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.
FGFR inhibitor
SQCLC
Journal
Lung cancer (Amsterdam, Netherlands)
ISSN: 1872-8332
Titre abrégé: Lung Cancer
Pays: Ireland
ID NLM: 8800805
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
13
07
2022
revised:
08
08
2022
accepted:
24
08
2022
pubmed:
14
9
2022
medline:
21
9
2022
entrez:
13
9
2022
Statut:
ppublish
Résumé
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. 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). 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36099710
pii: S0169-5002(22)00605-5
doi: 10.1016/j.lungcan.2022.08.016
pii:
doi:
Substances chimiques
Piperazines
0
Protein Kinase Inhibitors
0
Pyrroles
0
RNA, Messenger
0
Thiophenes
0
Rogaratinib
98BSN6N516
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
154-159Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
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.