Fibroblast growth factor receptor (FGFR) inhibitor rogaratinib in patients with advanced pretreated squamous-cell non-small cell lung cancer over-expressing FGFR mRNA: The SAKK 19/18 phase II study.

Background: Patients with advanced squamous-cell lung cancer (SQCLC) frequently (46%) exhibit tumor overexpression of fibroblast growth factor receptor (FGFR) messenger ribonucleic acid (mRNA). Rogaratinib is a novel oral pan-FGFR inhibitor with a good safety profile and anti-tumor activity in early clinical trials as a single agent in FGFR pathway-addicted tumors. SAKK 19/18 determined clinical activity of rogaratinib in patients with advanced SQCLC overexpressing FGFR1-3 mRNA.
Methods: Patients with advanced SQCLC failing standard systemic treatment and with FGFR1-3 mRNA tumor overexpression as defined in the protocol received rogaratinib 600 mg BID until disease progression or intolerable toxicity. A 6-months progression-free survival rate (6mPFS) ≤15 % was considered uninteresting (H0), whereas a 6mPFS ≥38 % was considered promising (H1). According to a Simon 2-stage design, 2 out of 10 patients of the first stage were required to be progression-free at 6 months. Comprehensive Genomic Profiling was performedusing the Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific).
Results: Between July 2019 and November 2020, 49 patients were screened and 20 were classified FGFR-positive. Among a total of 15 patients, 6mPFS was reached in 1 patient (6.7 %), resulting in trial closure for futility after the first stage. There were 7 (46.7 %) patients with stable disease and 5 (33.3 %) patients with progressive disease. Median PFS was 1.6 (95 % CI 0.9-3.5) months and median overall survival (OS) 3.5 (95 % CI 1.0-5.9) months. Most frequent treatment-related adverse events (TRAEs) included hyperphosphatemia in 8 (53 %), diarrhea in 5 (33 %), stomatitis in 3 (20 %) and nail changes in 3 (20 %) patients. Grade ≥3 TRAEs occurred in 6 (40 %) patients. No associations between mutational profile and treatment outcome were observed.
Conclusion: Despite preliminary signals of activity, rogaratinib failed to improve PFS in patients with advanced SQCLC overexpressing FGFR mRNA. FGFR inhibitors in SQCLC remain a challenging field, and more in-depth understanding of pathway crosstalks may lead to the development of drug combinations with FGFR inhibitors resulting in improved outcomes.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AA: Advisory board: MSD Oncology, Roche, Takeada, Pfizer, Bristol-Myers Squibb, AstraZeneca, Eli-Lilly, Roche. Speaker Bureau: Eli-Lilly, AstraZeneca, Amgen. SA Consulting or Advisory Role:Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Eisai, Roche, Novartis, Merck Serono, MSD Oncology, Pfizer, Takeda, AbbVie, Research Funding:Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, AbbVie.Expert Testimony: Roche, AstraZeneca, Bristol Myers Squibb. Travel, Accommodations, Expenses: Roche Pharma AG, Lilly, Bristol Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Amgen LH: no conflict of interests, MS: no conflict of interests CW: no conflict of interests. SH: no conflict of interests. MK: Consulting or Advisory role: Roche, AstraZeneca, Takeda, BMS, MSD Oncology. Travel, Accommodations, Expenses: Pfizer, Roche, Takeda EF: no conflict of interests. NM: Stock and Other Ownership interests:MaxVAX SA Research Funding:MaxiVax Patents, Royalties, Other Intellectual Property:I am an inventor on patent owned by MaxiVAX SA and on patent co-owned by Geneva University Hospital and MaxiVAX SA Uncompensated Relationships: MaxiVax. LM: Consulting or Advisory Role:Takeda, Roche, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer Travel, Accommodations, Expenses: Takeda, Bristol Myers Squibb, Merck, Roche, AstraZeneca PJ: no conflict of interests. IA: no conflict of interests. BC: no conflict of interests. SSP: Honoraria: Novartis Consulting or Advisory Role:Diaceutics Ireland Limited, Merck (Schweiz) AG, AstraZeneca AG MJ: Consulting or Advisory Role:Novartis, AstraZeneca, Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Debiopharm Group, Merck, Roche, Sanofi. Research Funding:AstraZeneca, Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Immunophotonics, InnoMedica, Janssen Oncology, Lilly, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda. MF Consulting or Advisory Role:BMS, AstraZeneca, MSD, Takeda, Roche, Lilly Speakers' Bureau:Pfizer Research Funding:BMS, AstraZeneca.
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