Outcomes of PD-(L)1 inhibitor continuation or rechallenge after first-line progression in recurrent or metastatic head and neck squamous cell carcinoma.

6059 Background: PD-(L)1 inhibitors are a standard first-line (1L) backbone for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, many patients progress after 1L PD-(L)1–based therapy, and optimal post-progression strategies remain undefined. In particular, the benefit of continuing or rechallenging PD-(L)1 inhibitors beyond progression is unclear. Methods: In this multicenter retrospective study, we included patients diagnosed with R/M HNSCC (oral cavity, oropharynx, larynx, and hypopharynx) between 2016 and May 2025 at Samsung Medical Center and Mass General Brigham. Eligible patients received 1L PD-(L)1–containing regimen, experienced disease progression, and underwent subsequent second-line systemic therapy. Patients were categorized by post-progression strategy: continuation or rechallenge with PD-(L)1 inhibitors versus non–PD-(L)1–based therapy. Overall survival (OS) was defined as the time from initiation of 1L therapy to death from any cause. Results: A total of 252 patients with R/M HNSCC met eligibility criteria. Median age was 64; 191 (76%) were male; 68 (27.0%) were HPV-positive; and 217 (86%) were PD-L1 positive (CPS ≥1). Twenty-six patients (10.3%) received anti-PD-(L)1 monotherapy, and 84 (33%) remained on 1L therapy for ≥6 months. Median OS for the entire cohort was 18 months (95% CI, 15.9-20.1). Median OS was 21.1 months among patients who continued or were rechallenged with PD-(L)1 inhibitor (n = 112) versus 14.4 months in those who were not (n = 140) (p < 0.001). On multivariable analysis including post-progression PD-(L)1 continuation/rechallenge, HPV status, PD-L1 expression, age, sex, ECOG performance status, and duration of 1L PD-(L)1 therapy, continuation or rechallenge with PD-(L)1 inhibitors (HR 0.583, p=0.003) and 1L PD-(L)1 duration ≥6 months (HR 0.487, p<0.001) were independently associated with improved OS. Conclusions: In this study, continuation or rechallenge with PD-(L)1 inhibitors after progression on 1L therapy was associated with improved OS in patients with R/M HNSCC, independent of PD-L1 expression or HPV status. Prolonged benefit from 1L PD-(L)1 therapy was also independently associated with favorable survival. These findings suggest that selected patients may derive continued clinical benefit from anti-PD-(L)1–based strategies beyond progression and support prospective studies to refine patient selection and optimize post-progression treatment strategies.