Continuation of immune checkpoint inhibitor therapy after progression in head and neck squamous cell carcinoma: A multicenter study

Background: Immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, disease progression after first-line ICI therapy remains a major clinical challenge, and the benefit of ICI continuation or rechallenge after progression has not been fully elucidated. Methods: In this multicenter retrospective study, we included patients diagnosed with HNSCC between 2016 and May 2025 at Samsung Medical Center and Massachusetts General Hospital. This study included patients who received first-line ICI therapy with or without other agents. Overall survival (OS) was compared between patients who received second-line ICI continuation (ICI-based regimens) and those who received non-ICI treatments. Results: A total of 278 patients received first-line ICI therapy with or without chemotherapy, including 85 (30.6%) with HPV-positive HNSCC, 133 (47.8%) with HPV-negative disease, and 60 (21.6%) with unknown HPV status. Among them, 242 patients (87.0%) experienced disease progression after first-line ICI ± chemotherapy, and 210 proceeded to second-line treatment. Of these 210 patients, 73(34.8%) received ICI-based therapy- while the remaining 137 (65.2%) received cytotoxic chemotherapy or other non-ICI regimens. The median OS from the start of first-line therapy was 17.0 months (95% CI, 14.5-19.5). Median OS was 21.1 months for patients who received second-line ICI continuation and 14.3 months for those who received non-ICI treatments (HR 0.61, 95% CI 0.43-0.85, P = 0.004). The median OS from the start of second-line therapy was 12.2 months for patients who received ICI with or without other agents and 8.0 months for those who received chemotherapy (P = 0.003). In subgroup analyses stratified by first-line ICI efficacy, patients with a first-line treatment duration of < 6 months showed a modest OS advantage with ICI-based second-line therapy compared with non-ICI regimens (11.2 vs. 8.0 months; P = 0.042). In patients whose first-line treatment duration was ≥ 6 months, the difference was substantially more pronounced, with ICI-based therapy demonstrating a markedly longer OS compared with non-ICI treatment (12.7 vs. 7.8 months; P = 0.035). Conclusions: ICI continuation was associated with a significant OS benefit compared with non-ICI regimens in patients with recurrent or metastatic HNSCC who progressed after first-line ICIs. These findings indicate that continuing ICI-based treatment may be a feasible option regardless of the duration of first-line PFS, with a more pronounced benefit in patients who initially achieved durable disease control with first-line ICI therapy.