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

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.

A phase Ia/Ib study of novel anti‐ErbB3 monoclonal antibody, barecetamab (ISU104) in refractory solid cancers and monotherapy or in combination with cetuximab in recurrent or metastatic head and neck cancer

“…Previous anti‐ErbB3 agents' studies explored various biomarkers, including ErbB3 IHC, NRG1 mRNA and FAT1 mutations 24‐27 . In this study, the H‐score of EGFR and the sum of EFGR/ErbB3 and EGFR/NRG1 ISH were significantly correlated with the anti‐tumor effect of barecetamab and CET combination therapy.…”

“…A study comparing patritumab and CET‐platinum‐based first‐line chemotherapy vs placebo showed negative results 25 . A single‐arm phase II trial of CDX‐3379 and CET combination therapy in CET‐resistant HNSCC showed an ORR of 6.7% and precluded further investigation 26 . These negative results suggest the need for a proper line of therapy, sequence of therapy and biomarker enrichment strategy for the design of phase II trials.…”

“…25 A single-arm phase II trial of CDX-3379 and CET combination therapy in CET-resistant HNSCC showed an ORR of 6.7% and precluded further investigation. 26 These negative results suggest the need for a proper line of therapy, sequence of therapy and biomarker enrichment strategy for the design of phase II trials. Although these drugs act on the same receptor, ErbB3, the mechanism of action could differ due to their binding characteristics (differences in epitopes, binding affinity and conformation of interaction) and Fc domains (IgG1, IgG2 or glycoengineered IgG1).…”

The diverse functions of FAT1 in cancer progression: good, bad, or ugly?

“…They reported that the overall response rate 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, suggesting that FAT1 mutation may play a role in resistance to EGFR-targeting therapy through activation of HER3. Upon further follow up these correlations did not however hold upon completion of the trial [ 90 ]. FAT1 mutation may be an indicator for outcome in these specific combination strategies.…”

HER3 Alterations in Cancer and Potential Clinical Implications

“…However, a phase II trial of CDX-3379 and cetuximab in patients with recurrent/metastatic cetuximab-resistant, HPV negative head and neck cancer reported a modest overall response rate with severe dose-limiting toxicities. This result impeded further clinical development of CDX-3379 and cetuximab as a combination [ 144 ].…”