Pattern of inferior early progression-free survival with immunotherapy versus chemotherapy in head and neck cancer: A meta-analysis of randomized trials

Introduction: Platinum-based chemotherapy combined with immunotherapy has long been the standard first-line treatment for advanced head and neck squamous cell carcinoma (HNSCC). Recently, pembrolizumab-based regimens guided by PD-L1 expression have introduced immunotherapy-only approaches as viable options for selected patients. However, early data from randomized trials suggest that immunotherapy may result in inferior short-term progression-free survival (PFS) compared with chemotherapy, likely due to delayed immune activation or possible hyperprogression of the disease. To clarify these time-dependent effects, we performed a meta-analysis comparing the early efficacy of immunotherapy versus chemotherapy in advanced HNSCC. Methods: We systematically searched PubMed, Embase, and the Cochrane Library for phase II-III RCTs evaluating first-line immunotherapy(Pembrolizumab, Nivoluab+Ipilimumab, Durvalumab, Durvalumab+Tremelimumab) with platinum-based chemotherapy in advanced HNSCC. Eligible trials were required to have Kaplan-Meier PFS curves for immunotherapy and chemotherapy arms. Trials including post-first-line settings were excluded. Kaplan-Meier PFS curves were digitized, and reconstructed individual patient data were derived via the Guyot method. Pooled Kaplan-Meier survival curves were then generated, and hazard ratio (HR) values comparing immunotherapy and chemotherapy arms were calculated at 3, 6, 9, and 12 months to assess changes in treatment effect over time. Hazard ratios (HRs) were estimated through a two-stage meta-analytic method, with each study weighted according to its sample size and variance to accommodate inter-trial differences. Results: Three eligible RCTs were identified. Immunotherapy exhibited a pronounced early disadvantage in PFS compared with chemotherapy, with HRs of 3.77 (95% CI, 3.17-4.48) at 3 months and 2.20 (95% CI, 1.80-2.68) at 6 months. This gap narrowed over time but was still statistically significant by the 9th (HR 1.86; 95% CI, 1.62-2,13) and the 12th month (HR 1.73; 95% CI, 1.49-2.01). Pooled Kaplan-Meier PFS curves mirrored these findings, showing inferior short-term performance of immunotherapy followed by gradual convergence of both arms, with the immunotherapy arm ultimately crossing over the chemotherapy arm around the 12th month. Conclusion: Among patients with metastatic HNSCC, first-line ICI monotherapy initially shows inferior outcomes compared to chemotherapy, but the survival benefit becomes evident around the 12th month as the delayed effects of immunotherapy emerge. These results highlight the importance of close early monitoring and lend support to combination or sequential regimens to counteract early disease progression while maintaining long-term benefit.