Importance: Immune checkpoint inhibitor (ICI) monotherapy for patients with recurrent, unresectable, or metastatic (RUM) head and neck squamous cell carcinoma (HNSCC) is associated with poor outcomes. Low-dose, hypofractionated, quad-shot radiotherapy (QSRT) may enhance the efficacy of ICIs. Objective: To evaluate the efficacy and toxic effects of ICIs in combination with QSRT for patients with RUM HNSCC that is amenable to QSRT. Design, Setting, and Participants: This single-arm, phase 2, nonrandomized clinical trial was conducted at a single, academic, National Cancer Institute-designated Comprehensive Cancer Center and included patients with RUM HNSCC who were going to receive treatment with pembrolizumab monotherapy and had a targetable site in the head and neck that was amenable to QSRT (based on location, prior radiotherapy dose, and tolerance). Patients were enrolled and treated between February 2021 and May 2024. Interventions: Pembrolizumab (200 mg/m2) was administered every 3 weeks until disease progression, intolerance, or a maximum duration of 2 years. QSRT comprised 14.8 Gy in four 3.7-Gy fractions that were delivered twice daily on consecutive days. QSRT courses were delivered cyclically between pembrolizumab cycles. Main Outcomes and Measures: The primary outcome was overall response rate per Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with at least 1 response assessment. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and clinician-rated (Common Terminology Criteria for Adverse Events, version 5.0) and patient-reported (patient-reported outcomes version of the Common Terminology Criteria for Adverse Events, version 1.0) adverse effects (AEs). Results: Of the 29 individuals who were screened, 21 enrolled, and 15 patients (median range age, 61 33-86 years) were eligible for response analysis: 5 women (33.3%), 10 men (66.7%), 9 individuals with oropharyngeal/oral cavity primary tumors, and 14 current/former smokers (93.3%). Fourteen patients had received prior systemic therapy, and 11 had received prior RT. Among evaluable patients, the overall response rate was 47% (95% CI, 21%-73%). Median PFS and OS among the treated patients (n = 20) were 9.2 months (95% CI, 3-17) and 14.9 months (95% CI, 5 to not estimable), respectively. For the 15 patients who were evaluable for the primary end point, median PFS was 11.5 months (95% CI, 5.1 to not estimable), and median OS was 15.3 months (95% CI, 6.3 to not estimable). Grade 3 and 4 AEs occurred for 6 and 2 patients, respectively. Patient-reported AEs did not substantially change over time. Conclusions and Relevance: This nonrandomized trial demonstrated the feasibility of pembrolizumab plus QSRT for patients with RUM HNSCC and provides preliminary evidence of a potential benefit to this novel combination that warrants investigation in future randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04454489.
Hughes et al. (Thu,) studied this question.