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Background <p><i>FGF/FGFR</i> 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.</p> Objective <p>We examined whether response to gunagratinib, a pan-FGFR1–4 inhibitor, differs by <i>FGF/FGFR</i> alteration type in recurrent or metastatic head and neck cancer.</p> Methods <p>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, <i>n</i> = 10; phase IIa ICP-CL-00304 at the recommended phase II dose [RP2D] of 20 mg once daily, <i>n</i> = 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.</p> Results <p>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 (<i>n</i> = 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 (<i>N</i> = 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.</p> Conclusions <p>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.</p> Clinical Trial Registration <p>ClinicalTrials.gov, NCT03758664 (registered 29 November, 2018) and NCT05372120 (registered 12 May, 2022, retrospectively).</p>

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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

  • 期刊论文

  • 发表日期：

    2026年8月2日

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  • Liqiong Xue,
  • Guopei Zhu,
  • Peiguo Wang,
  • Kunyu Yang,
  • Yan Sun,
  • Weidong Li,
  • Zhendong Li,
  • Cuihong Jiang,
  • Qingqing Cai,
  • Meiyu Fang,
  • Man Hu,
  • Minghua Ge,
  • Wei Zhou,
  • Sichen Li,
  • Ye Guo

摘要

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).