Platinum Selection in Immune Checkpoint Inhibitor-Based Therapy for Recurrent or Metastatic Head and Neck Cancer: A Multi-Institutional Retrospective Study

Platinum Selection in Immune Checkpoint Inhibitor-Based Therapy for Recurrent or Metastatic Head and Neck Cancer: A Multi-Institutional Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Platinum Selection in Immune Checkpoint Inhibitor-Based Therapy for Recurrent or Metastatic Head and Neck Cancer: A Multi-Institutional Retrospective Study JUMPEI YOSHIDA, NAOKI FUKUDA, TAKUMI ITO, KENJI NAKANO, CHIYOE KITAGAWA, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7990042/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract The KEYNOTE-048 trial established pembrolizumab plus platinum and 5-fluorouracil (5-FU) as the standard first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). In the present study, the efficacy and safety of cisplatin and carboplatin in combination with pembrolizumab were compared using real-world data. In this retrospective study, 76 patients with R/M HNSCC treated with pembrolizumab plus 5-FU and either cisplatin (n=41) or carboplatin (n=35) were analysed. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and the incidence of grade ≥3 haematological and grade ≥2 non-haematological adverse events. The median PFS was 4.1 months with cisplatin and 7.1 months with carboplatin (p=0.58). The median OS values were 14.8 and 20.7 months, respectively (p=0.88). The ORR values were similar (34.1% vs. 34.3%, p=0.99). Grade ≥3 haematological adverse events were more frequent with cisplatin than with carboplatin (87.8% vs. 48.6%, p<0.01), as were grade ≥2 non-haematological adverse events (97.6% vs. 54.3%, p<0.01). Cisplatin showed no advantage over carboplatin regarding OS, PFS, and ORR but caused increased toxicity in ICI-based therapy for R/M HNSCC. These findings support carboplatin as the preferred platinum with pembrolizumab, balancing efficacy and safety. Biological sciences/Cancer Health sciences/Oncology Cisplatin Carboplatin Pembrolizumab Immune checkpoint inhibitors Head and Neck cancer Figures Figure 1 INTRODUCTION Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide, with an estimated 891,453 new cases and 458,107 deaths reported in 2020 [ 1 ]. While survival rates have improved in recent decades, HNSCC remains one of the most fatal cancers globally, highlighting the need for more effective treatment strategies. Historically, numerous Phase III trials have investigated the use of cisplatin, carboplatin, methotrexate, paclitaxel, 5-fluorouracil (5-FU), and their combination therapies [ 2 – 7 ]. Based on favourable clinical outcomes, cisplatin plus 5-FU was recognized as the standard treatment approach [ 2 – 7 ]. In the EXTREME trial, the addition of cetuximab to a platinum plus 5-FU regimen resulted in a significant improvement in overall survival (OS) for first-line treatment of head and neck cancer, compared with platinum and 5-FU [ 8 ]. Owing to the high toxicity of cisplatin and its limited tolerability, the EXTREME trial allowed for the use of carboplatin as a substitute [ 8 , 9 ]. Although based on retrospective analysis, reports from the EXTREME era suggested that cisplatin was associated with a higher objective response rate (ORR), while OS was comparable between cisplatin and carboplatin [ 10 , 11 ]. Recently, the EXTREME regimen has been replaced by pembrolizumab plus platinum and 5-FU, which have become the new standard of care for the first-line treatment of recurrent or metastatic (R/M) HNSCC [ 12 – 14 ]. Although carboplatin remains an acceptable option, whether it is a more suitable combination partner in the era of immune checkpoint inhibitors (ICIs) remains unclear. Treatment of R/M HNSCC is primarily palliative, focusing on disease control and symptom relief to extend survival and maintain the quality of life [ 15 , 16 ]. To identify the optimal platinum agent for ICI-based regimens, we assessed the efficacy and tolerability of cisplatin and carboplatin. Methods Ethics approval and consent to participate This retrospective study was conducted following the ethical standards outlined in the Declaration of Helsinki and was approved by the Institutional Review Board of the Japanese Foundation for Cancer Research (Approval No. 2025-GB-040). Given the retrospective design of the study, the requirement for written informed consent was waived. Instead, information regarding the study was disclosed on the institutional website, and patients were provided with the opportunity to opt out. Study Design and Patients This retrospective study was performed at the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and NHO Nagoya Medical Centre between December 2019 and March 2025. Patients with R/M HNSCC originating from the oropharynx, oral cavity, hypopharynx, or larynx were included in the study. The eligibility criteria also included an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–2, age ≥18 years, and at least one evaluable lesion, as defined by the Response Evaluation Criteria in Solid Tumours (RECIST). All the patients received pembrolizumab combined with cisplatin, carboplatin, and 5-FU. Patients who received systemic platinum-based therapy or developed platinum-refractory disease within 6 months were excluded. The following clinical variables were included in the analysis: age, sex, combined positive score (CPS), creatinine clearance (Ccr), body mass index (BMI), prior exposure to platinum-based chemotherapy, p16 status, ECOG PS, smoking history, and primary tumour site. Procedures Patients received pembrolizumab in combination with either carboplatin (area under the curve [AUC], 5 mg/m²) or cisplatin (100 mg/m²), along with 5-FU (1000 mg/m² per day for 4 consecutive days), administered every 3 weeks for up to 6 cycles. After completion of six cycles, pembrolizumab monotherapy was continued as maintenance treatment. The dose reduction criteria and extent of dose modification for each drug were determined at the discretion of the treating physician. The relative dose intensity (RDI) was defined as the ratio of the actual dose delivered per unit time to the planned dose per unit time. Cumulative relative dose intensity (cRDI) was calculated as the ratio of total actual dose to total planned dose; both metrics were evaluated for the initial chemo-immunotherapy combination phase (cycles 1–6). Treatment discontinuation was defined as failure to complete the six planned chemotherapy cycles. Outcomes The primary endpoint was OS, defined as the time from the initiation of first-line therapy to death from any cause or censoring at the last follow-up. Secondary endpoints included progression-free survival (PFS), defined as the time from treatment initiation to documented disease progression or death from any cause, whichever occurred first. Patients without an event were censored at the last follow-up. Additional secondary points were the incidence of grade ≥2 non-haematological adverse events (NHAEs) and grade ≥3 haematological adverse events (HAEs), and the ORR. All tumour responses were assessed using the RECIST version 1.1. Statistical analysis All statistical analyses were performed using Stata SE software version 18.0; (StataCorp, College Station, TX, USA). Continuous variables were summarised as medians and compared between groups using the Wilcoxon rank-sum test. Categorical variables were analysed using the chi-squared test or Fisher’s exact test, with the latter applied when the expected cell count was <5. The median follow-up duration was calculated using the reverse Kaplan–Meier method and compared using the log-rank test. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were conducted to identify the prognostic factors. The proportional hazards assumption was assessed using Schoenfeld residuals. In the multivariate analysis, variables that violated this assumption were analyzed using stratified Cox regression models. In Cox proportional hazards regression analyses, age, Ccr, and BMI were treated as continuous variables. Statistical significance was set at a two-sided p-value <0.05. Results Between December 2019 and March 2025, 76 eligible patients with R/M HNSCC were included in the analysis; cisplatin and carboplatin were administered to 41 and 35 patients, respectively. The baseline patient characteristics stratified according to treatment regimen are summarised in Table 1. Patients in the cisplatin group were significantly younger (median age: 57 vs. 73 years, p < 0.01) and had a higher creatinine clearance (median: 97.4 vs. 60.0%/min, p < 0.01) than those in the carboplatin group. The distributions of CPS status ( p = 0.049), smoking history ( p = 0.04), and primary tumour site ( p < 0.01) also differed between the groups. The treatment delivery metrics are presented in Table 2. Platinum cRDI was significantly lower in the cisplatin group than in the carboplatin group ( p = 0.02). Treatment discontinuation owing to adverse events was more frequently observed in the cisplatin group than in the carboplatin group (36.6% vs. 14.3%; p = 0.03). Detailed outcome data are shown in Table 3. The median follow-up period was 32.4 months. Median PFS was 4.1 months in the cisplatin group and 7.1 months in the carboplatin group (Fig. 1A). Median OS was 14.8 and 20.7 months, respectively (Fig. 1B). The ORR was 34.2%, with comparable rates in the cisplatin (34.1%) and carboplatin (34.3%) groups. In the univariate analysis, the HR for PFS with carboplatin compared to cisplatin was 0.86 (95% CI: 0.51–1.46, p = 0.58), and the HR for OS was 0.95 (95% CI: 0.51–1.78, p = 0.88). PS 1 and PS 2 were strongly associated with shorter PFS ( p = 0.04 and p=0.01), and OS ( p <0.01 and p = 0.01, respectively). CPS ≥20 was significantly associated with longer PFS ( p = 0.03). These variables were then included as covariates in the multivariate model. In the multivariate analysis, the HRs for carboplatin were 0.70 (95% CI: 0.40–1.23) for PFS and 0.68 (95% CI: 0.34–1.34) for OS. The ORRs were comparable between the cisplatin and carboplatin groups (34.1% vs. 34.3%, p = 0.99). Grade ≥3 HAEs were significantly more common in the cisplatin group than in the carboplatin group (87.8% vs. 48.6%, p < 0.01). Specifically, decreased white blood cell count (46.3% vs. 17.1%, p < 0.01), decreased neutrophil count (65.9% vs. 34.3%, p < 0.01), and febrile neutropenia (17.1% vs. 0%, p = 0.01) were relatively frequent in the cisplatin group. Grade ≥2 NHAEs were also considerably more observed in the cisplatin (97.6% vs. 54.3%, p < 0.01). Notably, nausea (53.7% vs. 11.4%, p < 0.01), anorexia (46.3% vs. 22.9%, p = 0.03), malaise (22.0% vs. 2.9%, p = 0.02), and diarrhoea (24.4% vs. 2.9%, p < 0.01) occurred relatively often in patients receiving cisplatin. Discussion Cisplatin has long been a cornerstone in the treatment of R/M HNSCC owing to its potent antitumour activity [2-7]. It remains preferentially used in patients with a good PS and preserved organ function, even in the post-EXTREME era [8]. However, the substantial toxicity of cisplatin can adversely affect health-related quality of life [9]. In clinical practice, carboplatin is frequently selected for patients who are older or have impaired renal function, as was observed in our study. In our retrospective analysis based on real-world data, cisplatin demonstrated no superiority over carboplatin in terms of OS and PFS. Moreover, it failed to show any advantage in ORR when used in combination with pembrolizumab and 5-FU. Despite the inclusion of patients with an ECOG PS 2, the observed median PFS was consistent with that reported in the KEYNOTE-048 trial, and the median OS showed a trend toward improvement [12,13]. These OS outcomes were also similar to those observed in the Japanese subgroup of KEYNOTE-048 [17,18]. Although CPS was not significantly associated with OS in the univariate analysis, it was retained in the multivariate model because of its significant association with PFS and its established role as a prognostic biomarker in R/M HNSCC [12,13]. To evaluate the robustness of our findings, we conducted multiple sensitivity analyses, including models incorporating additional clinical covariates (p16 status, primary tumour site, smoking history, age, and Ccr), as well as truncated Cox models at 24 months. All sensitivity analyses of OS and PFS demonstrated results consistent with those of the primary analysis (Supplementary Table 1 A, B). Grade ≥2 non-hematologic toxicities were analyzed, as they are considered clinically meaningful events that compromise quality of life, and affect treatment decision. The incidence of both grade ≥3 HAEs and grade ≥2 NHAEs was significantly higher in the cisplatin group than in the carboplatin group. Grade ≥3 NHAEs were also more frequently observed in the cisplatin group (Supplementary Table 2 A). In contrast, the number of grade ≥2 immune-related adverse events was comparable between the two groups (Supplementary Table 2 B). Notably, platinum cRDI was significantly lower in the cisplatin group, and the proportion of AE-related discontinuations was higher than that in the carboplatin group. Considering its increased toxicity and decreased treatment delivery, carboplatin may be preferable when sustained platinum administration is prioritised. Compared to the overall population in KEYNOTE-048, the prevalence of severe adverse events in our cohort was high. However, the toxicity profile was similar to that reported in a Japanese subgroup, suggesting that ethnic and clinical practice factors may influence the differences [17,18]. The regimen of cisplatin at 100 mg/m² on day 1 combined with continuous intravenous infusion of 5-FU at 1,000 mg/m² per day from days 1 to 4 has been reported to be excessively intensive in Japanese patients [19]. The high incidence of adverse events observed in this study may be attributable to this dosing intensity. In the era of ICIs, their potent antitumour activity appears to diminish the clinical relevance of the selection between cisplatin and carboplatin. Given its favourable toxicity profile, carboplatin is a better-tolerated and clinically appropriate alternative, and our findings support this substitution. While our study focused on platinum selection, chemotherapy choice in ICI-based regimens is increasingly guided by the consideration of toxicity [20,21]. Future research is required to clarify the optimal chemotherapy backbone in ICI-based regimens and refine treatment approaches that balance efficacy and tolerability. Limitations First, the retrospective nature of this study may have introduced selection bias and unmeasured confounding factors. To address this limitation, we conducted multivariate and sensitivity analyses, adjusting for key prognostic variables, and used standardised outcome definitions. Second, the sample size was relatively small. However, our study reflects a real-world patient population and offers valuable insights into treatment patterns in current clinical practice. Third, the median follow-up duration differed between treatment groups, with a longer follow-up in the cisplatin arm. Although this discrepancy may have affected the estimation of OS, the log-rank test showed no significant difference in the follow-up duration between the groups. To further address this potential bias, we conducted truncated analyses at 24 months, which yielded results consistent with those of the primary analysis (Supplementary Table 1 A, B). Fourth, because most patients were Japanese, the generalisability of our results to other ethnic groups and healthcare systems may be limited. Conclusion In conclusion, cisplatin showed no advantage over carboplatin in terms of OS, PFS, and ORR. Additionally, cisplatin was associated with considerably higher toxicity in the context of ICI-based therapy for R/M HNSCC. These findings support the selection of carboplatin as the preferred platinum with pembrolizumab when considering the balance between efficacy and safety. Further investigation is necessary to validate these findings and inform future treatment strategies. Declarations Acknowledgement We would like to thank Editage (www.editage.com) for English language editing and appreciate the support of resident Erisa Toda and intern Mari Naito in patient care. Author contribution s Study conception: J. Y, N. F, T. I; Manuscript writing: J.Y, NF; Data acquisition: J.Y, T.I; Literature review: J.Y, N.F; Imaging evaluation: J.Y, N.F, K.N, C.K, H.M, S.T; Manuscript Supervision: C.K, H.M, S.T, Y.M; Final approval: all authors. Data availability statement The data supporting the findings of this study are not publicly available owing to patient confidentiality but can be obtained from the corresponding author upon reasonable request. Funding This research received no external funding. Competing Interest J.Y: Honoraria for lectures from Kyowa Kirin. N.F: Research funding to the author’s institution from Eisai; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, MSD, Merck Biopharma, Lilly, Eisai, Novartis, Thermo Fisher Scientific, Daiichi Sankyo, and AstraZeneca. C.K: Research funding to the author’s institution from Daiichi Sankyo, AstraZeneca, MSD, Abbvie, Ono Pharmaceutical, ALX Oncology, and Sanofi; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, Chugai Pharma, Daiichi Sankyo, AstraZeneca, MSD, Taiho Pharmaceutical, and Eisai. S.T: Research funding to the author’s institution from Daiichi Sankyo, Sanofi, Eisai, and Bayer; honoraria for lectures and presentations, including speaker bureaus, from Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, MSD, Chugai Pharma, Bristol-Myers Squibb Japan, Ono Pharmaceutical, and Lilly Japan; consulting from Bayer. Y.M: Research funding to the author’s institution from MSD, Daiichi Sankyo, UCB Japan; honoraria for lectures and presentations, including speaker bureaus, from Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Eisai, Bristol-Myers Squibb, Merk biopharma, Janssen and Astellas Pharma. References Bray, F. et al . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74, 229–263 (2024). Forastiere, A. A. et al . Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J. Clin. Oncol. 10, 1245–1251 (1992). Jacobs, C. et al . A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J. Clin. Oncol. 10, 257–263 (1992). Schornagel, J. H. et al . Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: A European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J. Clin. Oncol. 13, 1649–1655 (1995). Schrijvers, D. et al. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. J. Clin. Oncol. 16, 1054–1059 (1998). Forastiere, A. A. et al. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J. Clin. Oncol. 19, 1088–1095 (2001). Gibson, M. K. et al . Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An intergroup trial of the Eastern Cooperative Oncology Group. J. Clin. Oncol. 23, 3562–3567 (2005). Vermorken, J. B. et al . Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359, 1116–1127 (2008). Lokich, J. & Anderson, N. Carboplatin versus cisplatin in solid tumors: An analysis of the literature. Ann. Oncol. 9, 13–21 (1998). Sano, D. et al . Real-world treatment outcomes of the EXTREME regimen as first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck: A multi-center retrospective cohort study in Japan. Anticancer Res. 39, 6819–6827 (2019). Fukuda, N. et al . Comparison of the efficacy and safety of the EXTREME regimen for treating recurrent or metastatic head and neck squamous cell carcinoma in older and younger adult patients. Cancer Rep. 4 . Cancer Rep. (Hoboken) 4, e1322 (2021). 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 394, 1915–1928 (2019). Burtness, B. et al . Pembrolizumab alone or with chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048: Subgroup analysis by programmed death ligand-1 combined positive score. J. Clin. Oncol. 40, 2321–2332 (2022). Harrington, K. J. et al . Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: Updated results of the phase III KEYNOTE-048 study. J. Clin. Oncol. 41, 790–802 (2023). Rischin, D. et al . Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 128, 105815 (2022). Peyrade, F. et al . Systemic treatment and medical management of metastatic squamous cell carcinoma of the head and neck: Review of the literature and proposal for management changes. Oral Oncol. 49, 482–491 (2013). Takahashi, S. et al . First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048. Int. J. Clin. Oncol. 27, 1805–1817 (2022). Oridate, N. et al . First-line pembrolizumab with or without chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up of the Japanese population of KEYNOTE‑048. Int. J. Clin. Oncol. 29, 1825–1839 (2024). Kiyota, N. et al . Systemic chemotherapy with cisplatin plus 5-FU (PF) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Efficacy and safety of a lower dose of PF (80/800) at a single institution in Japan. Jpn. J. Clin. Oncol. 39, 225–230 (2009). Dzienis, M. et al . Pembrolizumab plus carboplatin and paclitaxel as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-B10): A single-arm phase IV trial. J. Clin. Oncol. 42, 2989–2999 (2024). Sun, L., Cohen, R. B. & Dimitrios Colevas, A. Platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). Oral Oncol. 158, 106997 (2024). Tables Tables 1 to 5 are available in the Supplementary Files section Additional Declarations Competing interest reported. J.Y: Honoraria for lectures from Kyowa Kirin. N.F: Research funding to the author’s institution from Eisai; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, MSD, Merck Biopharma, Lilly, Eisai, Novartis, Thermo Fisher Scientific, Daiichi Sankyo, and AstraZeneca. C.K: Research funding to the author’s institution from Daiichi Sankyo, AstraZeneca, MSD, Abbvie, Ono Pharmaceutical, ALX Oncology, and Sanofi; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, Chugai Pharma, Daiichi Sankyo, AstraZeneca, MSD, Taiho Pharmaceutical, and Eisai. S.T: Research funding to the author’s institution from Daiichi Sankyo, Sanofi, Eisai, and Bayer; honoraria for lectures and presentations, including speaker bureaus, from Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, MSD, Chugai Pharma, Bristol-Myers Squibb Japan, Ono Pharmaceutical, and Lilly Japan; consulting from Bayer. Y.M: Research funding to the author’s institution from MSD, Daiichi Sankyo, UCB Japan; honoraria for lectures and presentations, including speaker bureaus, from Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Eisai, Bristol-Myers Squibb, Merk biopharma, Janssen and Astellas Pharma. 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10:10:40","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":143585,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7990042/v1/bbd83dcb1d3f6abebf01612a.html"},{"id":98765313,"identity":"b2d459a8-71ff-4e32-9fef-dc24457a1d2f","added_by":"auto","created_at":"2025-12-22 10:10:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":644051,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for progression-free survival (A) and overall survival (B) stratified by platinum agent.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7990042/v1/071e242224663d490865b194.png"},{"id":107928057,"identity":"dc7c4c48-0939-4c51-aff0-7b6b3bcb15c2","added_by":"auto","created_at":"2026-04-27 16:06:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":895176,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7990042/v1/b92b13d6-ed61-420a-9409-eb2529a8b978.pdf"},{"id":98779671,"identity":"504eca1a-d18a-4010-a6ca-0f23ecd69829","added_by":"auto","created_at":"2025-12-22 12:30:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23156,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-7990042/v1/7e50c8f80d77f70b61789630.docx"},{"id":98765321,"identity":"2fe27099-9977-48ae-9754-2ef38f8cf3fe","added_by":"auto","created_at":"2025-12-22 10:10:40","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":43183,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7990042/v1/99deb2ec5f7e25b7bc078d20.docx"}],"financialInterests":"Competing interest reported. J.Y: Honoraria for lectures from Kyowa Kirin.\nN.F: Research funding to the author’s institution from Eisai; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, MSD, Merck Biopharma, Lilly, Eisai, Novartis, Thermo Fisher Scientific, Daiichi Sankyo, and AstraZeneca.\nC.K: Research funding to the author’s institution from Daiichi Sankyo, AstraZeneca, MSD, Abbvie, Ono Pharmaceutical, ALX Oncology, and Sanofi; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, Chugai Pharma, Daiichi Sankyo, AstraZeneca, MSD, Taiho Pharmaceutical, and Eisai.\nS.T: Research funding to the author’s institution from Daiichi Sankyo, Sanofi, Eisai, and Bayer; honoraria for lectures and presentations, including speaker bureaus, from Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, MSD, Chugai Pharma, Bristol-Myers Squibb Japan, Ono Pharmaceutical, and Lilly Japan; consulting from Bayer.\nY.M: Research funding to the author’s institution from MSD, Daiichi Sankyo, UCB Japan; honoraria for lectures and presentations, including speaker bureaus, from Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Eisai, Bristol-Myers Squibb, Merk biopharma, Janssen and Astellas Pharma.","formattedTitle":"Platinum Selection in Immune Checkpoint Inhibitor-Based Therapy for Recurrent or Metastatic Head and Neck Cancer: A Multi-Institutional Retrospective Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHead and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide, with an estimated 891,453 new cases and 458,107 deaths reported in 2020 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While survival rates have improved in recent decades, HNSCC remains one of the most fatal cancers globally, highlighting the need for more effective treatment strategies.\u003c/p\u003e \u003cp\u003eHistorically, numerous Phase III trials have investigated the use of cisplatin, carboplatin, methotrexate, paclitaxel, 5-fluorouracil (5-FU), and their combination therapies [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Based on favourable clinical outcomes, cisplatin plus 5-FU was recognized as the standard treatment approach [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In the EXTREME trial, the addition of cetuximab to a platinum plus 5-FU regimen resulted in a significant improvement in overall survival (OS) for first-line treatment of head and neck cancer, compared with platinum and 5-FU [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Owing to the high toxicity of cisplatin and its limited tolerability, the EXTREME trial allowed for the use of carboplatin as a substitute [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although based on retrospective analysis, reports from the EXTREME era suggested that cisplatin was associated with a higher objective response rate (ORR), while OS was comparable between cisplatin and carboplatin [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, the EXTREME regimen has been replaced by pembrolizumab plus platinum and 5-FU, which have become the new standard of care for the first-line treatment of recurrent or metastatic (R/M) HNSCC [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Although carboplatin remains an acceptable option, whether it is a more suitable combination partner in the era of immune checkpoint inhibitors (ICIs) remains unclear. Treatment of R/M HNSCC is primarily palliative, focusing on disease control and symptom relief to extend survival and maintain the quality of life [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. To identify the optimal platinum agent for ICI-based regimens, we assessed the efficacy and tolerability of cisplatin and carboplatin.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was conducted following the ethical standards outlined in the Declaration of Helsinki and was approved by the Institutional Review Board of\u0026nbsp;the Japanese Foundation for Cancer Research\u0026nbsp;(Approval No. 2025-GB-040). Given the retrospective design of the study, the requirement for written informed consent was waived. Instead, information regarding the study was disclosed on the institutional website, and patients were provided with the opportunity to opt out.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design and Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;This retrospective study was\u0026nbsp;performed\u0026nbsp;at the Cancer Institute Hospital, Japanese Foundation for Cancer Research,\u0026nbsp;and\u0026nbsp;NHO Nagoya Medical Centre between December 2019 and March 2025. Patients with R/M HNSCC originating from the oropharynx, oral cavity, hypopharynx, or larynx were included in the study. The eligibility criteria also included an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–2, age ≥18 years, and at least one evaluable lesion, as defined by the Response Evaluation Criteria in Solid Tumours (RECIST). All the patients received pembrolizumab combined with cisplatin, carboplatin, and 5-FU. Patients who received systemic platinum-based therapy or developed platinum-refractory disease within 6 months were excluded. The following clinical variables were included in the analysis: age, sex, combined positive score (CPS), creatinine clearance (Ccr), body mass index (BMI), prior exposure to platinum-based chemotherapy, p16 status, ECOG PS, smoking history, and primary tumour site.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Patients received pembrolizumab in combination with either carboplatin (area under the curve [AUC], 5 mg/m²) or cisplatin (100 mg/m²), along with 5-FU (1000 mg/m² per day for 4 consecutive days), administered every 3 weeks for up to 6 cycles. After completion of six cycles, pembrolizumab monotherapy was continued as maintenance treatment. The dose reduction criteria and extent of dose modification for each drug were determined at the discretion of the treating physician. The relative dose intensity (RDI) was defined as the ratio of the actual dose delivered per unit time to the planned dose per unit time. Cumulative relative dose intensity (cRDI) was calculated as the ratio of total actual dose to total planned dose;\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003eboth metrics were evaluated for the initial chemo-immunotherapy combination phase (cycles 1–6).\u0026nbsp;\u003c/strong\u003e\u003c/strong\u003e\u003cstrong\u003eTreatment\u0026nbsp;\u003c/strong\u003ediscontinuation was defined as failure to complete the six planned chemotherapy cycles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The primary endpoint was OS, defined as the time from the initiation of first-line therapy to death from any cause or censoring at the last follow-up. Secondary endpoints included progression-free survival (PFS), defined as the time from treatment initiation to documented disease progression or death from any cause, whichever occurred first. Patients without an event were censored at the last follow-up. Additional secondary points were the incidence of grade ≥2 non-haematological adverse events (NHAEs) and grade ≥3 haematological adverse events (HAEs), and the ORR. All tumour responses were assessed using the RECIST version 1.1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All statistical analyses were performed using Stata SE software version 18.0; (StataCorp, College Station, TX, USA). Continuous variables were summarised as medians and compared between groups using the Wilcoxon rank-sum test. Categorical variables were analysed using the chi-squared test or\u0026nbsp;Fisher’s exact test,\u0026nbsp;with the latter applied when the expected cell count was \u0026lt;5. The median follow-up duration was calculated using the reverse Kaplan–Meier method and compared using the log-rank test. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were conducted to identify the prognostic factors.\u0026nbsp;The proportional hazards assumption was assessed using Schoenfeld residuals.\u0026nbsp;In the multivariate analysis,\u0026nbsp;variables that violated this assumption were analyzed using stratified Cox regression models.\u0026nbsp;In\u0026nbsp;Cox proportional hazards regression analyses, age, Ccr, and BMI were treated as continuous variables. Statistical significance was set at a two-sided p-value \u0026lt;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween December 2019 and March 2025, 76 eligible patients with R/M HNSCC were included in the analysis; cisplatin and carboplatin were administered to 41 and 35 patients, respectively. The baseline patient characteristics stratified according to treatment regimen are summarised in Table 1. Patients in the cisplatin group were significantly younger (median age: 57 vs. 73 years, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01) and had a higher creatinine clearance (median: 97.4 vs. 60.0%/min, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01) than those in the carboplatin group. The distributions of CPS status (\u003cem\u003ep\u003c/em\u003e = 0.049), smoking history (\u003cem\u003ep\u003c/em\u003e = 0.04), and primary tumour site (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01) also differed between the groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The treatment delivery metrics are presented in Table 2. Platinum cRDI was significantly lower in the cisplatin group than in the carboplatin group (\u003cem\u003ep\u003c/em\u003e = 0.02). Treatment discontinuation owing to adverse events was more frequently observed in the cisplatin group than in the carboplatin group (36.6% vs. 14.3%; \u003cem\u003ep\u003c/em\u003e = 0.03).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Detailed outcome data are shown in Table 3. The median follow-up period was 32.4 months. Median PFS was 4.1 months in the cisplatin group and 7.1 months in the carboplatin group (Fig. 1A). Median OS was 14.8 and 20.7 months, respectively (Fig. 1B). The ORR was 34.2%, with comparable rates in the cisplatin (34.1%) and carboplatin (34.3%) groups. In the univariate analysis, the HR for PFS with carboplatin compared to cisplatin was 0.86 (95% CI: 0.51–1.46, \u003cem\u003ep\u003c/em\u003e = 0.58), and the HR for OS was\u0026nbsp;0.95 (95% CI: 0.51–1.78, \u003cem\u003ep\u003c/em\u003e = 0.88). PS 1 and PS 2 were strongly associated with shorter PFS (\u003cem\u003ep\u003c/em\u003e = 0.04 and p=0.01), and OS (\u003cem\u003ep\u003c/em\u003e \u0026lt;0.01 and \u003cem\u003ep\u003c/em\u003e = 0.01, respectively). CPS ≥20 was significantly associated with longer PFS (\u003cem\u003ep\u003c/em\u003e = 0.03). These variables were then included as covariates in the multivariate model. In the multivariate analysis, the HRs for carboplatin were 0.70 (95% CI: 0.40–1.23) for PFS and 0.68 (95% CI: 0.34–1.34) for OS. The ORRs were comparable between the cisplatin and carboplatin groups (34.1% vs. 34.3%, p = 0.99). Grade ≥3 HAEs were significantly more common in the cisplatin group than in the carboplatin group (87.8% vs. 48.6%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01). Specifically, decreased white blood cell count (46.3% vs. 17.1%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01), decreased neutrophil count (65.9% vs. 34.3%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01), and febrile neutropenia (17.1% vs. 0%, \u003cem\u003ep\u003c/em\u003e = 0.01) were relatively frequent in the cisplatin group. Grade ≥2 NHAEs were also considerably more observed in the cisplatin (97.6% vs. 54.3%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01). Notably, nausea (53.7% vs. 11.4%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01), anorexia (46.3% vs. 22.9%, \u003cem\u003ep\u003c/em\u003e = 0.03), malaise (22.0% vs. 2.9%, \u003cem\u003ep\u003c/em\u003e = 0.02), and diarrhoea (24.4% vs. 2.9%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01) occurred relatively often in patients receiving cisplatin.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCisplatin has long been a cornerstone in the treatment of R/M HNSCC owing to its potent antitumour activity [2-7]. It remains preferentially used in patients with a good PS and preserved organ function, even in the post-EXTREME era [8]. However, the substantial toxicity of cisplatin can adversely affect health-related quality of life [9]. In clinical practice, carboplatin is frequently selected for patients who are older or have impaired renal function, as was observed in our study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In our retrospective analysis based on real-world data, cisplatin demonstrated no superiority over carboplatin in terms of OS and PFS. Moreover, it failed to show any advantage in ORR when used in combination with pembrolizumab and 5-FU. Despite the inclusion of patients with an ECOG PS 2, the observed median PFS was consistent with that reported in the KEYNOTE-048 trial, and the median OS showed a trend toward improvement [12,13]. These OS outcomes were also similar to those observed in the Japanese subgroup of KEYNOTE-048 [17,18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Although CPS was not significantly associated with OS in the univariate analysis, it was retained in the multivariate model because of its significant association with PFS and its established role as a prognostic biomarker in R/M HNSCC [12,13]. To evaluate the robustness of our findings, we conducted multiple sensitivity analyses, including models incorporating additional clinical covariates (p16 status, primary tumour site, smoking history, age, and Ccr), as well as truncated Cox models at 24 months. All sensitivity analyses of OS and PFS demonstrated results consistent with those of the primary analysis (Supplementary Table 1 A, B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Grade ≥2 non-hematologic toxicities were analyzed, as they are considered clinically meaningful events that compromise quality of life, and affect treatment decision.\u0026nbsp;The incidence of both grade ≥3 HAEs and grade ≥2 NHAEs was significantly higher in the cisplatin group than in the carboplatin group. Grade ≥3 NHAEs were also more frequently observed in the cisplatin group (Supplementary Table 2 A).\u0026nbsp;In contrast, the number of grade ≥2 immune-related adverse events was comparable between the two groups (Supplementary Table 2\u0026nbsp;B). Notably, platinum cRDI was significantly lower in the cisplatin group, and the proportion of AE-related discontinuations was higher than that in the carboplatin group.\u0026nbsp;Considering its increased toxicity and decreased treatment delivery, carboplatin may be preferable when sustained platinum administration is prioritised. Compared to the overall population in KEYNOTE-048, the prevalence of severe adverse events in our cohort was high. However, the toxicity profile was similar to that reported in a Japanese subgroup, suggesting that ethnic and clinical practice factors \u0026nbsp;may influence the differences [17,18]. The regimen of cisplatin at 100 mg/m² on day 1 combined with continuous intravenous infusion of 5-FU at 1,000 mg/m² per day from days 1 to 4 has been reported to be excessively intensive in Japanese patients [19]. The high incidence of adverse events observed in this study may be attributable to this dosing intensity.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In the era of ICIs, their potent antitumour activity appears to diminish the clinical relevance of the selection between cisplatin and carboplatin. Given its favourable toxicity profile, carboplatin is a better-tolerated and clinically appropriate alternative, and our findings support this substitution. While our study focused on platinum selection, chemotherapy choice in ICI-based regimens is increasingly guided by the consideration of toxicity [20,21]. Future research is required to clarify the optimal chemotherapy backbone in ICI-based regimens and refine treatment approaches that balance efficacy and tolerability.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;First, the retrospective nature of this study may have introduced selection bias and unmeasured confounding factors. To address this limitation, we conducted multivariate and sensitivity analyses, adjusting for key prognostic variables, and used standardised outcome definitions.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Second, the sample size was relatively small. However, our study reflects a real-world patient population and offers valuable insights into treatment patterns in current clinical practice.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Third, the median follow-up duration differed between treatment groups, with a longer follow-up in the cisplatin arm. Although this discrepancy may have affected the estimation of OS,\u0026nbsp;the log-rank test\u0026nbsp;showed no significant difference in the follow-up duration between the groups. To further address this potential bias, we conducted truncated analyses at 24 months, which yielded results consistent with those of the primary analysis (Supplementary Table 1 A, B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Fourth, because most patients were Japanese, the generalisability of our results to other ethnic groups and healthcare systems may be limited.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e\u0026nbsp;In conclusion, cisplatin showed no advantage over carboplatin in terms of OS, PFS, and ORR. Additionally, cisplatin was associated with considerably higher toxicity in the context of ICI-based therapy for R/M HNSCC. These findings support the selection of carboplatin as the preferred platinum with pembrolizumab when considering the balance between efficacy and safety. Further investigation is necessary to validate these findings and inform future treatment strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWe would like to thank Editage (www.editage.com) for English language editing and appreciate the support of resident Erisa Toda and intern Mari Naito in patient care.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conception: J. Y, N. F, T. I; Manuscript writing: J.Y, NF; Data acquisition: J.Y, T.I; Literature review: J.Y, N.F; Imaging evaluation: J.Y, N.F, K.N, C.K, H.M, S.T; Manuscript Supervision: C.K, H.M, S.T, Y.M; Final approval: all authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are not publicly available owing to patient confidentiality but can be obtained from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJ.Y:\u003c/strong\u003e Honoraria for lectures from Kyowa Kirin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eN.F:\u003c/strong\u003e Research funding to the author’s institution from Eisai; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, MSD, Merck Biopharma, Lilly, Eisai, Novartis, Thermo Fisher Scientific, Daiichi Sankyo, and AstraZeneca.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC.K:\u003c/strong\u003e Research funding to the author’s institution from Daiichi Sankyo, AstraZeneca, MSD, Abbvie, Ono Pharmaceutical, ALX Oncology, and Sanofi; honoraria for lectures and presentations, including speaker bureaus, from Ono Pharmaceutical, Chugai Pharma, Daiichi Sankyo, AstraZeneca, MSD, Taiho Pharmaceutical, and Eisai.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eS.T:\u003c/strong\u003e Research funding to the author’s institution from Daiichi Sankyo, Sanofi, Eisai, and Bayer; honoraria for lectures and presentations, including speaker bureaus, from Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, MSD, Chugai Pharma, Bristol-Myers Squibb Japan, Ono Pharmaceutical, and Lilly Japan; consulting from Bayer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eY.M:\u003c/strong\u003e Research funding to the author’s institution from MSD, Daiichi Sankyo, UCB Japan; honoraria for lectures and presentations, including speaker bureaus, from Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Eisai, Bristol-Myers Squibb, Merk biopharma, Janssen and Astellas Pharma.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray, F. et al\u003cem\u003e.\u003c/em\u003e Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA Cancer J. Clin.\u003c/em\u003e \u003cstrong\u003e74, \u003c/strong\u003e229\u0026ndash;263 (2024).\u003c/li\u003e\n\u003cli\u003eForastiere, A. A. et al\u003cem\u003e.\u003c/em\u003e Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e10,\u003c/strong\u003e 1245\u0026ndash;1251 (1992).\u003c/li\u003e\n\u003cli\u003eJacobs, C. et al\u003cem\u003e.\u003c/em\u003e A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e10,\u003c/strong\u003e 257\u0026ndash;263 (1992).\u003c/li\u003e\n\u003cli\u003eSchornagel, J. H. et al\u003cem\u003e.\u003c/em\u003e Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: A European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e13,\u003c/strong\u003e 1649\u0026ndash;1655 (1995).\u003c/li\u003e\n\u003cli\u003eSchrijvers, D. et al. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e16,\u003c/strong\u003e 1054\u0026ndash;1059 (1998).\u003c/li\u003e\n\u003cli\u003eForastiere, A. A. et al. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e19,\u003c/strong\u003e 1088\u0026ndash;1095 (2001).\u003c/li\u003e\n\u003cli\u003eGibson, M. K. et al\u003cem\u003e.\u003c/em\u003e Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An intergroup trial of the Eastern Cooperative Oncology Group. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e23,\u003c/strong\u003e 3562\u0026ndash;3567 (2005).\u003c/li\u003e\n\u003cli\u003eVermorken, J. B. et al\u003cem\u003e.\u003c/em\u003e Platinum-based chemotherapy plus cetuximab in head and neck cancer. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e \u003cstrong\u003e359,\u003c/strong\u003e 1116\u0026ndash;1127 (2008).\u003c/li\u003e\n\u003cli\u003eLokich, J. \u0026amp; Anderson, N. Carboplatin versus cisplatin in solid tumors: An analysis of the literature. \u003cem\u003eAnn. Oncol.\u003c/em\u003e \u003cstrong\u003e9,\u003c/strong\u003e 13\u0026ndash;21 (1998).\u003c/li\u003e\n\u003cli\u003eSano, D. et al\u003cem\u003e.\u003c/em\u003e Real-world treatment outcomes of the EXTREME regimen as first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck: A multi-center retrospective cohort study in Japan. \u003cem\u003eAnticancer Res.\u003c/em\u003e \u003cstrong\u003e39,\u003c/strong\u003e 6819\u0026ndash;6827 (2019).\u003c/li\u003e\n\u003cli\u003eFukuda, N. et al\u003cem\u003e.\u003c/em\u003e Comparison of the efficacy and safety of the EXTREME regimen for treating recurrent or metastatic head and neck squamous cell carcinoma in older and younger adult patients. \u003cem\u003eCancer Rep.\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e. \u003cem\u003eCancer Rep. (Hoboken)\u003c/em\u003e \u003cstrong\u003e4,\u003c/strong\u003e e1322 (2021).\u003c/li\u003e\n\u003cli\u003eBurtness, B. et al\u003cem\u003e.\u003c/em\u003e 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. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e394,\u003c/strong\u003e 1915\u0026ndash;1928 (2019).\u003c/li\u003e\n\u003cli\u003eBurtness, B. et al\u003cem\u003e.\u003c/em\u003e Pembrolizumab alone or with chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048: Subgroup analysis by programmed death ligand-1 combined positive score. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e40,\u003c/strong\u003e 2321\u0026ndash;2332 (2022).\u003c/li\u003e\n\u003cli\u003eHarrington, K. J. et al\u003cem\u003e.\u003c/em\u003e Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: Updated results of the phase III KEYNOTE-048 study. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e41,\u003c/strong\u003e 790\u0026ndash;802 (2023).\u003c/li\u003e\n\u003cli\u003eRischin, D. et al\u003cem\u003e.\u003c/em\u003e Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. \u003cem\u003eOral Oncol.\u003c/em\u003e \u003cstrong\u003e128,\u003c/strong\u003e 105815 (2022).\u003c/li\u003e\n\u003cli\u003ePeyrade, F. et al\u003cem\u003e.\u003c/em\u003e Systemic treatment and medical management of metastatic squamous cell carcinoma of the head and neck: Review of the literature and proposal for management changes. \u003cem\u003eOral Oncol.\u003c/em\u003e \u003cstrong\u003e49,\u003c/strong\u003e 482\u0026ndash;491 (2013).\u003c/li\u003e\n\u003cli\u003eTakahashi, S. et al\u003cem\u003e.\u003c/em\u003e First-line pembrolizumab \u0026plusmn; chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048. \u003cem\u003eInt. J. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e27, \u003c/strong\u003e1805\u0026ndash;1817 (2022).\u003c/li\u003e\n\u003cli\u003eOridate, N. et al\u003cem\u003e.\u003c/em\u003e First-line pembrolizumab with or without chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up of the Japanese population of KEYNOTE‑048. \u003cem\u003eInt. J. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e29,\u003c/strong\u003e 1825\u0026ndash;1839 (2024).\u003c/li\u003e\n\u003cli\u003eKiyota, N. et al\u003cem\u003e.\u003c/em\u003e Systemic chemotherapy with cisplatin plus 5-FU (PF) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Efficacy and safety of a lower dose of PF (80/800) at a single institution in Japan. \u003cem\u003eJpn. J. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e39,\u003c/strong\u003e 225\u0026ndash;230 (2009).\u003c/li\u003e\n\u003cli\u003eDzienis, M. et al\u003cem\u003e.\u003c/em\u003e Pembrolizumab plus carboplatin and paclitaxel as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-B10): A single-arm phase IV trial. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e42,\u003c/strong\u003e 2989\u0026ndash;2999 (2024).\u003c/li\u003e\n\u003cli\u003eSun, L., Cohen, R. B. \u0026amp; Dimitrios Colevas, A. Platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). \u003cem\u003eOral Oncol.\u003c/em\u003e \u003cstrong\u003e158,\u003c/strong\u003e 106997 (2024).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cisplatin, Carboplatin, Pembrolizumab, Immune checkpoint inhibitors, Head and Neck cancer","lastPublishedDoi":"10.21203/rs.3.rs-7990042/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7990042/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe KEYNOTE-048 trial established pembrolizumab plus platinum and 5-fluorouracil (5-FU) as the standard first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). In the present study, the efficacy and safety of cisplatin and carboplatin in combination with pembrolizumab were compared using real-world data. In this retrospective study, 76 patients with R/M HNSCC treated with pembrolizumab plus 5-FU and either cisplatin (n=41) or carboplatin (n=35) were analysed. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and the incidence of grade ≥3 haematological and grade ≥2 non-haematological adverse events. The median PFS was 4.1 months with cisplatin and 7.1 months with carboplatin (p=0.58). The median OS values were 14.8 and 20.7 months, respectively (p=0.88). The ORR values were similar (34.1% vs. 34.3%, p=0.99). Grade ≥3 haematological adverse events were more frequent with cisplatin than with carboplatin (87.8% vs. 48.6%, p\u0026lt;0.01), as were grade ≥2 non-haematological adverse events (97.6% vs. 54.3%, p\u0026lt;0.01). Cisplatin showed no advantage over carboplatin regarding OS, PFS, and ORR but caused increased toxicity in ICI-based therapy for R/M HNSCC. These findings support carboplatin as the preferred platinum with pembrolizumab, balancing efficacy and safety.\u003c/p\u003e","manuscriptTitle":"Platinum Selection in Immune Checkpoint Inhibitor-Based Therapy for Recurrent or Metastatic Head and Neck Cancer: A Multi-Institutional Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 10:10:35","doi":"10.21203/rs.3.rs-7990042/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-30T04:55:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-27T14:41:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218026272621676728327675286338836687956","date":"2026-03-27T14:19:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-23T15:05:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3881367778661841383298338582193260653","date":"2026-01-07T13:46:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-17T14:06:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-26T08:02:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-01T04:57:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-01T04:56:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-30T13:36:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cc7145f2-628a-4f5d-affa-0d2968d7827f","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":59841305,"name":"Biological sciences/Cancer"},{"id":59841306,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-04-27T16:04:34+00:00","versionOfRecord":{"articleIdentity":"rs-7990042","link":"https://doi.org/10.1038/s41598-026-50081-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-04-24 15:59:47","publishedOnDateReadable":"April 24th, 2026"},"versionCreatedAt":"2025-12-22 10:10:35","video":"","vorDoi":"10.1038/s41598-026-50081-5","vorDoiUrl":"https://doi.org/10.1038/s41598-026-50081-5","workflowStages":[]},"version":"v1","identity":"rs-7990042","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7990042","identity":"rs-7990042","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}