Second-line cetuximab monotherapy following PD-1 inhibitor treatments in patients with recurrent/metastatic head and neck carcinoma.

6055 Background: PD-1 inhibitors, alone or in combination with chemotherapy, are standard first-line therapy for recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). No established second-line standard exists for majority of patients who progress on immunotherapy. Cetuximab, the only approved targeted biologic agent in HNSCC, has historically shown modest activity as monotherapy, with a 13% response rate. We hypothesized that cetuximab administered after PD-1 inhibitors may demonstrate enhanced efficacy due to potentially synergistic, immunomodulatory effects. Methods: This non-randomized single-institution study included patients with R/M HNSCC who experienced disease progression or intolerance to PD-1 inhibitor therapy, with or without chemotherapy, and were subsequently treated with cetuximab monotherapy. Imaging was performed every 6 weeks, and response was assessed per RECIST v1.1. Outcomes included best overall response (BOR), progression-free survival (PFS), overall survival (OS), and toxicity. Survival outcomes were estimated using Kaplan–Meier methods. Results: Twenty-seven patients (8 female, 19 male) were included; 5 were HPV-positive. All HPV-positives had metastatic disease, while all HPV-negatives had recurrent disease. Two patients experienced anaphylaxis with the first cetuximab infusion, and two died from tumor-related complications prior to first restaging; all were included in outcome analyses. Nine patients (33.3%) achieved a partial response (PR), while 18 (66.7%) were non-responders, including 10 (37.0%) with stable disease (SD), 4 (14.8%) with progressive disease (PD), and 4 (14.8%) non-evaluable. Median follow-up was 32.4 mos, with 21 deaths observed. Median OS was 11.6 mos (95% CI, 8.0–21.0) in all patients, 15.5 mos (95% CI, 4.2–24.9) in responders and 11.4 mos (95% CI, 5.3–25.0) in non-responders, with 18.0 mos (95% CI, 4.4–32.0) in patients with SD. Median PFS was 4.4 mos overall, 5.3 mos (2.7 to 11.5) in responders, and 4.4 mos (2.6 to 6.2) in non-responders, with 5.9 mos (2.5 to 7.0) in patients with SD. Median OS was 32.0 mos (11.7 to NE) in HPV-positive patients and 10.8 mos (5.3 to 18.0) in HPV-negatives. Two patients experienced anaphylactic reaction with the initial cetuximab administration. All treated patients developed acneiform skin rash, with 17 (68%) experiencing grade 3, necessitating oral antibiotics. Conclusions: Cetuximab monotherapy following PD-1 inhibitor therapy demonstrated encouraging clinical activity in patients with R/M HNSCC, with improved outcomes compared with historical cetuximab monotherapy. These findings suggest that sequential targeting of immune-mediated pathways may provide clinical benefit after an immunotherapy failure. Larger prospective studies are warranted to validate these results and to better define response patterns in the immunotherapy setting. Clinical trial information: NCT04375384 .