Cytokine dynamics in a phase II trial of metronomic carboplatin/paclitaxel combined with cemiplimab in recurrent/metastatic head and neck squamous cell carcinoma.

6044 Background: Standard-dose chemotherapy combined with immunotherapy improves response rates in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but its use is often constrained by significant toxicity. Metronomic chemotherapy (MCT) offers a potentially better-tolerated alternative while preserving immune-modulatory properties. We evaluated cytokine profiles and their longitudinal dynamics to investigate the relationship between immune-mediated mechanisms and clinical outcomes in patients treated with MCT plus cemiplimab. Methods: Single- arm phase II trial (NCT04862650). R/M HNSCC pts received first-line cemiplimab 350 mg IV Q3W (≤35 cycles) plus weekly carboplatin (AUC1) and paclitaxel (25 mg/m²) for 24 weeks. Primary endpoint was overall response rate (ORR) per RECIST v1.1 at week 12. Forty immune-modulatory cytokines were assessed at baseline, week 3, and week 6 using the Luminex xMAP platform. Results: From Nov 2021 to Dec 2024, 40 evaluable patients were enrolled (median age was 66 years, 82.5% were male; 35% were HPV-positive). Median follow-up was 10 months (range 1–28). ORR was 42.5% (15% CR) and Median OS was 14.8 months (95% CI, 10.3–23.9). Responders had significantly higher IFN-β at all timepoints (P=.008–.04). Elevated IL-4, IL-5, and IL-10 at baseline were associated with improved ORR. Overall, LIGHT, FasL and TGF-α decreased while PD-L1 increased over time (all q<0.001). Compared to baseline, on week 6, responders showed decreased VEGF-A, TSLP, FasL, and IL-4 (P < .03), while non-responders exhibited increased IFN-γ, PD-L1, and IL-6Rα (P < .04). Changes in IFN-γ (HR 3.23, P=.006) and IL-4Rα (HR 3.06, P=.008) from baseline to week 3 were associated with worse overall survival. Conclusions: MCT combined with cemiplimab demonstrated clinically meaningful antitumor activity. Alterations in plasma concentrations of select cytokines were associated with therapeutic response and overall survival. These results are hypothesis-generating and support the need for prospective validation. Clinical trial information: NCT04862650 .