Cetuximab and immune checkpoint inhibitors treatments in recurrent/metastatic head and neck squamous cell carcinoma

Cetuximab and immune checkpoint inhibitors treatments in recurrent/metastatic head and neck squamous cell carcinoma | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 6 May 2025 V1 Latest version Share on Cetuximab and immune checkpoint inhibitors treatments in recurrent/metastatic head and neck squamous cell carcinoma Authors : Yu-Ming Wang , Sheng-Dean Luo , Ching-Nung Wu , Shao‑Chun Wu , Wei-Chih Chen , Yao-Hsu Yang , Jin-Ching Lee , and Tai-Jan Chiu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174651326.67245140/v1 185 views 140 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) presents significant therapeutic challenges. While cetuximab (EGFR inhibitor) and immune checkpoint inhibitors (ICIs) have improved outcomes, optimal treatment sequencing remains undefined. Methods: This retrospective analysis evaluated 822 RMHNSCC patients treated between January 2016 and December 2022 across multiple Taiwanese centers. Patients received either cetuximab monotherapy (n=401), ICI monotherapy (n=248), or sequential therapy with both agents (n=173). Sequential therapy comprised cetuximab followed by ICI (C→I, n=102) or ICI followed by cetuximab (I→C, n=71). Primary endpoint was overall survival (OS), with progression-free survival (PFS), objective response rate (ORR), and adverse events as secondary endpoints. Results: At median follow-up of 31.4 months, ICI monotherapy demonstrated significantly improved median OS versus cetuximab monotherapy (13.2 vs. 9.4 months; hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.61-0.86; p=0.001). Sequential therapy showed median OS of 14.8 months, significantly higher than cetuximab monotherapy (HR 0.68; 95% CI 0.56-0.83; p<0.001) but comparable to ICI monotherapy (HR 0.91; 95% CI 0.74-1.13; p=0.39). The sequence of administration (C→I vs. I→C) did not significantly impact OS (15.1 vs. 14.5 months; HR 0.94; 95% CI 0.67-1.31; p=0.72). Multivariable analysis confirmed these findings after adjusting for confounding factors. Conclusion: Our findings establish ICI therapy’s superior efficacy over cetuximab monotherapy in RMHNSCC patients, aligning with previous clinical trials. Sequential therapy with both agents provides additional clinical benefit regardless of administration sequence. This suggests both approaches (C→I and I→C) are effective options, offering clinicians flexibility in treatment planning based on individual patient characteristics, comorbidities, and treatment history. Further prospective studies are needed to identify biomarkers for optimal treatment selection and sequencing in this challenging population. Cetuximab and immune checkpoint inhibitors treatments in recurrent/metastatic head and neck squamous cell carcinoma Abstract Background: Recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) presents significant therapeutic challenges. While cetuximab (EGFR inhibitor) and immune checkpoint inhibitors (ICIs) have improved outcomes, optimal treatment sequencing remains undefined. Methods: This retrospective analysis evaluated 822 RMHNSCC patients treated between January 2016 and December 2022 across multiple Taiwanese centers. Patients received either cetuximab monotherapy (n=401), ICI monotherapy (n=248), or sequential therapy with both agents (n=173). Sequential therapy comprised cetuximab followed by ICI (C→I, n=102) or ICI followed by cetuximab (I→C, n=71). Primary endpoint was overall survival (OS), with progression-free survival (PFS), objective response rate (ORR), and adverse events as secondary endpoints. Results: At median follow-up of 31.4 months, ICI monotherapy demonstrated significantly improved median OS versus cetuximab monotherapy (13.2 vs. 9.4 months; hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.61-0.86; p=0.001). Sequential therapy showed median OS of 14.8 months, significantly higher than cetuximab monotherapy (HR 0.68; 95% CI 0.56-0.83; p<0.001) but comparable to ICI monotherapy (HR 0.91; 95% CI 0.74-1.13; p=0.39). The sequence of administration (C→I vs. I→C) did not significantly impact OS (15.1 vs. 14.5 months; HR 0.94; 95% CI 0.67-1.31; p=0.72). Multivariable analysis confirmed these findings after adjusting for confounding factors. Conclusion: Our findings establish ICI therapy’s superior efficacy over cetuximab monotherapy in RMHNSCC patients, aligning with previous clinical trials. Sequential therapy with both agents provides additional clinical benefit regardless of administration sequence. This suggests both approaches (C→I and I→C) are effective options, offering clinicians flexibility in treatment planning based on individual patient characteristics, comorbidities, and treatment history. Further prospective studies are needed to identify biomarkers for optimal treatment selection and sequencing in this challenging population. Keywords: Head and neck cancer, immunotherapy, targeted therapy, cetuximab, sequential therapy, PD-1 inhibitors, EGFR inhibitors Summary *Immune checkpoint inhibitors demonstrate superior efficacy over cetuximab monotherapy in recurrent/metastatic HNSCC patients, with median overall survival of 13.2 months versus 9.4 months. *Sequential therapy combining both agents provides additional clinical benefit, achieving a median overall survival of 14.8 months, significantly better than cetuximab alone. *Treatment sequence flexibility is supported by evidence: both cetuximab-followed-by-ICI and ICI-followed-by-cetuximab strategies show comparable outcomes (15.1 vs. 14.5 months). *In the subgroup receiving both agents, primary tumor location in the oropharynx or hypopharynx emerged as independent prognostic factors for improved survival. *This large Taiwanese cohort study uniquely addresses the limited evidence on optimal sequencing of cetuximab and ICIs, providing real-world data to guide treatment decisions in clinical practice. Introduction Head and Neck Squamous Cell Carcinoma (HNSCC) represents a significant global health burden with distinct regional epidemiological patterns, particularly in East Asian countries like Taiwan. HNSCC encompasses malignancies arising from the mucosal epithelium of the upper aerodigestive tract, including the oral cavity, oropharynx, larynx, and hypopharynx. These anatomical sites are crucial for fundamental functions such as speech, swallowing, and respiration, making HNSCC particularly devastating for patients’ quality of life and functional status[1]. The etiology of HNSCC in Taiwan reflects a complex interplay between environmental exposures and genetic factors. While tobacco smoking and alcohol consumption remain universal risk factors, the practice of betel quid chewing is distinctively prevalent in Taiwan and contributes substantially to the region’s HNSCC burden. The areca nut (betel nut) contains numerous carcinogens that induce DNA damage, leading to malignant transformation in the oral mucosa. Concurrently, human papillomavirus (HPV) infection has emerged as a significant etiologic factor, particularly in oropharyngeal cancers. HPV-associated HNSCC presents with distinct molecular profiles, clinical behavior, and generally more favorable prognosis compared to HPV-negative tumors traditionally linked to tobacco and alcohol use[2,3]. This etiologic heterogeneity necessitates tailored therapeutic approaches based on tumor biology and risk factors. Despite advances in multimodality treatment paradigms for HNSCC, therapeutic outcomes remain suboptimal. Only 30-40% of patients present with localized disease amenable to potentially curative surgical resection or function-preserving concurrent chemoradiotherapy (CCRT). The majority of patients either present with locally advanced disease or develop locoregional recurrence or distant metastases after primary treatment[4]. These patients with recurrent/metastatic HNSCC (RMHNSCC) face a particularly poor prognosis, with historical median survival rates rarely exceeding one year. The therapeutic landscape for RMHNSCC has evolved significantly over the past decade, with two major breakthroughs: cetuximab-based regimens and immune checkpoint inhibitors (ICIs)[5-8]. The landmark EXTREME trial established the superiority of adding cetuximab—a monoclonal antibody targeting the epidermal growth factor receptor (EGFR)—to platinum-based chemotherapy and fluorouracil for patients with RMHNSCC[6,9]. This regimen demonstrated improved overall survival (OS), progression-free survival (PFS), and objective response rates compared to chemotherapy alone, establishing a new standard of care. More recently, immune checkpoint inhibitors targeting the programmed death-1 (PD-1) pathway have revolutionized RMHNSCC treatment. Pembrolizumab and nivolumab have demonstrated significant clinical efficacy in both first-line and platinum-refractory settings. The KEYNOTE-048 trial showed that pembrolizumab, either as monotherapy in patients with high PD-L1 expression or in combination with chemotherapy regardless of PD-L1 status, improved survival outcomes compared to the EXTREME regimen[7,8]. Despite these advances, the optimal therapeutic sequence and potential synergistic effects between cetuximab and ICIs remain poorly defined. Preclinical evidence suggests that cetuximab may enhance antitumor immunity through antibody-dependent cellular cytotoxicity (ADCC) and modulation of the tumor microenvironment, potentially augmenting ICI efficacy. Conversely, ICIs might sensitize tumors to subsequent EGFR-targeted therapy. However, clinical data on the optimal sequencing strategy are limited and often conflicting. This observational study aims to address this critical knowledge gap by investigating the efficacy of different treatment sequences combining cetuximab and ICIs in patients with RMHNSCC. By analyzing real-world outcomes in a large cohort of Taiwanese patients, we seek to provide evidence-based guidance for optimizing treatment sequencing and ultimately improving survival outcomes in this challenging patient population. Patients and Methods Ethical Considerations This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Chang Gung Memorial Hospital’s Kaohsiung and Chiayi branches (protocol numbers: 202201019B0 and 202301333B0C601). Due to the retrospective nature of the analysis and minimal risk to participants, the requirement for informed consent was waived as per institutional protocols. Study Design and Population We performed a multicenter, retrospective cohort study using data from the Chang Gung Research Database (CGRD), a comprehensive repository of clinical information from the Chang Gung Healthcare System. Eligible patients included those with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) who received cetuximab-based therapy, immune checkpoint inhibitors (ICIs), or both at Chang Gung Memorial Hospitals between January 2016 and December 2021, with follow-up through December 2022 (Figure 1). Inclusion Criteria Patients were eligible for enrollment if they met all of the following criteria: 1. Histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx 2. Recurrent or metastatic disease following platinum-based concurrent chemoradiotherapy (CCRT) with a documented disease-free interval of at least six months 3. Age ≥18 years 4. Complete clinical and radiological assessment, including: 5. Computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck region 6. Abdominal sonography 7. Either bone scan or positron emission tomography for comprehensive staging 8. Prior treatment with a minimum of two cycles of either cetuximab-based therapy or immune checkpoint inhibitor (ICI) treatment Exclusion Criteria Patients were excluded if they: 1. Had concurrent primary malignancies at the time of HNSCC diagnosis 2. Lacked complete clinical or pathological TNM staging information 3. Received only one cycle of cetuximab-based therapy or ICI treatment 4. Had incomplete follow-up data Treatment Protocols Treatment decisions, including the choice between cetuximab-based regimens and ICIs (pembrolizumab or nivolumab), dosing schedules, and sequence of administration, were at the discretion of the treating physicians based on patients’ clinical characteristics, tumor biomarker expression (PD-L1 CPS/TPS/TC), performance status, and organ function. Cetuximab was administered at an initial loading dose of 400 mg/m² followed by weekly maintenance doses of 250 mg/m², either as monotherapy or in combination with platinum-based chemotherapy. Pembrolizumab was administered at 200 mg every three weeks, while nivolumab was given at 240 mg every two weeks or 480 mg every four weeks. Data Collection Comprehensive clinical data were extracted from electronic medical records, including: Patient demographics (age, sex) Lifestyle factors (smoking status, alcohol consumption, betel nut chewing) Tumor characteristics (primary site, TNM staging, p16 expression status) Laboratory parameters (serum albumin at diagnosis) Tumor biomarkers (PD-L1 expression measured by Combined Positive Score [CPS], Tumor Proportion Score [TPS], or Tumor Cell [TC] expression) Treatment history (previous surgery, radiation therapy, systemic therapies) Treatment details (type of therapy, start and end dates, number of cycles, reason for discontinuation) Clinical outcomes (response assessment, date of progression, survival status) After applying inclusion and exclusion criteria, a total of 822 patients were included in the final analysis (Figure 1). Outcome Measures The primary endpoint was overall survival (OS), defined as the time from diagnosis of recurrent/metastatic disease to death from any cause. Patients who were alive at the time of data cutoff were censored at the date of last follow-up. The secondary endpoint was treatment duration, defined as the time from initiation of cetuximab or ICI therapy to treatment discontinuation for any reason (disease progression, intolerable toxicity, patient preference, or death). Additional analyses were conducted to compare OS and treatment duration between different treatment cohorts (cetuximab monotherapy, ICI monotherapy, and sequential therapy) and to evaluate the impact of treatment sequence (cetuximab followed by ICI versus ICI followed by cetuximab) on clinical outcomes. Statistical Analysis Patient characteristics were summarized using descriptive statistics. Categorical variables were compared using Pearson’s chi-squared test or Fisher’s exact test when appropriate (expected cell count <5). Continuous variables were compared using Student’s t-test or Mann-Whitney U test based on the normality of distribution. Survival analyses were performed using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Univariate and multivariate analyses using Cox proportional hazards regression models were conducted to identify prognostic factors associated with OS. Variables with p<0.1 in univariate analysis were included in the multivariate model. Potential confounding factors adjusted for in the multivariate analysis included age, sex, primary tumor site, p16 status, smoking history, alcohol consumption, betel nut chewing, performance status, and previous treatments. Statistical significance was set at p<0.05 using two-sided tests. All statistical analyses were performed using SPSS Statistics V22.0 software (IBM Corp., Armonk, NY, USA). Results A total of 811 patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) received either cetuximab-based or immune checkpoint inhibitor (ICI)-based treatments. The clinical characteristics of the study population are summarized in Table 1. The median age was 55 years, with a predominance of male patients (93.9%, n=772). The primary tumor sites were distributed as follows: oral cavity (40.5%), oropharynx (28.0%), hypopharynx (20.7%), and larynx (10.8%). The majority of patients (>70%) reported a history of cigarette smoking, alcohol consumption, and betel nut chewing. The median pre-treatment serum albumin level was 3.9 g/dL. P16 status was assessed in 264 patients, with only 29 (10.9%) demonstrating p16-positive tumors. At initial diagnosis, 86 patients (10.5%) presented with metastatic disease, while the remainder developed recurrence following primary treatment. Notably, programmed death-ligand 1 (PD-L1) expression testing was performed in less than 10% of patients prior to ICI treatment initiation. Survival analysis revealed differential outcomes based on treatment modality. The median overall survival (OS) was 10.6 months in the ICI/cetuximab combination group, 8.7 months in the ICI monotherapy group, and 7.2 months in the cetuximab monotherapy group (Figure 2A). Subgroup analyses demonstrated significantly prolonged OS with ICI/cetuximab combination therapy (HR: 0.77, 95% CI: 0.61-0.97; p=0.023) and ICI monotherapy (HR: 0.65, 95% CI: 0.49-0.87; p=0.008) compared to cetuximab monotherapy (Table 2). In univariate analyses, factors associated with improved OS included younger age (p=0.026); primary tumor location in the oropharynx (p<0.001), larynx (p<0.001), or hypopharynx (p=0.030); absence of betel nut chewing history (p=0.037); presence of diabetes mellitus (DM) (p=0.006); higher serum albumin levels (p<0.001); and treatment with either ICI/cetuximab combination (p=0.026) or ICI monotherapy (p=0.004) (Table 2). Multivariate analysis identified the following independent favorable prognostic factors: younger age (p=0.012), female gender (p=0.025), primary tumor site in the oropharynx (p=0.001) or larynx (p=0.003), presence of diabetes mellitus (p=0.015), higher serum albumin levels (p<0.001), and receipt of ICI-based treatment (p=0.019) (Table 2). Outcomes Based on Treatment Sequence We analyzed outcomes in RMHNSCC patients who received both immune checkpoint inhibitors (ICIs) and cetuximab through various treatment sequences. As detailed in Table 3, patients were categorized into three distinct groups: concurrent administration of ICI with cetuximab (n=36), sequential administration of ICI following cetuximab (n=20), and sequential administration of cetuximab following ICI (n=41). Median age varied across treatment groups: 52 years for patients receiving concurrent ICI and cetuximab, 58 years for those receiving ICI after cetuximab, and 50 years for those receiving cetuximab after ICI. Primary tumor site distribution showed notable patterns, with oral cavity and oropharynx predominating in both the concurrent therapy group and the ICI-following-cetuximab group. In contrast, the cetuximab-following-ICI group had a higher proportion of patients with hypopharyngeal and laryngeal primary tumors. P16 status was unavailable for more than half of the patients across all ICI/cetuximab treatment groups. The median treatment duration was 202.5 days for concurrent ICI and cetuximab, 182 days for ICI following cetuximab, and 220 days for cetuximab following ICI. Univariate analysis of overall survival identified male gender and serum albumin levels as significant prognostic factors (Table 4). In multivariate analysis, primary tumor sites in the oropharynx or hypopharynx and the sequential administration of ICI following cetuximab emerged as independent prognostic factors associated with improved survival outcomes (Table 4 and Figure 2B). Discussion The treatment landscape for recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) has evolved significantly with the introduction of immune checkpoint inhibitors (ICIs) and targeted therapies like cetuximab. Our multi-center retrospective analysis provides valuable insights into the efficacy of different treatment sequences involving these agents. Comparison of Treatment Sequences and Survival Outcomes Our findings demonstrated no statistically significant difference in overall survival (OS) between patients receiving concurrent cetuximab and ICI versus sequential administration of these therapies. The median OS was 10.6 months for concurrent administration, 12.1 months for cetuximab following ICI, and 9.1 months for ICI following cetuximab. These results differ from those reported by Sacco et al.[10], who found pembrolizumab combined with cetuximab had superior response rates compared to either agent alone. This discrepancy may be attributed to differences in patient populations; our cohort had previously undergone platinum-based concurrent chemoradiotherapy (CCRT), while in the Sacco study, 88% of patients received the combination as first-line treatment. Our findings align more closely with those reported by Lien et al.[11] for platinum-sensitive patients. The relatively shorter OS observed in our study compared to others may be explained by the known poor prognosis of patients refractory to platinum therapy, as documented in previous literature. The phase II study by Chung et al.[14] similarly noted that RMHNSCC patients had inferior OS outcomes when they had received prior therapies, although concurrent nivolumab and cetuximab remained effective in both treatment-naïve and previously treated populations. Efficacy of Sequential versus Concurrent Administration Few studies have specifically examined the comparative efficacy of different sequencing strategies for cetuximab and ICIs in RMHNSCC. Our Cox regression analysis revealed no significant OS differences between concurrent ICI/cetuximab administration and sequential approaches (either ICI following cetuximab failure or cetuximab following ICI failure). This finding is consistent with Yang et al.[12], who reported no statistically significant differences in progression-free survival or OS between ICI following cetuximab and cetuximab following ICI in treatment-naïve RMHNSCC patients. Similarly, Lien et al.[11] found comparable survival outcomes between concurrent administration and sequential therapy. To our knowledge, our study is among the first to demonstrate equivalent survival outcomes between concurrent cetuximab-ICI therapy and sequential treatment approaches. The biological rationale for combining these agents is supported by research showing synergistic effects of anti-PD1 therapy and cetuximab in enhancing cancer cell killing through antigen-specific cytotoxic T-lymphocyte activation[13]. Several phase II clinical trials have reported promising OS results with cetuximab-ICI combinations[10,14], while others have shown that sequential administration (ICI after cetuximab progression or vice versa) can also effectively extend OS in RMHNSCC patients[15,16]. Comparative Treatment Efficacy and Prognostic Factors In univariate Cox regression analysis, both ICI monotherapy and ICI-cetuximab combinations demonstrated superior OS benefits compared to cetuximab alone. However, in multivariate analysis, only ICI monotherapy—not concurrent ICI-cetuximab therapy—maintained statistically significant OS advantages. This finding may reflect selection bias, as landmark trials like Keynote-040 and Checkmate-141 have shown that approximately 20% of RMHNSCC patients achieve durable responses to anti-PD-1 therapy, translating to substantial survival benefits[7,17]. Our multivariate analyses identified several independent prognostic factors in RMHNSCC, including age, gender, primary tumor site, diabetes mellitus, serum albumin levels, and ICI treatment. Particularly noteworthy in the subgroup receiving both cetuximab and ICI was the emergence of serum albumin as an independent prognostic factor in univariate OS analysis. This corroborates findings by Saito et al.[18], who established high serum albumin as a favorable prognostic biomarker for ICI therapy in HNSCC. Suzuki et al.[19] similarly identified pretreatment serum albumin as a predictor of long-term survival in RMHNSCC patients receiving nivolumab. Within our ICI-cetuximab cohort, primary tumor location (specifically oropharynx and hypopharynx) and the sequencing strategy of ICI following cetuximab demonstrated significant OS benefits in multivariate analysis. This anatomic prognostic pattern aligns with previous studies showing superior survival for oropharyngeal versus oral squamous cell carcinoma in patients treated with either ICI or cetuximab[20,21]. References: 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries . CA Cancer J Clin 2021, 71 (3):209-249.2. Chiu TJ, Chen CH, Chien CY, Li SH, Tsai HT, Chen YJ: High ERCC1 expression predicts cisplatin-based chemotherapy resistance and poor outcome in unresectable squamous cell carcinoma of head and neck in a betel-chewing area . J Transl Med 2011, 9 :31.3. Wang CP, Chen TC, Hsu WL, Hsiao JR, Chen PR, Chen MK, Hua CH, Tsai MH, Ko JY, Lou PJ et al : Rising incidence of HPV positive oropharyngeal cancer in Taiwan between 1999 and 2014 where betel nut chewing is common . BMC Cancer 2022, 22 (1):296.4. 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Posner MR, Lorch JH, Goloubeva O, Tan M, Schumaker LM, Sarlis NJ, Haddad RI, Cullen KJ: Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial . Ann Oncol 2011, 22 (5):1071-1077.24. Vermorken JB, Psyrri A, Mesia R, Peyrade F, Beier F, de Blas B, Celik I, Licitra L: Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial . Ann Oncol 2014, 25 (4):801-807.25. Zhang S, Zheng M, Nie D, Xu L, Tian H, Wang M, Liu W, Feng Z, Han F: Efficacy of cetuximab plus PD-1 inhibitor differs by HPV status in head and neck squamous cell carcinoma: a systematic review and meta-analysis . J Immunother Cancer 2022, 10 (10). Tables and Figure Legends Table 1. Baseline characteristics of patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) receiving cetuximab and/or immune checkpoint inhibitors (ICIs). Data are presented as median (interquartile range) or n (%). RMHNSCC: recurrent/metastatic head and neck squamous cell carcinoma; ICI: immune checkpoint inhibitor; TPS: tumor proportion score; CPS: combined positive score; TC: tumor cell. Table 2. Univariate and multivariate Cox regression analyses of prognostic factors for overall survival in patients with recurrent/metastatic head and neck squamous cell carcinoma. Data are presented as hazard ratio (HR) with 95% confidence interval (CI). Significant p-values (<0.05) are shown in bold italics. DM: diabetes mellitus; ICI: immune checkpoint inhibitor. Table 3. Demographic and clinical characteristics of 97 patients with recurrent/metastatic head and neck squamous cell carcinoma receiving different sequences of cetuximab and immune checkpoint inhibitor therapy. Data are presented as median (interquartile range) or n (%). ICI+cetuximab: concurrent administration; ICI→cetuximab: immune checkpoint inhibitor followed by cetuximab; Cetuximab→ICI: cetuximab followed by immune checkpoint inhibitor. Significant p-values (<0.05) are shown in bold italics. DM: diabetes mellitus. Table 4. Univariate and multivariate Cox regression analyses of prognostic factors for overall survival in patients with recurrent/metastatic head and neck squamous cell carcinoma receiving both immune checkpoint inhibitors and cetuximab. Data are presented as hazard ratio (HR) with 95% confidence interval (CI). Significant p-values (<0.05) are shown in bold italics. DM: diabetes mellitus; ICI: immune checkpoint inhibitor. Figure 1. Patient selection flowchart for the study of recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) patients treated with cetuximab and/or immune checkpoint inhibitors (ICIs). This flowchart illustrates the patient selection process from the four Chang-Gung Memorial hospitals cancer registration database. From an initial 1,105 HNSCC patients (excluding nasopharyngeal carcinoma) registered between 2016-2021, 283 patients were excluded based on specific criteria: history of esophageal or salivary gland cancer (n=38), missing tumor stage data (n=2), concomitant other cancer within 5 years of HNSCC diagnosis including NPC (n=166), and patients receiving only a single administration of systemic targeted therapy or anti-PD-1 treatment (n=77). The final study cohort comprised 822 patients with RMHNSCC who received cetuximab and/or immune checkpoint inhibitor therapy. Figure 2. Kaplan-Meier curves of overall survival in patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) treated with different therapeutic strategies and different sequences of cetuximab and immune checkpoint inhibitors. This figure (A) illustrates the overall survival outcomes among 822 RMHNSCC patients stratified by treatment regimen: combination of immune checkpoint inhibitors and cetuximab (ICI+Cetuximab, n=97, solid blue line), immune checkpoint inhibitors alone (ICI, n=79, dotted green line), and cetuximab alone (n=646, dashed orange line). Median survival times were 10.6 months for ICI+Cetuximab, 8.7 months for ICI alone, and 7.2 months for cetuximab alone. The log-rank test showed a statistically significant difference among the three treatment groups (p=0.002). The number of patients at risk at each follow-up time point (0-72 months) is displayed at the bottom of the figure. Figure (B) demonstrates the overall survival outcomes among 97 RMHNSCC patients who received both cetuximab and immune checkpoint inhibitors (ICIs), stratified by treatment sequence: concurrent administration of cetuximab and ICI (cet + ICI, n=36, solid blue line), sequential administration of cetuximab followed by ICI (cet → ICI, n=41, dotted green line), and ICI followed by cetuximab (ICI → cet, n=20, dashed orange line). Median survival times were 10.6 months for concurrent therapy, 12.1 months for cetuximab followed by ICI, and 9.1 months for ICI followed by cetuximab. Log-rank analysis showed no statistically significant difference in overall survival among the three sequencing strategies (p=0.972). The number of patients at risk during the follow-up period (0-72 months) is displayed at the bottom of the figure. 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Authors Affiliations Yu-Ming Wang Kaohsiung Chang Gung Memorial Hospital View all articles by this author Sheng-Dean Luo Kaohsiung Chang Gung Memorial Hospital View all articles by this author Ching-Nung Wu Kaohsiung Chang Gung Memorial Hospital View all articles by this author Shao‑Chun Wu Kaohsiung Chang Gung Memorial Hospital View all articles by this author Wei-Chih Chen Kaohsiung Chang Gung Memorial Hospital View all articles by this author Yao-Hsu Yang Chiayi Chang Gung Memorial Hospital View all articles by this author Jin-Ching Lee National Sun Yat-sen University Department of Marine Biotechnology and Resources View all articles by this author Tai-Jan Chiu [email protected] Kaohsiung Chang Gung Memorial Hospital View all articles by this author Metrics & Citations Metrics Article Usage 185 views 140 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yu-Ming Wang, Sheng-Dean Luo, Ching-Nung Wu, et al. 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