Phase 2 trial of dual EGFR inhibition with cetuximab and afatinib in patients with recurrent/metastatic head and neck squamous cell cancers (HNSCC).

Abstract

6023 Background: Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) but its clinical activity is limited by resistance mechanisms. Our previous HNSCC trial of chemotherapy, cetuximab and erlotinib demonstrated a 62.5% objective response rate (ORR) including 2 durable complete responses (CR), with greater inhibition of phosphorylated EGFR in post-treatment biopsies. Because human epidermal growth factor receptor (HER)-2 and HER3 are overexpressed in cetuximab-resistant HNSCC, we postulated that the combination of cetuximab and afatinib, an irreversible, pan-HER inhibitor, would overcome resistance by inhibiting EGFR/HER dimers and inhibiting nuclear translocation and resulting non-canonical EGFR activities in R/M HNSCC. Methods: The primary objective of this single-arm phase II trial was ORR to the combination of cetuximab and afatinib in patients with R/M HNSCC refractory to platinum-based chemotherapy and/or immune checkpoint therapy. Cetuximab was administered at standard doses weekly/bi-weekly. Afatinib was initially dosed at 40 mg orally daily, amended to 30 mg orally daily after 25 patients, to improve tolerability. Key secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS) and toxicity. Radiographic tumor assessment was performed, using RECIST version 1.1 every 8 weeks. Biopsy was obtained at baseline, 4 weeks after treatment initiation and at end of treatment, where medically feasible. Results: The study protocol was approved by the institutional review board and written informed consent was obtained from all participants. Fifty patients were enrolled between 7/3/2017 and 10/16/2024 at Yale Cancer Center, 47 were evaluable for response. Median age was 63 years (range 43-81 years), 39 (83%) were male, 21 (44.7%) had p16 positive tumors, 26 (55.3%) were p16 negative. Most common primary tumor location was oropharynx (n, %: 21, 44.7). ORR was 23.4% (2 complete responses, 9 partial responses, 95% CI: 12.3%-38%) for the entire population, 10 responses were in p16- patients (ORR 38.5%) and 1 response (4.8%) in a patient with p16+ disease. Median PFS was 3.8 months (95% CI: 2.1-not reached) for p16- patients and 1.8 months (95% CI: 1.7-8.9) for p16+ patients. Median OS was 7.5 months (95% CI: 4.8-12). Commonest adverse events (n, %) were diarrhea (19, 40), anemia (17, 36) rash (14, 30) and fatigue (13, 28). Correlative analyses are underway. Conclusions: This trial of dual EGFR targeting demonstrated high clinical efficacy, especially in the p16- population. Adverse events were consistent with those associated with EGFR inhibitor treatment. Clinical trial information: NCT02979977 .