FGF/FGFR Alteration Type as a Candidate Enrichment Biomarker for Gunagratinib in Recurrent or Metastatic Head and Neck Cancer: An Exploratory Analysis of Two Early-Phase Trials.

Abstract

Background: FGF/FGFR alterations are recurrent but heterogeneous in head and neck cancer, and which types predict benefit from selective fibroblast growth factor receptor (FGFR) inhibition is unknown.

Objective: We examined whether response to gunagratinib, a pan-FGFR1-4 inhibitor, differs by FGF/FGFR alteration type in recurrent or metastatic head and neck cancer.

Methods: Patients with recurrent or metastatic head and neck cancer and fibroblast growth factor(FGF)/FGFR alterations treated with gunagratinib in two prospective trials were combined (phase I ICP-CL-00301, n = 10; phase IIa ICP-CL-00304 at the recommended phase II dose [RP2D] of 20 mg once daily, n = 27). Confirmed objective response rate (Response Evaluation Criteria in Solid Tumours [RECIST] Version 1.1, investigator assessed) was the primary endpoint. Exploratory analyses examined efficacy by alteration type, with an RP2D sensitivity analysis and post-hoc CCND1 outcomes.

Results: Among 37 patients (23 head and neck squamous cell carcinoma, 9 nasopharyngeal carcinoma, 5 other; 78.4% with three or more prior therapy lines), confirmed the objective response rate at the RP2D (n = 27) was 7.4% (95% confidence interval 0.9-24.3) and disease control rate 55.6%, with no responses among FGFR-mutant patients (0/6) and single responses among fusions (1/2) and amplifications (1/6). In the pooled cohort (N = 37, including ten treated at sub-RP2D doses), objective response rate was 13.5% (95% confidence interval 4.5-28.8), disease control rate 56.8%, median progression-free survival 4.1 months, median duration of response 11.0 months and median overall survival 7.4 months. Four of five responses arose in receptor-level FGFR alterations rather than FGF3/4/19 amplification alone; because both mutation responses occurred at sub-RP2D doses, this pattern is hypothesis generating. Grade ≥3 treatment-related adverse events occurred in 35.1%, most commonly hyperphosphataemia; no treatment-related deaths occurred.

Conclusions: At the RP2D, gunagratinib monotherapy had limited activity (0/6 among FGFR-mutant tumours). In the pooled cohort, confirmed responses concentrated among FGFR receptor-level alterations rather than the FGF3/4/19-amplified majority; because part of this signal came from sub-RP2D dosing, alteration type is a candidate enrichment criterion requiring prospective RP2D testing.

Clinical trial registration: ClinicalTrials.gov, NCT03758664 (registered 29 November, 2018) and NCT05372120 (registered 12 May, 2022, retrospectively).