Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

SIMPLE SUMMARY: This phase II, Simon 2-stage, multicenter study evaluated the efficacy of the combination of CDX-3379 and cetuximab, monoclonal antibodies against ErbB3 and EGFR, respectively, in patients with recurrent/metastatic, HPV-negative, cetuximab-resistant head and neck cancer. The primary endpoint was overall response rate (ORR) in genomically unselected patients. Enhanced response was hypothesized in the FAT1-mutated cohort. The ORR in genomically unselected patients was 2/30 (6.7%), which did not meet criteria for further investigation. The overall response rate was 1/10 (complete response; 10%) in the FAT1-mutated versus 0/17 (0%) in the FAT1-wildtype cohorts. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%), leading to dose modification in 21 patients (70%). The modest ORR coupled to clinically significant and dose-limiting toxicity preclude further development of this combination. ABSTRACT: In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8–22.1). Median PFS and OS were 2.2 (95% CI: 1.3–3.6) and 6.6 months (95% CI: 2.7–7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30–44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0–19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.