Combination of immunotherapy and anti-EGFR agents in immunotherapy refractory head neck cancer recurrent and metastatic head neck squamous cell carcinoma

Combination of immunotherapy and anti-EGFR agents in immunotherapy refractory head neck cancer recurrent and metastatic head neck squamous cell carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Combination of immunotherapy and anti-EGFR agents in immunotherapy refractory head neck cancer recurrent and metastatic head neck squamous cell carcinoma Yun-Chien Chang, Tien-Hua Chen, Peter Mu-Hsin Chang, Muh-Hwa Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9000074/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Background Immunotherapy has become a standard treatment for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC); however, response rates remain modest, and long-term survival is limited. Preclinical studies suggest that inhibiting the epidermal growth factor receptor (EGFR) pathway may enhance antigen presentation and augment the efficacy of immune checkpoint inhibitors. This study evaluated the real-world efficacy and safety of combining immunotherapy with anti-EGFR agents in patients with R/M HNSCC. Methods We conducted a retrospective study at Taipei Veterans General Hospital involving patients diagnosed with R/M HNSCC between January 2020 and July 2024 who received combination therapy comprising immunotherapy and anti-EGFR agents. The primary endpoint was the objective response rate (ORR) according to RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety assessed by CTCAE v5.0. Results A total of 29 patients were included in the analysis. The cohort was characterized by a high proportion of platinum-refractory disease (59%) and 38% of patients received the combination as second-line treatment or later. The ORR was 44% (95% CI: 26%–64%), including 3 complete responses (10%) and 10 partial responses (34%). The DCR was 66%. The median PFS was 6.9 months (95% CI: 2.9–9.2), and the median OS was 15.1 months (95% CI: 8.4–not reached). Notably, in the subgroup with a PD-L1 combined positive score (CPS) < 1, the ORR was 37.5%. Treatment-related adverse events occurred in 79% of patients but were exclusively Grade 1 or 2; no Grade 3 or higher adverse events were observed. Conclusion The combination of immunotherapy and anti-EGFR agents demonstrated promising antitumor activity and a favorable safety profile in patients with R/M HNSCC. These findings suggest this regimen may be a viable therapeutic strategy, particularly for patients with platinum-refractory disease or low PD-L1 expression who traditionally have poor outcomes. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Head and neck squamous cell carcinoma (HNSCC) represents a significant global health burden, contributing substantially to cancer-related morbidity and mortality, with more than 600,000 new cases diagnosed each year worldwide [ 1 ]. Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) develops in over 50% of patients with locoregionally advanced disease [ 2 ]. R/M HNSCC are partially driven by immune evasion mechanisms. A key factor in this process is the expression of programmed death ligands (PD-L1), which bind to the programmed death 1 (PD-1) receptor and suppress T-cell activity through immune checkpoint pathways. Immune checkpoint inhibitors have demonstrated significant efficacy and manageable safety profiles in HNSCC [ 3 – 5 ]. The pivotal CheckMate-141 and KEYNOTE-040 trials showed that anti-PD1 monoclonal antibodies improved overall survival compared to standard single-agent therapies in patients with R/M HNSCC [ 3 , 6 ]. Additionally, the KEYNOTE-048 trial demonstrated that pembrolizumab monotherapy significantly improved overall survival in patients with a combined positive score (CPS) ≥ 1, exhibited non-inferiority in the overall study population, and was associated with a more favorable safety profile compared to cetuximab combined with chemotherapy [ 7 ]. Based on these findings, current guidelines recommend pembrolizumab in combination with platinum and 5-fluorouracil as the first-line treatment for unresectable R/M HNSCC [ 2 , 8 ]. Despite these advancements, there is still limited number of patient can gain clinical benefit from immunotherapy, with a median overall survival (OS) about 8 months and a 1-year OS rate of about 40% [ 3 , 6 ]. Resistance to immunotherapy has been attributed to mechanisms such as loss of IFNγ signaling and impaired antigen presentation [ 9 ]. Interestingly, preclinical studies have demonstrated that epidermal growth factor receptor (EGFR) pathway inhibition enhances antigen presentation and augments the efficacy of immunotherapy [ 10 – 12 ]. Mechanistically, cetuximab induces antibody-dependent cellular cytotoxicity (ADCC), leading to the lysis of tumor cells by natural killer (NK) cells. This process facilitates the cross-priming of cytotoxic CD8 + T cells by activated dendritic cells. Furthermore, activated NK cells secrete IFNγ alongside other proinflammatory cytokines and chemokines, thereby remodeling the tumor microenvironment to favor immune cell recruitment and activation.[ 13 ] Several phase II studies have indicated that adding anti-EGFR agents to immunotherapy may augment efficacy and improve overall response rates in patients with platinum-refractory R/M HNSCC [ 13 – 15 ]. However, real-world data regarding this combination strategy remain scarce. Therefore, we conducted a retrospective study to evaluate the efficacy of combining anti-EGFR agents with immunotherapy in a real-world clinical setting. Methods 2.1 Study design and participants We retrospectively identified patients at Taipei Veterans General Hospital diagnosed with R/M HNSCC between January 2020 and July 2024. Patients who received a combination of immunotherapy and anti-EGFR agents were selected for further analysis. Clinical characteristics of these patients were systematically recorded, including sex, age, Eastern Cooperative Oncology Group (ECOG) performance status, smoking history, HPV status, initial tumor staging, primary tumor location, PD-L1 expression, disease status (locoregional recurrence only vs. metastatic disease), prior immunotherapy regimen, platinum-refractory status, number of prior systemic treatment lines, type of anti-EGFR agent used during combination therapy, and whether chemotherapy was included in the combination regimen. According to current clinical guidelines, human papilloma virus (HPV) status is assessed exclusively in cases of oropharyngeal cancer and is determined through immunohistochemical staining for p16 as a surrogate marker. Initial tumor staging was classified according to the American Joint Committee on Cancer (AJCC) staging system (seventh edition). Primary tumor locations were categorized as the oral cavity, oropharynx, larynx, and hypopharynx. PD-L1 expression was assessed using the PD-L1 combined positive score (CPS) via the PD-L1 28 − 8 and 22C3 immunohistochemistry assays. Based on the KEYNOTE-048 study, CPS was categorized into 3 groups: <1, 1–19, and ≥ 20. Platinum-refractory disease was defined as disease relapse occurring within six months of platinum-based therapy. This study was approved by the Institutional Review Board (IRB) and Ethics Committee of Taipei Veterans General Hospital. Details of ethics approval are provided in the Declarations section. 2.2 Outcomes The primary endpoint of this study was the objective response rate (ORR), defined as the proportion of patients who achieved a complete response (CR) or partial response (PR), as assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Several secondary endpoints were evaluated, including the disease control rate (DCR), defined as the percentage of patients who achieved CR, PR or stable disease (SD); progression-free survival (PFS), defined as the duration from the initiation of combination therapy to disease progression (PD); Additionally, the duration of response (DoR) was assessed, defined as the time from the initiation of combination therapy to PD in patients who achieved an objective response. Adverse events and laboratory abnormalities were systematically documented throughout the treatment period and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). 2.3 Statistical analysis All statistical analyses were conducted using GraphPad Prism version 8.0.1. The ORR and DCR were reported as percentages with 95% confidence intervals (CIs). OS and PFS were estimated using the Kaplan-Meier method, with median OS, median PFS, and their respective 95% CIs presented. For OS estimation, patients who were still alive at the end of the study or lost to follow-up were censored at the time of their last medical visit. For PFS estimation, patients without disease progression at the end of the study or lost to follow-up were censored at the time of their last tumor imaging. To identify prognostic factors associated with OS, a univariate Cox proportional hazards model was applied to clinicopathologic variables, including ECOG performance status, smoking history, primary tumor site, initial tumor staging, number of prior systemic treatments, and PD-L1 CPS. Variables with an insufficient number of cases in the comparison groups were excluded from univariate analysis. Results 3.1 Patient characteristics As depicted in Figure 1, between January 1, 2020, and July 31, 2024, a total of 353 and 237 patients underwent anti-EGFR therapy and immunotherapy, respectively. Cross-referencing these cohorts identified 38 individuals who received concurrent treatment. Nine patients were subsequently excluded due to mortality within one month (n=4) or loss to follow-up (n=5). Ultimately, the final cohort comprised 29 patients with R/M HNSCC treated with the combination regimen. Figure 1. Patient Enrollment Flowchart A total of 353 patients received anti-EGFR therapy and 237 patients received immunotherapy between January 2020 and July 2024. Among them, 38 patients had received both immunotherapy and anti-EGFR therapy. After reviewing their medical history, 4 patients were excluded due to mortality within one month and 5 patients were excluded due to lost follow up. Ultimately, 29 patients who received combination therapy were included in the study. Baseline demographics and disease characteristics are summarized in Table 1. The cohort had a median age of 60.8 years, with a male predominance (90%) and the majority of patients having an ECOG performance status of 0–1 (82%). A history of smoking was reported in 72% of patients. Most participants presented with stage III or IV disease (89%), and primary tumors were predominantly located in the oral cavity or oropharynx (73%). Among the five patients evaluated for HPV status, three were positive. Distant metastases were present in 9 patients (31%), and 17 patients (59%) had a PD-L1 combined positive score (CPS) of ≥1. Notably, 59% of the cohort had platinum-refractory disease, and 38% received the combination regimen as a second-line treatment. Cetuximab was the most common anti-EGFR agent (59%), and chemotherapy was not incorporated into the combination regimen in 16 patients (55%) Table 1. Patient characteristics Patient characteristics Total population (n=29) % Age, y/o (95% CI) 60.8 (56.4-65.2) Sex Female male 3 26 10 90 ECOG PS 0 1 2 17 7 5 58 24 18 Smoking Yes No 21 8 72 28 HPV status Yes No 2 3 40 60 Staging I II III IV 1 2 10 16 3 7 34 55 Primary disease location Oral cavity Oropharynx Larynx Hypopharynx 17 4 1 7 59 14 3 24 CPS Unknown = 20 5 6 9 8 17 21 31 28 Disease status Locoregional recurrence only Metastasis 20 9 69 31 Platinum refractory* Yes No 17 12 59 41 Lines of treatment prior receiving combination therapy 0 1 18 11 62 38 Anti-EGFR agent during combined therapy Cetuximab Afatinib 17 12 59 41 Receive chemotherapy during combination therapy Yes No 13 16 45 55 * disease relapse within 6 months after platinum-based therapy CI = confidence interval, CPS = combined positive score, ECOG PS = Eastern Cooperative Oncology Group Performance Status, EGFR = epidermal growth factor receptor, HPV = human papilloma virus 3.2 Efficacy A total of 29 patients were evaluable for response. The best overall response for each patient is illustrated in the waterfall plot (Figure 2). As summarized in Table 2, 3 patients (10%) achieved CR, 10 (34%) achieved PR, 6 (22%) had stable disease (SD), and 10 (34%) experienced progressive disease (PD). The ORR was 44% (95% CI: 26%–64%), and the DCR was 66% (95% CI: 46%–82%). Objective responses stratified by CPS group are presented in Table 3. CPS data were available for 25 patients. When stratified by CPS expression, responses were distributed as follows: in the CPS <1 group (n=8), 1 patient achieved CR and 2 achieved PR; in the CPS 1–19 group (n=8), there was 1 CR and 3 PRs; and in the CPS ≥20 group (n=9), 1 CR and 3 PRs were observed. Notably, all three patients who achieved CR had primary tumors located in the oral cavity, with CPS scores of 0, 2.3, and 82, respectively. These three patients received combination therapy with pembrolizumab and cetuximab as first-line systemic treatment for R/M HNSCC. Two of them also received concomitant chemotherapy consisting of cisplatin, fluorouracil, and leucovorin. Figure 2. Waterfall Plot of Best Tumor Size Change from Baseline Each bar represents an individual patient's best percentage change in tumor size from baseline. Positive values indicate tumor growth, while negative values indicate tumor shrinkage. The dotted lines represent the thresholds for progressive disease (≥20% increase) and partial response (≥30% decrease) based on RECIST v1.1 criteria. Patients with tumor progression are shown in red, those with stable disease in black, those with tumor reduction meeting the criteria for partial response in blue, and those with complete remission in green. Asterisks (*) indicate patients who had tumor progression with new lesions. Table 2. Treatment response Total population (n=29) Best overall response, No. (%) CR PR SD PD 3 (10%) 10 (34%) 6 (22%) 10 (34%) Objective response rate, No. (%) 95% confidence interval, % 13 (44%) 26%-64% Disease control rate, No. (%) 95% confidence interval, % 19 (66%) 46%-82% CR = complete remission, PD = progressive disease, PR = partial response, SD = stable disease Table 3 PD-L1 status and treatment response CR PR SD PD PD-L1 status, CPS (n= 25) < 1 1-19 ≥ 20 1 1 1 2 3 3 2 2 2 3 2 3 CPS = combined positive score, PD = progressive disease, PR = partial response, SD = stable disease, TPS = tumor proportion score At the time of data cutoff, 15 patients (51%) had died, while the remaining patients were still alive. 8 (28%) patients remained on combination therapy. Treatment was discontinued in 19 patients due to disease progression and in 2 patients due to withdrawal of patient preference. The median PFS was 6.9 months (95% CI: 2.9–9.2 months), and the median OS was 15.1 months (95% CI: 8.4 months–not reached). Kaplan-Meier curves for PFS and OS are illustrated in Figures 3 and 4. Among the 13 responders, the median DOR was 8.51 months (95% CI: 6.17–18.20 months). Univariate analysis identified no significant associations between clinicopathological factors and OS (Table 4). Figure 3. Kaplan-Meier Estimates of Progression Free Survival. Kaplan-Meier survival curves illustrating progression-free survival in patients treated with immunotherapy plus anti-EGFR therapy. Figure 4. Kaplan-Meier Estimates of Overall survival. Kaplan-Meier survival curves illustrating overall survival in patients treated with immunotherapy plus anti-EGFR therapy. Table 4. Univariate analysis Clinicopathologic factors Hazard ratio 95% CI p Smoking Yes No 6.20 REF 1.38-36.85 0.08 Primary site Oral cavity Non-oral cavity 1.90 REF 0.64-5.61 0.25 Disease status Metastasis Locoregional recurrence only 1.05 REF 0.33-3.35 0.93 Platinum refractory Yes No 0.88 REF 0.31-2.48 0.80 Previous systemic treatment ≥ 1 0 0.76 REF 0.26-2.17 0.60 Chemotherapy during combination therapy Yes No 1.67 REF 0.60-4.62 0.32 CPS ≥ 20 < 20 0.62 REF 0.19-2.05 0.43 3.3 Safety As summarized in Table 5, treatment-related adverse events were reported in 23 (79%) of the 29 patients. All observed adverse events were grade 1 or 2 in severity; no grade 3 or higher events were recorded. The most common hematologic toxicity was anemia (41%), followed by leukopenia (24%). Among non-hematologic toxicities, nausea and vomiting (21%), mucositis (21%), and hyponatremia (21%) were the most frequently observed. Grade 2 events included anemia (24%), weight loss (10%), diarrhea (10%), leukopenia (6%), mucositis (6%), and pneumonitis (3%). No treatment-related deaths occurred, and no adverse event resulted in treatment discontinuation in this study Table 5. Treatment related adverse events Total population (n = 29) Grade 1 Grade 2 Incidence (%) Blood and lymphatic system disorders Anemia Leukopenia Thrombocytopenia 5 5 2 7 2 0 41.4% 24.1% 6.9% Endocrine disorders Hypothyroidism 1 0 3.4% Gastrointestinal disorders Diarrhea Nausea/Vomiting Mucositis 0 5 4 3 1 2 10.3% 20.7% 20.7% Metabolism and electrolyte Hypokalemia Hyponatremia Liver function impairment 2 6 3 0 0 0 6.9% 20.7% 10.3% Constitutional / Others Weight loss Acne / Skin rash Pneumonitis Dysgeusia Decreased appetite 1 4 1 2 2 3 0 1 0 1 13.8% 13.8% 6.9% 6.9% 10.3% Discussion In our study, the combination regimen demonstrated promising efficacy, achieving an ORR of 44% and a DCR of 66%. The median PFS was 6.9 months, the median OS was 15.1 months, and the median DoR was 8.51 months. In comparison, the pivotal KEYNOTE-048 trial reported an ORR of approximately 17–23% and a median OS of 12 months for pembrolizumab monotherapy, while the pembrolizumab-chemotherapy arm yielded an ORR of 36–43% and a median OS of 13 months [ 7 ]. Our results compare favorably with these historical controls, demonstrating numerically higher ORR and prolonged OS. It is worth noting that our cohort possessed less favorable baseline characteristics than the KEYNOTE-048 population. Specifically, only 59% of our patients had a PD-L1 CPS ≥ 1, compared with 85% in KEYNOTE-048. Furthermore, our study included a substantial proportion of patients with platinum-refractory disease (59%) and those receiving treatment in the second-line setting or beyond (38%)—subgroups historically associated with significantly poorer clinical outcomes. Several Phase II studies have previously explored the synergy between immunotherapy and anti-EGFR blockade, demonstrating ORRs of 35–50% and median OS durations of 10–15 months [ 13 – 15 ]. Our real-world results align closely with these benchmarks, confirming that the efficacy observed in controlled clinical trials is reproducible in routine clinical practice. Of particular note is the efficacy observed in the CPS < 1 subgroup, where an ORR of 37.5% and a DCR of 62.5% were achieved, consisting of one CR, two PR, and two SD. Historically, immunotherapy response rates in this population have ranged from 10% to 30%. [ 3 , 7 , 16 ] Consequently, our findings suggest that this combination regimen may help circumvent the limitations associated with low PD-L1 expression and offer additional clinical benefit to this subgroup. Immunotherapy and anti-EGFR agents are generally regarded as relatively safe treatment options. Mucosal inflammation and rash are the most common adverse event related to anti-EGFR agents and most are self-limited [ 17 ]. Nonetheless, immunotherapy-related adverse events (iRAEs) represent a significant clinical concern due to its potential severity and impact on patient outcomes, especially pneumonitis. Previous studies in lung cancer have explored the potential toxicity associated with the combination of immunotherapy and EGFR tyrosine kinase inhibitors (TKIs), reporting iRAEs occurred in approximately 30% of patients [ 18 , 19 ]. In another phase II study, there was one patient (3.4%) experienced a Grade 2 treatment-related pneumonitis event [ 14 ]. In our study, there was also one patient experienced grade 2 pneumonitis but no grade 3 or higher adverse event report and no adverse events led to treatment discontinuation. This study has several limitations. First, the small sample size may have contributed to increased variability and a higher risk of false-negative findings. Larger prospective studies are warranted to validate these results. Additionally, 38% of the patients had received combination therapy as second line treatment, and 59% were platinum-refractory. Both factors are associated with poor prognosis and reduced survival outcomes. Therefore, the efficacy of combination therapy warrants further investigation in treatment-naïve or platinum-sensitive populations. Lastly, as this was a retrospective analysis, patients had undergone various treatments prior to receiving combination therapy, potentially introducing heterogeneity and bias. A randomized controlled trial is needed to more definitively assess the efficacy of combination therapy in patients with immunotherapy-refractory RM HNSCC. Improving overall survival in patients with R/M HNSCC remains a substantial clinical challenge. This study evaluated the efficacy of combining immunotherapy with anti-EGFR agents in patients with R/M HNSCC. The results demonstrated that an objective response can be achieved with combination therapy. Furthermore, the safety profile of the regimen was acceptable, with no severe treatment-related adverse events observed. These findings suggested that the combination of immunotherapy and anti-EGFR agents may represent a viable therapeutic strategy for patients with R/M HNSCC. Abbreviations - HNSCC Head and neck squamous cell carcinoma - R/M HNSCC Recurrent and/or metastatic head and neck squamous cell carcinoma - EGFR Epidermal growth factor receptor - ICI Immune checkpoint inhibitor - PD-1 Programmed cell death protein 1 - PD-L1 Programmed death-ligand 1 - CT Computed tomography - MRI Magnetic resonance imaging - RECIST Response Evaluation Criteria in Solid Tumors - ORR Objective response rate - DCR Disease control rate - PFS Progression-free survival - OS Overall survival - HR Hazard ratio - CI Confidence interval - AEs Adverse events - IRB Institutional Review Board - CPS Combined positive score - TKI Tyrosine kinase inhibitor - mAb Monoclonal antibody Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Taipei Veterans General Hospital (IRB number: 2024-01-016BC). The requirement for informed consent was waived by the IRB of Taipei Veterans General Hospital due to the retrospective nature of the study. Consent for publication Not applicable Funding Not applicable. Author Contribution MHY and PMHC conceived the study. THC collected and analyzed the data. YCC wrote the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. Pfister DG, et al. Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw J Natl Compr Canc Netw. 2020;18(7):873–98. Cohen EEW, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156–67. Ferris RL. Immunology and Immunotherapy of Head and Neck Cancer. J Clin Oncol. 2015;33(29):3293–304. Siu LL, et al. Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial. JAMA Oncol. 2019;5(2):195–203. Ferris RL, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856–67. Burtness B, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915–28. Machiels JP, et al. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1462–75. Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20(1):25–39. Lizotte PH, et al. A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing. Cancer Immunol Res. 2018;6(12):1511–23. Trotta AM, et al. Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy. Cancer Immunol Res. 2016;4(4):366–74. Ferris RL, et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev. 2018;63:48–60. Chung CH, et al. Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2022;28(11):2329–38. Kao HF, et al. Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase II Study with Biomarker Analysis. Clin Cancer Res. 2022;28(8):1560–71. Sacco AG, et al. Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet Oncol. 2021;22(6):883–92. Ferris Robert L et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375(19): pp. 1856–67. Stanbouly D, et al. Adverse events secondary to cetuximab therapy in head & neck cancer therapy and risk factors for serious outcomes. Oral Oncol. 2022;131:105952. Yang JC, et al. Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation. J Thorac Oncol. 2019;14(3):553–9. Yang JC, et al. Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report. J Thorac Oncol. 2019;14(5):933–9. Additional Declarations No competing interests reported. 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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-9000074","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":630471557,"identity":"27dca780-8a8e-48df-8902-cfe97e14ea17","order_by":0,"name":"Yun-Chien Chang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yun-Chien","middleName":"","lastName":"Chang","suffix":""},{"id":630471559,"identity":"df948eba-1c9e-4e43-80d4-f2264ab03339","order_by":1,"name":"Tien-Hua Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYFAC5oYPUBbjAyDBw0dYC2PjDJhmA5AWNlK0sEmASUIa5GckNjbz7tkmZ3D+8LHKrzl2MmwMzA8f3cCjxeAGUAvPs9vGBjfS0m7LbksGOozN2DgHnxaJxPbHPAduJ264wWN2W3IbM1ALD5s0Pi1gh4G1nD//rVhyWz1hLQw3YFoO5LAxftx2mLAWgzMPGxvnHLhtLHkjzViacdtxHjZmAn6Rb08+2PDmwG05vvOHH378ua3anp+9+eFjvA5DBsw8YJJY5SDA+IMU1aNgFIyCUTBiAABrO0ym0W208AAAAABJRU5ErkJggg==","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tien-Hua","middleName":"","lastName":"Chen","suffix":""},{"id":630471561,"identity":"d33c448c-6d41-4384-a1ce-a222d4c405d9","order_by":2,"name":"Peter Mu-Hsin Chang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"Mu-Hsin","lastName":"Chang","suffix":""},{"id":630471564,"identity":"5d3dab9d-decf-4216-843b-854848966a1f","order_by":3,"name":"Muh-Hwa Yang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Muh-Hwa","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2026-03-01 08:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9000074/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9000074/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108072742,"identity":"8999e1e3-d010-4747-bc2a-64054f1f2859","added_by":"auto","created_at":"2026-04-29 06:15:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":50412,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient Enrollment Flowchart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 353 patients received anti-EGFR therapy and 237 patients received immunotherapy between January 2020 and July 2024. Among them, 38 patients had received both immunotherapy and anti-EGFR therapy. After reviewing their medical history, 4 patients were excluded due to mortality within one month and 5 patients were excluded due to lost follow up. Ultimately, 29 patients who received combination therapy were included in the study.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9000074/v1/096e2172d744e10646e0373a.png"},{"id":108181462,"identity":"b96ec949-143a-4b76-b4c8-6f767057ef92","added_by":"auto","created_at":"2026-04-30 08:58:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45090,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWaterfall Plot of Best Tumor Size Change from Baseline\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach bar represents an individual patient's best percentage change in tumor size from baseline. Positive values indicate tumor growth, while negative values indicate tumor shrinkage. The dotted lines represent the thresholds for progressive disease (≥20% increase) and partial response (≥30% decrease) based on RECIST v1.1 criteria. Patients with tumor progression are shown in red, those with stable disease in black, those with tumor reduction meeting the criteria for partial response in blue, and those with complete remission in green. Asterisks (*) indicate patients who had tumor progression with new lesions.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9000074/v1/4b0320a3a3558db821073257.png"},{"id":108181149,"identity":"a9d80941-0012-41b3-bdab-21cc836d400f","added_by":"auto","created_at":"2026-04-30 08:57:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":61479,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Estimates of Progression Free Survival.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier survival curves illustrating progression-free survival in patients treated with immunotherapy plus anti-EGFR therapy.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-9000074/v1/151fffadb2630ebf5f97e79f.png"},{"id":108072745,"identity":"f21b2d40-1a30-4e6e-a0b7-45430392ee6b","added_by":"auto","created_at":"2026-04-29 06:15:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":60482,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Estimates of Overall survival.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier survival curves illustrating overall survival in patients treated with immunotherapy plus anti-EGFR therapy.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-9000074/v1/f917d8d6877e9aa96736088c.png"},{"id":108183776,"identity":"72247397-9eaf-4b33-857c-7855643efcf9","added_by":"auto","created_at":"2026-04-30 09:02:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":555106,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9000074/v1/9e931cba-aa54-4b23-b884-37a921591dd5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Combination of immunotherapy and anti-EGFR agents in immunotherapy refractory head neck cancer recurrent and metastatic head neck squamous cell carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHead and neck squamous cell carcinoma (HNSCC) represents a significant global health burden, contributing substantially to cancer-related morbidity and mortality, with more than 600,000 new cases diagnosed each year worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) develops in over 50% of patients with locoregionally advanced disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. R/M HNSCC are partially driven by immune evasion mechanisms. A key factor in this process is the expression of programmed death ligands (PD-L1), which bind to the programmed death 1 (PD-1) receptor and suppress T-cell activity through immune checkpoint pathways.\u003c/p\u003e \u003cp\u003eImmune checkpoint inhibitors have demonstrated significant efficacy and manageable safety profiles in HNSCC [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The pivotal CheckMate-141 and KEYNOTE-040 trials showed that anti-PD1 monoclonal antibodies improved overall survival compared to standard single-agent therapies in patients with R/M HNSCC [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Additionally, the KEYNOTE-048 trial demonstrated that pembrolizumab monotherapy significantly improved overall survival in patients with a combined positive score (CPS)\u0026thinsp;\u0026ge;\u0026thinsp;1, exhibited non-inferiority in the overall study population, and was associated with a more favorable safety profile compared to cetuximab combined with chemotherapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Based on these findings, current guidelines recommend pembrolizumab in combination with platinum and 5-fluorouracil as the first-line treatment for unresectable R/M HNSCC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite these advancements, there is still limited number of patient can gain clinical benefit from immunotherapy, with a median overall survival (OS) about 8 months and a 1-year OS rate of about 40% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Resistance to immunotherapy has been attributed to mechanisms such as loss of IFNγ signaling and impaired antigen presentation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Interestingly, preclinical studies have demonstrated that epidermal growth factor receptor (EGFR) pathway inhibition enhances antigen presentation and augments the efficacy of immunotherapy [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Mechanistically, cetuximab induces antibody-dependent cellular cytotoxicity (ADCC), leading to the lysis of tumor cells by natural killer (NK) cells. This process facilitates the cross-priming of cytotoxic CD8\u0026thinsp;+\u0026thinsp;T cells by activated dendritic cells. Furthermore, activated NK cells secrete IFNγ alongside other proinflammatory cytokines and chemokines, thereby remodeling the tumor microenvironment to favor immune cell recruitment and activation.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSeveral phase II studies have indicated that adding anti-EGFR agents to immunotherapy may augment efficacy and improve overall response rates in patients with platinum-refractory R/M HNSCC [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, real-world data regarding this combination strategy remain scarce. Therefore, we conducted a retrospective study to evaluate the efficacy of combining anti-EGFR agents with immunotherapy in a real-world clinical setting.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and participants\u003c/h2\u003e \u003cp\u003eWe retrospectively identified patients at Taipei Veterans General Hospital diagnosed with R/M HNSCC between January 2020 and July 2024. Patients who received a combination of immunotherapy and anti-EGFR agents were selected for further analysis.\u003c/p\u003e \u003cp\u003eClinical characteristics of these patients were systematically recorded, including sex, age, Eastern Cooperative Oncology Group (ECOG) performance status, smoking history, HPV status, initial tumor staging, primary tumor location, PD-L1 expression, disease status (locoregional recurrence only vs. metastatic disease), prior immunotherapy regimen, platinum-refractory status, number of prior systemic treatment lines, type of anti-EGFR agent used during combination therapy, and whether chemotherapy was included in the combination regimen. According to current clinical guidelines, human papilloma virus (HPV) status is assessed exclusively in cases of oropharyngeal cancer and is determined through immunohistochemical staining for p16 as a surrogate marker. Initial tumor staging was classified according to the American Joint Committee on Cancer (AJCC) staging system (seventh edition). Primary tumor locations were categorized as the oral cavity, oropharynx, larynx, and hypopharynx. PD-L1 expression was assessed using the PD-L1 combined positive score (CPS) via the PD-L1 28\u0026thinsp;\u0026minus;\u0026thinsp;8 and 22C3 immunohistochemistry assays. Based on the KEYNOTE-048 study, CPS was categorized into 3 groups: \u0026lt;1, 1\u0026ndash;19, and \u0026ge;\u0026thinsp;20. Platinum-refractory disease was defined as disease relapse occurring within six months of platinum-based therapy. This study was approved by the Institutional Review Board (IRB) and Ethics Committee of Taipei Veterans General Hospital. Details of ethics approval are provided in the Declarations section.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Outcomes\u003c/h2\u003e \u003cp\u003eThe primary endpoint of this study was the objective response rate (ORR), defined as the proportion of patients who achieved a complete response (CR) or partial response (PR), as assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\u003c/p\u003e \u003cp\u003eSeveral secondary endpoints were evaluated, including the disease control rate (DCR), defined as the percentage of patients who achieved CR, PR or stable disease (SD); progression-free survival (PFS), defined as the duration from the initiation of combination therapy to disease progression (PD); Additionally, the duration of response (DoR) was assessed, defined as the time from the initiation of combination therapy to PD in patients who achieved an objective response.\u003c/p\u003e \u003cp\u003eAdverse events and laboratory abnormalities were systematically documented throughout the treatment period and graded according to the National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were conducted using GraphPad Prism version 8.0.1. The ORR and DCR were reported as percentages with 95% confidence intervals (CIs). OS and PFS were estimated using the Kaplan-Meier method, with median OS, median PFS, and their respective 95% CIs presented. For OS estimation, patients who were still alive at the end of the study or lost to follow-up were censored at the time of their last medical visit. For PFS estimation, patients without disease progression at the end of the study or lost to follow-up were censored at the time of their last tumor imaging. To identify prognostic factors associated with OS, a univariate Cox proportional hazards model was applied to clinicopathologic variables, including ECOG performance status, smoking history, primary tumor site, initial tumor staging, number of prior systemic treatments, and PD-L1 CPS. Variables with an insufficient number of cases in the comparison groups were excluded from univariate analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs depicted in Figure 1, between January 1, 2020, and July 31, 2024, a total of 353 and 237 patients underwent anti-EGFR therapy and immunotherapy, respectively. Cross-referencing these cohorts identified 38 individuals who received concurrent treatment. Nine patients were subsequently excluded due to mortality within one month (n=4) or loss to follow-up (n=5). Ultimately, the final cohort comprised 29 patients with R/M HNSCC treated with the combination regimen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1. Patient Enrollment Flowchart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 353 patients received anti-EGFR therapy and 237 patients received immunotherapy between January 2020 and July 2024. Among them, 38 patients had received both immunotherapy and anti-EGFR therapy. After reviewing their medical history, 4 patients were excluded due to mortality within one month and 5 patients were excluded due to lost follow up. Ultimately, 29 patients who received combination therapy were included in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBaseline demographics and disease characteristics are summarized in Table 1. The cohort had a median age of 60.8 years, with a male predominance (90%) and the majority of patients having an ECOG performance status of 0\u0026ndash;1 (82%). A history of smoking was reported in 72% of patients. Most participants presented with stage III or IV disease (89%), and primary tumors were predominantly located in the oral cavity or oropharynx (73%). Among the five patients evaluated for HPV status, three were positive. Distant metastases were present in 9 patients (31%), and 17 patients (59%) had a PD-L1 combined positive score (CPS) of \u0026ge;1. Notably, 59% of the cohort had platinum-refractory disease, and 38% received the combination regimen as a second-line treatment. Cetuximab was the most common anti-EGFR agent (59%), and chemotherapy was not incorporated into the combination regimen in 16 patients (55%)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal population\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge, y/o (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e60.8 (56.4-65.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Female\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;male\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG PS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;0\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHPV status\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaging\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;I\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;II\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;III\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary disease location\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Oral cavity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Oropharynx\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Larynx\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Hypopharynx\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCPS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Unknown\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1-19\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026gt;= 20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease status\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Locoregional recurrence only\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatinum refractory*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLines of treatment prior receiving combination therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;0\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnti-EGFR agent during combined therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Cetuximab\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Afatinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReceive chemotherapy during combination therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* disease\u0026nbsp;relapse within 6 months after platinum-based therapy\u003c/p\u003e\n\u003cp\u003eCI = confidence interval, CPS = combined positive score, ECOG PS = Eastern Cooperative Oncology Group Performance Status, EGFR = epidermal growth factor receptor, HPV = human papilloma virus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Efficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 29 patients were evaluable for response. The best overall response for each patient is illustrated in the waterfall plot (Figure 2). As summarized in Table 2, 3 patients (10%) achieved CR, 10 (34%) achieved PR, 6 (22%) had stable disease (SD), and 10 (34%) experienced progressive disease (PD). The ORR was 44% (95% CI: 26%\u0026ndash;64%), and the DCR was 66% (95% CI: 46%\u0026ndash;82%). Objective responses stratified by CPS group are presented in Table 3. CPS data were available for 25 patients. When stratified by CPS expression, responses were distributed as follows: in the CPS \u0026lt;1 group (n=8), 1 patient achieved CR and 2 achieved PR; in the CPS 1\u0026ndash;19 group (n=8), there was 1 CR and 3 PRs; and in the CPS \u0026ge;20 group (n=9), 1 CR and 3 PRs were observed. Notably, all three patients who achieved CR had primary tumors located in the oral cavity, with CPS scores of 0, 2.3, and 82, respectively. These three patients received combination therapy with pembrolizumab and cetuximab as first-line systemic treatment for R/M HNSCC. Two of them also received concomitant chemotherapy consisting of cisplatin, fluorouracil, and leucovorin.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2. Waterfall Plot of Best Tumor Size Change from Baseline\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach bar represents an individual patient\u0026apos;s best percentage change in tumor size from baseline. Positive values indicate tumor growth, while negative values indicate tumor shrinkage. The dotted lines represent the thresholds for progressive disease (\u0026ge;20% increase) and partial response (\u0026ge;30% decrease) based on RECIST v1.1 criteria. Patients with tumor progression are shown in red, those with stable disease in black, those with tumor reduction meeting the criteria for partial response in blue, and those with complete remission in green. Asterisks (*) indicate patients who had tumor progression with new lesions.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment response\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 270px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 270px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal population\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBest overall response, No. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;CR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;PR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;PD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 270px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (10%)\u003c/p\u003e\n \u003cp\u003e10 (34%)\u003c/p\u003e\n \u003cp\u003e6 (22%)\u003c/p\u003e\n \u003cp\u003e10 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObjective response rate, No. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;95% confidence interval, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 270px;\"\u003e\n \u003cp\u003e13 (44%)\u003c/p\u003e\n \u003cp\u003e26%-64%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease control rate, No. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;95% confidence interval, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 270px;\"\u003e\n \u003cp\u003e19 (66%)\u003c/p\u003e\n \u003cp\u003e46%-82%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCR = complete remission, PD = progressive disease, PR = partial response, SD = stable disease\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 554px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePD-L1 status and treatment response\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePD-L1 status, CPS (n= 25)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026lt; 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;1-19\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCPS = combined positive score, PD = progressive disease, PR = partial response, SD = stable disease, TPS = tumor proportion score\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt the time of data cutoff, 15 patients (51%) had died, while the remaining patients were still alive. 8 (28%) patients remained on combination therapy. Treatment was discontinued in 19 patients due to disease progression and in 2 patients due to withdrawal of patient preference. The median PFS was 6.9 months (95% CI: 2.9\u0026ndash;9.2 months), and the median OS was 15.1 months (95% CI: 8.4 months\u0026ndash;not reached). Kaplan-Meier curves for PFS and OS are illustrated in Figures 3 and 4. Among the 13 responders, the median DOR was 8.51 months (95% CI: 6.17\u0026ndash;18.20 months). Univariate analysis identified no significant associations between clinicopathological factors and OS (Table 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3. Kaplan-Meier Estimates of Progression Free Survival.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier survival curves illustrating progression-free survival in patients treated with immunotherapy plus anti-EGFR therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4. Kaplan-Meier Estimates of Overall survival.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier survival curves illustrating overall survival in patients treated with immunotherapy plus anti-EGFR therapy.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinicopathologic factors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHazard ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6.20\u003c/p\u003e\n \u003cp\u003eREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.38-36.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary site\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Oral cavity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Non-oral cavity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.90\u003c/p\u003e\n \u003cp\u003eREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.64-5.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease status\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Locoregional recurrence only\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003cp\u003eREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.33-3.35\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatinum refractory\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003cp\u003eREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.31-2.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious systemic treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u0026ge; 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003cp\u003eREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.26-2.17\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy during combination therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.67\u003c/p\u003e\n \u003cp\u003eREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.60-4.62\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCPS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026ge; 20\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026lt; 20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003cp\u003eREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.19-2.05\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e3.3 Safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs summarized in Table 5, treatment-related adverse events were reported in 23 (79%) of the 29 patients. All observed adverse events were grade 1 or 2 in severity; no grade 3 or higher events were recorded. The most common hematologic toxicity was anemia (41%), followed by leukopenia (24%). Among non-hematologic toxicities, nausea and vomiting (21%), mucositis (21%), and hyponatremia (21%) were the most frequently observed. Grade 2 events included anemia (24%), weight loss (10%), diarrhea (10%), leukopenia (6%), mucositis (6%), and pneumonitis (3%). No treatment-related deaths occurred, and no adverse event resulted in treatment discontinuation in this study\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 582px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment related adverse events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 346px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal population (n = 29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIncidence (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBlood and lymphatic system disorders\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAnemia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLeukopenia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eThrombocytopenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e41.4%\u003c/p\u003e\n \u003cp\u003e24.1%\u003c/p\u003e\n \u003cp\u003e6.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndocrine disorders\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHypothyroidism\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastrointestinal disorders\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDiarrhea\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNausea/Vomiting\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMucositis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10.3%\u003c/p\u003e\n \u003cp\u003e20.7%\u003c/p\u003e\n \u003cp\u003e20.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetabolism and electrolyte\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHypokalemia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHyponatremia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLiver function impairment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6.9%\u003c/p\u003e\n \u003cp\u003e20.7%\u003c/p\u003e\n \u003cp\u003e10.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConstitutional / Others\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eWeight loss\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAcne / Skin rash\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePneumonitis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDysgeusia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDecreased appetite\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13.8%\u003c/p\u003e\n \u003cp\u003e13.8%\u003c/p\u003e\n \u003cp\u003e6.9%\u003c/p\u003e\n \u003cp\u003e6.9%\u003c/p\u003e\n \u003cp\u003e10.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, the combination regimen demonstrated promising efficacy, achieving an ORR of 44% and a DCR of 66%. The median PFS was 6.9 months, the median OS was 15.1 months, and the median DoR was 8.51 months. In comparison, the pivotal KEYNOTE-048 trial reported an ORR of approximately 17\u0026ndash;23% and a median OS of 12 months for pembrolizumab monotherapy, while the pembrolizumab-chemotherapy arm yielded an ORR of 36\u0026ndash;43% and a median OS of 13 months [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our results compare favorably with these historical controls, demonstrating numerically higher ORR and prolonged OS.\u003c/p\u003e \u003cp\u003eIt is worth noting that our cohort possessed less favorable baseline characteristics than the KEYNOTE-048 population. Specifically, only 59% of our patients had a PD-L1 CPS\u0026thinsp;\u0026ge;\u0026thinsp;1, compared with 85% in KEYNOTE-048. Furthermore, our study included a substantial proportion of patients with platinum-refractory disease (59%) and those receiving treatment in the second-line setting or beyond (38%)\u0026mdash;subgroups historically associated with significantly poorer clinical outcomes.\u003c/p\u003e \u003cp\u003eSeveral Phase II studies have previously explored the synergy between immunotherapy and anti-EGFR blockade, demonstrating ORRs of 35\u0026ndash;50% and median OS durations of 10\u0026ndash;15 months [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Our real-world results align closely with these benchmarks, confirming that the efficacy observed in controlled clinical trials is reproducible in routine clinical practice.\u003c/p\u003e \u003cp\u003eOf particular note is the efficacy observed in the CPS\u0026thinsp;\u0026lt;\u0026thinsp;1 subgroup, where an ORR of 37.5% and a DCR of 62.5% were achieved, consisting of one CR, two PR, and two SD. Historically, immunotherapy response rates in this population have ranged from 10% to 30%. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] Consequently, our findings suggest that this combination regimen may help circumvent the limitations associated with low PD-L1 expression and offer additional clinical benefit to this subgroup.\u003c/p\u003e \u003cp\u003eImmunotherapy and anti-EGFR agents are generally regarded as relatively safe treatment options. Mucosal inflammation and rash are the most common adverse event related to anti-EGFR agents and most are self-limited [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Nonetheless, immunotherapy-related adverse events (iRAEs) represent a significant clinical concern due to its potential severity and impact on patient outcomes, especially pneumonitis. Previous studies in lung cancer have explored the potential toxicity associated with the combination of immunotherapy and EGFR tyrosine kinase inhibitors (TKIs), reporting iRAEs occurred in approximately 30% of patients [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In another phase II study, there was one patient (3.4%) experienced a Grade 2 treatment-related pneumonitis event [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our study, there was also one patient experienced grade 2 pneumonitis but no grade 3 or higher adverse event report and no adverse events led to treatment discontinuation.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the small sample size may have contributed to increased variability and a higher risk of false-negative findings. Larger prospective studies are warranted to validate these results. Additionally, 38% of the patients had received combination therapy as second line treatment, and 59% were platinum-refractory. Both factors are associated with poor prognosis and reduced survival outcomes. Therefore, the efficacy of combination therapy warrants further investigation in treatment-na\u0026iuml;ve or platinum-sensitive populations. Lastly, as this was a retrospective analysis, patients had undergone various treatments prior to receiving combination therapy, potentially introducing heterogeneity and bias. A randomized controlled trial is needed to more definitively assess the efficacy of combination therapy in patients with immunotherapy-refractory RM HNSCC.\u003c/p\u003e \u003cp\u003eImproving overall survival in patients with R/M HNSCC remains a substantial clinical challenge. This study evaluated the efficacy of combining immunotherapy with anti-EGFR agents in patients with R/M HNSCC. The results demonstrated that an objective response can be achieved with combination therapy. Furthermore, the safety profile of the regimen was acceptable, with no severe treatment-related adverse events observed. These findings suggested that the combination of immunotherapy and anti-EGFR agents may represent a viable therapeutic strategy for patients with R/M HNSCC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- HNSCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHead and neck squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- R/M HNSCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRecurrent and/or metastatic head and neck squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- EGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEpidermal growth factor receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- ICI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmune checkpoint inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- PD-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgrammed cell death protein 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- PD-L1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgrammed death-ligand 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- CT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- MRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- RECIST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResponse Evaluation Criteria in Solid Tumors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- ORR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- DCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDisease control rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- PFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- OS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- HR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- CI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- AEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- IRB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInstitutional Review Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- CPS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCombined positive score\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- TKI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTyrosine kinase inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e- mAb\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMonoclonal antibody\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Taipei Veterans General Hospital (IRB number: 2024-01-016BC). The requirement for informed consent was waived by the IRB of Taipei Veterans General Hospital due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eMHY and PMHC conceived the study. THC collected and analyzed the data. YCC wrote the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFerlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePfister DG, et al. Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw J Natl Compr Canc Netw. 2020;18(7):873\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen EEW, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerris RL. Immunology and Immunotherapy of Head and Neck Cancer. J Clin Oncol. 2015;33(29):3293\u0026ndash;304.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiu LL, et al. 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Cancer Immunol Res. 2016;4(4):366\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerris RL, et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev. 2018;63:48\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung CH, et al. Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2022;28(11):2329\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKao HF, et al. Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase II Study with Biomarker Analysis. Clin Cancer Res. 2022;28(8):1560\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSacco AG, et al. Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet Oncol. 2021;22(6):883\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerris Robert L et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375(19): pp. 1856\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStanbouly D, et al. Adverse events secondary to cetuximab therapy in head \u0026amp; neck cancer therapy and risk factors for serious outcomes. Oral Oncol. 2022;131:105952.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang JC, et al. Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation. J Thorac Oncol. 2019;14(3):553\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang JC, et al. Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report. J Thorac Oncol. 2019;14(5):933\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9000074/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9000074/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eImmunotherapy has become a standard treatment for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC); however, response rates remain modest, and long-term survival is limited. Preclinical studies suggest that inhibiting the epidermal growth factor receptor (EGFR) pathway may enhance antigen presentation and augment the efficacy of immune checkpoint inhibitors. This study evaluated the real-world efficacy and safety of combining immunotherapy with anti-EGFR agents in patients with R/M HNSCC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective study at Taipei Veterans General Hospital involving patients diagnosed with R/M HNSCC between January 2020 and July 2024 who received combination therapy comprising immunotherapy and anti-EGFR agents. The primary endpoint was the objective response rate (ORR) according to RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety assessed by CTCAE v5.0.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 29 patients were included in the analysis. The cohort was characterized by a high proportion of platinum-refractory disease (59%) and 38% of patients received the combination as second-line treatment or later. The ORR was 44% (95% CI: 26%\u0026ndash;64%), including 3 complete responses (10%) and 10 partial responses (34%). The DCR was 66%. The median PFS was 6.9 months (95% CI: 2.9\u0026ndash;9.2), and the median OS was 15.1 months (95% CI: 8.4\u0026ndash;not reached). Notably, in the subgroup with a PD-L1 combined positive score (CPS)\u0026thinsp;\u0026lt;\u0026thinsp;1, the ORR was 37.5%. Treatment-related adverse events occurred in 79% of patients but were exclusively Grade 1 or 2; no Grade 3 or higher adverse events were observed.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe combination of immunotherapy and anti-EGFR agents demonstrated promising antitumor activity and a favorable safety profile in patients with R/M HNSCC. These findings suggest this regimen may be a viable therapeutic strategy, particularly for patients with platinum-refractory disease or low PD-L1 expression who traditionally have poor outcomes.\u003c/p\u003e","manuscriptTitle":"Combination of immunotherapy and anti-EGFR agents in immunotherapy refractory head neck cancer recurrent and metastatic head neck squamous cell carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 06:15:13","doi":"10.21203/rs.3.rs-9000074/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-29T07:00:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-27T15:25:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-26T12:30:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-25T16:13:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323577680233459649694494106739614996389","date":"2026-04-23T03:25:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223250702980429183979446129623671449322","date":"2026-04-22T22:44:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"140287751889282807683899522598678488926","date":"2026-04-20T15:19:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-20T14:31:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-17T13:05:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-17T07:38:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-03-13T11:16:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0eccdca9-20d7-4743-8382-9e0a253c922e","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T07:11:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 06:15:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9000074","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9000074","identity":"rs-9000074","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}