Cancer Res Treat.  2024 Jan;56(1):37-47. 10.4143/crt.2023.433.

A Phase II Trial of Nintedanib in Patients with Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma: In-Depth Analysis of Nintedanib Arm from the KCSG HN 15-16 TRIUMPH Trial

• Kim KH
• Lim SM
• Ahn HK
• Lee YG
• Lee KW
• Ahn MJ
• Keam B
• Kim HR
• Lee HW
• An HJ
• Kim JS

• KMID: 2550321
• DOI: http://doi.org/10.4143/crt.2023.433

Abstract

Purpose
Precision oncology approach for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is necessary due to its dismal prognosis. We performed a genomic profile-based umbrella trial of patients with platinum-refractory HNSCC (KCSG-TRIUMPH). Here, we present an in-depth report of the the nintedanib arm (arm 3) of the current trial.
Materials and Methods
The TRIUMPH study was a multicenter, open-label, single-arm phase 2 trial, in which patients were assigned to treatment arms based on next-generation sequencing (NGS)–based, matching genomic profiles. Patients whose tumors harbor fibroblast growth factor receptor (FGFR) alteration were enrolled in the nintedanib arm (arm 3) as part of the TRIUMPH study. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and biomarker analysis.
Results
Between October 2017 and August 2020, 207 were enrolled in the TRIUMPH study, and eight were enrolled in the nintedanib arm. ORR and disease control rate were 42.9% and 57.1%, respectively. The median PFS was 5.6 months and the median duration of response was 9.1 months. Median OS was 11.1 months. One patient maintained the partial response for 36 months. Overall, the toxicity profiles were manageable.
Conclusion
Single-agent nintedanib has demonstrated significant efficacy in FGFR-mutated, recurrent or metastatic HNSCC patients, with tolerable toxicity profiles. The results from the study have provided the basis for routine NGS screening and FGFR-targeted therapy. Because of the small number of patients due to slow accrual in this study, further studies with a larger cohort are warranted for statistical power.

Keyword

Squamous cell carcinoma of head and neck; Precision medicine; Umbrella trial; NGS; Nintedanib

Figure

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  Fig. 1. Study scheme and consort diagram for nintedanib arm. (A) Overall scheme of the main TRIUMPH study. (B) Consort diagram showing trial profile for nintedanib arm (arm 3). EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; HER2, human epidermal growth factor receptor 2; HNSCC, head and neck squamous cell carcinoma; PD-L1, programmed death-ligand 1; PI3K, phosphoinositide 3-kinase.

• 

  Fig. 2. Kaplan-Meier survival curves. Progression-free survival (A) and overall survival (B) in patients with fibroblast growth factor receptor (FGFR) mutation/amplification treated with nintedanib in the efficacy set (n=7). CI, confidence interval.

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  Fig. 3. Waterfall and swimmer plot showing patient tumor response. (A) Waterfall plot for best percentage changes from baseline. (B) Swimmer plot for time on treatment by patient. FGFR, fibroblast growth factor receptor.

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  Fig. 4. Nintedanib response in a nasal cavity cancer patient. (A) Gross protruding nasal cavity mass at baseline, after 1st cycle (4 weeks since start of therapy), and at 1.5 years from treatment completion (4.5 years since start of therapy). (B) Neck computed tomography scans at baseline, at 1st response assessment (at 8 weeks), and after 2.5 years of treatment.

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  Fig. 5. Integrated clinical and genomic profile of patients screened for the nintedanib arm. (A) Clinical response and Oncoplot showing both patient-specific mutations in fibroblast growth factor receptor (FGFR) pathway as well as other, concurrent mutations in the major tumor-related molecular pathways. Copy number variations (CNV) are annotated. for each patient with FGFR gene amplifications. Nintedanib best response are also given for each patient, with the exception of those who ultimately failed to enroll or dropped out of trial before response evaluation, in which best response are annotated as NA (not available). (B) Lollipop plot showing immunoglobulin-like domains (IG, I-set), tyrosine kinase domain (Pkinase Tyr), and distribution of different mutation sites in single patient with FGFR3 multihit mutations. HPV, human papillomavirus; PD, progressive disease; PR, partial response; SD, stable disease.

Reference

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