Molecular correlates of response and survival in a phase II trial of weekly carboplatin/paclitaxel plus cemiplimab (wCP+C) in advanced/metastatic mucosal head and neck squamous cell carcinoma (a/mHNSCC)

Background: a/mHNSCC exhibits poor prognosis and limited immunotherapy efficacy. Weekly low-dose chemotherapy may enhance immunogenicity while reducing toxicity. We conducted a phase II trial of weekly low-dose chemotherapy plus cemiplimab as first-line treatment in a/mHNSCC, with integrated genomic profiling to explore molecular correlates of outcome. Patients received weekly carboplatin (AUC 1) and paclitaxel (30 mg/m²) plus cemiplimab (350 mg q3w). Forty-two patients were enrolled from Dec 2021-Dec 2024. Median age was 68 (range 42-81); 38/42 were male, and 27 (64%) were HPV-positive. Median OS (27 events) was 16.4 months (95% CI, 12.6-23.9); median PFS (36 events) was 5.62 months (95% CI, 5.0-10.3). Objective response rate (ORR) was 43% (18/42, PR or CR). The treatment was well-tolerated. These results were previously presented at ESMO 2025. We aim to present an exploratory analysis of pathogenic genomic mutations in this cohort and their correlation with ORR, PFS, and OS. Methods: Of the 42 enrolled patients, genomic analysis (Tempus xT/xF) was performed in 29. The 4 most prevalent pathogenic alterations were analyzed separately, while all genes with detected pathogenic alterations were grouped and analyzed by pathway or functional group, with time-to-event outcomes assessed via Kaplan-Meier and log-rank, and Cox models when appropriate. Prevalence of tumor mutations between responder groups (CR/PR versus PD as ORR) and extreme PFS groups (<3 versus >12 months) was performed with odds ratio. P-values< 0.05 were deemed statistically significant. Due to the hypothesis-generating nature of this report, p-value adjustments for multiple tests were not performed. Results: Pathogenic alterations included TP53 (N=14), CDKN2A (N=11), TERT promoter (N=8), and FGF3/FGF4 copy number gains (CNG; N=17). Mutations in NOTCH pathway genes (NOTCH1/3, FBXW7; N=7) were enriched in patients with primary progression (p = 0.02) and those with PFS <3 months versus >12 months (p = 0.03). NOTCH alterations conferred inferior PFS (HR 3.6; 95% CI, 1.4-9.3; p < 0.01) and OS (HR 2.9; 95% CI, 1.05-8.0; p = 0.04). TERT promoter mutations were associated with worse OS (HR 4.9; 95% CI, 1.7-14.5; p < 0.01) and trended toward poor PFS (HR 2.2; 95% CI, 0.9-5.2; p = 0.08). FGF3/FGF4 CNGs also trended toward inferior PFS (HR 2.6; 95% CI, 0.9-7.4; p = 0.08) and were associated with worse OS (HR 2.5; 95% CI, 1.0-6.6; p = 0.04). Conclusions: Weekly low-dose chemotherapy plus cemiplimab shows promising activity in a/mHNSCC. Exploratory genomic profiling suggests NOTCH pathway mutations may be markers of poor prognosis and resistance. TERT and FGF3/4 alterations may also confer inferior outcomes and warrant further study.