strongly suggest that the additional cadonilimab to TPC\u0026nbsp;chemotherapy showed robust and durable antitumoral efficacy in patients with immunotherapy resistant RM-NPC. A recent study reported that patients may regain sensitivity to immunotherapy after prolonged suspension of ICIs\u003csup\u003e10\u003c/sup\u003e. In this study, we also found that the patients with longer interval from the last administration of immunotherapy to the enrollment had a numerically higher ORR.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMeasurement of plasma EBV-DNA level at baseline and dynamic changes were proved to be a useful biomarker for outcomes and monitoring disease progression\u003csup\u003e31-33\u003c/sup\u003e. In this study, the combination therapy achieved 83.33% patients with \u0026ge; 50% decrease and 70.83% patients with \u0026ge; 90% decrease in plasma EBV DNA level. Noteworthily, we found that patients with plasma EBV DNA level decrease \u0026ge; 50% from baseline to the first post-treatment assessment had a significantly higher ORR, longer PFS and OS than those with plasma EBV DNA level decrease \u0026lt; 50%. These results were consistent with data from CAPTAIN study\u003csup\u003e33\u003c/sup\u003e, which hint the value of plasma EBV DNA changes as a reliable clinical efficacy predictor for immunotherapy rechallenge for patients with RM-NPC who progressed to anti-PD-1 therapy. Since almost all NPCs in endemic area are associated with EBV infection\u003csup\u003e34\u003c/sup\u003e, whether the clinical outcomes of immunotherapy rechallenge with cadonilimab plus TPC chemotherapy could be extrapolated to the non-endemic regions still needs further investigation.\u003c/p\u003e\n\u003cp\u003eThe safety profiles of cadonilimab plus TPC chemotherapy in RM-NPC were consistent with previous reports derived from the same patient population or patients with other cancers\u003csup\u003e10, 11, 14-17\u003c/sup\u003e. With chemotherapy addition in our study, however, TRAEs were still comparable to that of the other common regimens with grade \u0026ge; 3 TRAE of 58.6%-94% in RM-NPC\u003csup\u003e6, 7, 11\u003c/sup\u003e. In this study, grade \u0026ge; 3 TRAE were reported in 12 patients (48%) which was similar to that reported in a retrospectively study that patients with RM-NPC who progressed to anti-PD-1 therapy received camrelizumab plus famitinib (44.4%)\u003csup\u003e10\u003c/sup\u003e. The main grade \u0026ge; 3 TRAEs were anemia, hypoesthesia, fatigue, thrombocytopenia, rash, neutropenia, which was also consistent with previous reported safety profile\u003csup\u003e17, 19\u003c/sup\u003e. The irAEs in this study were similar to previous reported cadonilimab-related AEs, including hypothyroidism, musculoskeletal, pruritus, and rash\u003csup\u003e14, 15, 26\u003c/sup\u003e. These results suggests that the combination of cadonilimab and TPC chemotherapy did not results in any unexpected grade 3 or 4 TRAEs or irAEs in this trial, and the combination regimen is well tolerated.\u003c/p\u003e\n\u003cp\u003eSeveral limitations exist in this study. Firstly, although there is a notable numerical improvement of antitumoral efficacy of the study regimen compared with previous exploration in the same population, this was a single-arm study without control group, thus these promising results need to be validated in a large-scale prospective controlled trial. Secondly, the sample size was relatively small which may reduce the certainty of the reported efficacy and limit the exploration of predictive factors. Third, we did not attempt to explore the underlying molecular mechanisms, which is also valuable to understand exceptional clinical outcome in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, here, this study\u0026rsquo;s findings suggest that cadonilimab in combination with TPC chemotherapy exhibited unprecedented and extraordinary antitumoral efficacy and manageable toxicities in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. This regimen provides a potential effective treatment option for RM-NPC patients in the era of immunotherapy. Further randomized controlled clinical trial is warranted to validate the clinical benefit of this combination regimen.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was an open-label, single-arm, phase II study conducted at Sun Yat-Sen University Cancer Center. The study was performed in accordance with the Declaration of Helsinki and the International Standards of Good Clinical Practice. All protocols and amendments were approved by the Ethics Committee of Sun Yat-Sen University Cancer Center. The trial was registered at Chinese Ethics Committee of Registering Clinical Trials (ChiCRT2200067057). All participants were informed of the trial and provided written consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients with histologically confirmed differentiated or undifferentiated non-keratinizing RM-NPC, that is refractory to at least one-line prior chemotherapy and anti-PD-1 systemic therapy and unfit for radical local treatment, were enrolled. Other main eligibility criteria for this study included age 18-70 years, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, a life expectancy of at least 3 months, at least one measurable lesion assessed with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V.1.1), and adequate organ function. The major exclusion criteria included patients who receive TPC chemotherapy within 6 months before enrollment, patients who received the last radiotherapy or antineoplastic treatment within 3 weeks before enrollment, patients who experienced active tuberculosis or autoimmune disease, other uncontrolled malignancies, active hepatitis B or hepatitis C virus infection, and patients who were pregnant or breast feeding. The full eligibility criteria are available in the study protocol (available in the study protocol). All patients provided informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter screening, the eligible subjects received cadonilimab in combination with TPC regimen (NAB-paclitaxel, cisplatin/lobaplatin, and capecitabine) every 3 weeks for a maximum of 6 cycles as induction treatment, following by cadonilimab and capecitabine every 3 weeks as maintenance treatment until documented progressive disease (PD), death, intolerable toxicity, withdrawal of consent, or finishing scheduled 24-month treatment. Cadonilimab was intravenously given at dose of 10 mg/kg on day 1. The TPC regimen included NAB-paclitaxel administered at a dose of 200 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1, cisplatin at a dose of 60 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1, and capecitabine at a dose of 1000 mg/m\u003csup\u003e2\u003c/sup\u003e, taken orally twice a day on days 1 to 14, for each cycle. For those with cisplatin intolerance, cisplatin was replaced with lobaplatin at a dose of 30 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1. Dose modifications of cadonilimab were not permitted. Details about criteria of discontinuation of cadonilimab and step-wise strategies of dose adjustment of other drugs are provided in the study protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter the treatment initiated, tumor response was evaluated according to the RECIST V.1.1 base on the imaging examination at baseline, every two cycles during induction phase, every three cycles during maintenance therapy phase, and three months thereafter until PD, withdrawal of informed consents, death, initiation of other anti-tumor therapies, study discontinuation, whichever occurs first. Safety evaluation was evaluated in every cycle throughout the treatment period and 30 days after treatment discontinuation (90 days for immune-related AEs), and were graded according to the National Cancer Institute Common Terminology for Adverse Events Version 5.0 (NCI CTCAE V5.0).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was ORR, which was defined as the proportion of patients with complete response (CR) or partial response (PR) according to RECIST V.1.1. The secondary endpoints include PFS, defined as the time from treatment initiation to disease progression or death from any cause, whichever occurs first; overall survival (OS), defined as the time from treatment initiation until death; duration of response (DoR), defined as the time from the first evidence of response to disease progression or death; median time to response (mTTR), defined as the median time from treatment initiation to response and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was based on Simon\u0026rsquo;s optimal two-stage design, with one-sided type I error rate of 5% and power of 80%. The null hypothesis ORR was 20% and target ORR was 45%. In the first stage, 10 patients will be accrued. If there are 2 or fewer responders in these 10 patients, enrollment will discontinue. Otherwise, 12 additional patients will be accrued for a total of 22 patients. If there were more than 7 patients with PR or CR, then the treatment regimen was considered a success. With an estimated 10% shedding rate, a total of 25 patients should be finally included.\u003c/p\u003e\n\u003cp\u003eEfficacy analysis was performed in the intention-to-treat (ITT) population. Safety analyses were performed in patients who received at least one cycle of study treatment. ORR was calculated using the Clopper Pearson method and estimated 95% confidence intervals (CIs). Time to event endpoints (DoR, PFS, and OS) were analyzed using the Kaplan-Meier method. Clinical outcomes, demographic characteristics, and AEs were performed using proportions, frequencies, medians, and interquartile ranges (IQRs). We used R software V 4.3.0 to perform all statistical tests. A p value less than 0.05 was considered statistically significant.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDe-identified participant data will be made available to qualified researchers upon request, starting 24 months after the completion of the study, including follow-up. Researchers interested in accessing the data should submit a methodologically sound research proposal to the corresponding author, Y.-Q.X., via email at [email protected]. To obtain access, a data access agreement must be signed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (No. 62220106006, and No. 82203755), the Guangdong Basic and Applied Basic Research Foundation (No. 2021B1515120013). We thank the patients and their families for their willingness to participate in this trial, and the medical, nursing, and research staff at the study centers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrs Y-F Jiang, Y-Q Xiang, G-Y Liu and C Xie had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Y-F Jiang, W-X Bei, L Wang, N Lu, and C Xu contributed equally to this study. Drs Y-Q Xiang, G-Y Liu, and C Xie were joint senior authors. Conception and design: Y-Q Xiang, G-Y Liu, C Xie. Provision of study materials or patients: Y-F Jiang, L Wang, H Liang, L-R Ke. Data collection and assemble: Y-F Jiang, W-X Bei, C Xu, N Lu, L-R Ke, Y-F Ye, T Fang, S-Q He, S-H Ding, Q Liu, C-R Zhang, X-G Wang, W-X Xia, C Zhao. Data analysis and interpretation: Y-F Jiang, W-X Bei, C Xu, N Lu, Y-F Ye, C Xie, Y-Q Xiang. Manuscript writing: Y-F Jiang, L Wang, W-X Bei, C Xu, N Lu, C Xie, G-Y Liu, Y-Q Xiang. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors. Supervision: Y-Q Xiang, G-Y Liu, and C Xie.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChen, Y.-P. et al. Nasopharyngeal carcinoma. \u003cem\u003eLancet.\u003c/em\u003e \u003cstrong\u003e394\u003c/strong\u003e, 64-80 (2019).\u003c/li\u003e\n\u003cli\u003eFeng, R.-M., Zong, Y.-N., Cao, S.-M. \u0026amp; Xu, R.-H. Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics? \u003cem\u003eCancer Commun (Lond).\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 22 (2019).\u003c/li\u003e\n\u003cli\u003eNgan, H.-L., Wang, L., Lo, K.-W. \u0026amp; Lui, V.W.Y. 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A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non-small-cell lung cancer (AK104-202 study). \u003cem\u003eLung Cancer.\u003c/em\u003e \u003cstrong\u003e184\u003c/strong\u003e, 107355 (2023).\u003c/li\u003e\n\u003cli\u003eLim, D.W.-T. et al. Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma. \u003cem\u003eNat Commun.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 2781 (2023).\u003c/li\u003e\n\u003cli\u003eYau, T. et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. \u003cem\u003eJAMA Oncol.\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, e204564 (2020).\u003c/li\u003e\n\u003cli\u003eBaas, P. et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. \u003cem\u003eLancet.\u003c/em\u003e \u003cstrong\u003e397\u003c/strong\u003e, 375-386 (2021).\u003c/li\u003e\n\u003cli\u003eHellmann, M.D. et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. \u003cem\u003eLancet Oncol.\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 31-41 (2017).\u003c/li\u003e\n\u003cli\u003eXu, J.-Y. et al. Association of Plasma Epstein-Barr Virus DNA With Outcomes for Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma Receiving Anti-Programmed Cell Death 1 Immunotherapy. \u003cem\u003eJAMA Netw Open.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, e220587 (2022).\u003c/li\u003e\n\u003cli\u003eWang, F.-H. et al. Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02). \u003cem\u003eJ Clin Oncol.\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 704-712 (2021).\u003c/li\u003e\n\u003cli\u003eYang, Y. et al. Efficacy, safety, and biomarker analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN study). \u003cem\u003eJ Immunother Cancer.\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e (2021).\u003c/li\u003e\n\u003cli\u003eHau, P.M. et al. Targeting Epstein-Barr Virus in Nasopharyngeal Carcinoma. \u003cem\u003eFront Oncol.\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 600 (2020).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 Characteristics of the Patients at Baseline\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003eValue (N = 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eAge, years, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e44 (24-60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eGender, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e4 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e21 (84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eECOG* performance-status score, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e19 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eInitial stage\u0026dagger;, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eII-III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e9 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eIVa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e10 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eIVb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eLocation of recurrences/metastases, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eLocal recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eRegional lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e12 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e10 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eDistant lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e13 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eBone and soft tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e15 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eEBV DNA copy number, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026le; 3000 copies/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e13 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026gt; 3000 copies/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e12 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eTime from initial cancer diagnosis to study enrollment, months, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e25.43 (6.2-105.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003ePrior radiotherapy, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e22 (88)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003ePrior therapy lines for advanced disease, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e16 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eICI-free interval, months, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e2.03 (0.7-16.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003eNo. of types of prior ICI, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e20 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e4 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.64575645756457%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.354243542435423%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eThe\u0026nbsp;initial stage of all enrolled patients was referred to the TNM staging system of American Joint Committee on Cancer, 8\u003csup\u003eth\u003c/sup\u003e edition.\u003c/p\u003e\n \u003cp\u003e* Eastern Cooperative Oncology Group (ECOG) performance-status scores range\u003c/p\u003e\n \u003cp\u003efrom 0 to 5, with higher scores indicating greater disability.\u003c/p\u003e\n \u003cp\u003e\u0026dagger;\u0026nbsp;The\u0026nbsp;initial stage of all enrolled patients was referred to the TNM staging system of American Joint Committee on Cancer, 8\u003csup\u003eth\u003c/sup\u003e edition.\u003c/p\u003e\n \u003cp\u003eAbbreviations: EBV, Epstein-Barr virus; ICI, immune checkpoint inhibitor.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Antitumor activity\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003eResponse evaluation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003eValue (N = 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003eObjective response rate, no. (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e17 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 95% Cl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e0.48-0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003eDisease control rate, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e23 (92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 95% Cl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e0.81-1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003eBest overall response, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Complete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Partial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e14 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Stable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"72.03389830508475%\" valign=\"top\"\u003e\n \u003cp\u003eUnevaluable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.966101694915253%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Treatment related Adverse events\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"556\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.67625899280576%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.32374100719424%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN = 25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny TRAE, No. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1-2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypoesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e17 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e17 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e16 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e15 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eLeukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e15 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eBlood thyroid-stimulating hormone increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e13 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e12 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eCreatine phosphokinase elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e12 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eMusculoskeletal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e12 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypomagnesemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e10 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHyperuricemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e10 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e10 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003ePruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e10 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e9 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e9 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e9 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e9 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eMucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e8 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e8 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypoalbuminemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e7 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypokalemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e5 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypocalcemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e5 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHand-foot syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e5 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e5 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHiccups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e5 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e5 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eSerum creatinine elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e5 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e4 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e4 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eWeight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHyponatraemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eLipase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eFebrile neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eTotal bilirubin elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eAmylase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eColonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eALT elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eAST elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePotential irAEs, No. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e..\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e..\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e..\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eTSH elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e10 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e8 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eMusculoskeletal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e8 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003ePruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e7 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eMucositis oral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e6 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eLipase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eColonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.77477477477478%\" valign=\"top\"\u003e\n \u003cp\u003eAmylase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.315315315315315%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.594594594594595%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAbbreviations: TRAEs, treatment-related adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; irAEs, immune-related adverse events; TSH, thyroid stimulating hormone.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4232165/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4232165/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Treatment options are limited for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) after failure to anti-PD-1 therapy. Cadonilimab (AK104) is a humanized bispecific antibody that targets to PD-1 and CTLA-4. We aimed to evaluate the efficacy and safety of cadonilimab plus TPC chemotherapy (NAB-paclitaxel, cisplatin or lobaplatin, and capecitabine) in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. In this phase II clinical trial (ChiCRT2200067057), 25 patients were enrolled and received cadonilimab plus TPC chemotherapy every three weeks for up to six cycles followed by maintenance treatment of cadonilimab plus capecitabine. Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of progression-free survival, overall survival, duration of response, and safety. This trial met its prespecified primary endpoint of ORR (68%, 95% CI, 48-88), with 3 complete response (12%), 14 partial response (56%), 6 stable disease (24%). Grade ≥3 treatment-related adverse events were occurred in 12 (48%) patients, with the most common being anemia (6[24%]) and neutropenia (6[24%]). This phase II trial shows that cadonilimab in combination with TPC chemotherapy demonstrated satisfactory antitumoral efficacy and manageable toxicities in patients with systemic chemotherapy and anti-PD-1 therapy resistance RM-NPC.","manuscriptTitle":"Combination of cadonilimab (anti-PD-1 and CTLA-4 bispecific antibody) with chemotherapy in anti-PD-1 resistant recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-12 19:00:03","doi":"10.21203/rs.3.rs-4232165/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"940c3a2c-2896-4e58-92bd-06ce9ec2c143","owner":[],"postedDate":"April 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30419546,"name":"Health sciences/Oncology/Cancer/Head and neck cancer"},{"id":30419547,"name":"Health sciences/Oncology/Cancer/Cancer therapy/Cancer immunotherapy"}],"tags":[],"updatedAt":"2024-05-17T08:35:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-12 19:00:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4232165","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4232165","identity":"rs-4232165","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}