Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial
- PMID: 39828466
- DOI: 10.1016/j.cllc.2024.12.003
Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial
Abstract
Background: Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3-5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment.
Patients and methods: Eligible patients had ECOG performance status 0-2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR8); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety.
Results: Thirty-one patients were included (24/7 with/without prior TKI). ORR8 was 19.4% (95% CI 7.5-37.5); ORR was 32.3% (95% CI: 16.7-51.4); median PFS 5.75 months (95% CI: 2.27-9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9-9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea).
Conclusion: Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.
Keywords: Basket study; NSCLC; Objective response rate; Rare mutations; Tyrosine kinase inhibitor.
Copyright © 2024. Published by Elsevier Inc.
Conflict of interest statement
Disclosure Dr Goldman received grants/research support from AbbVie, Advaxis, AstraZeneca, BMS, Eli Lilly, Genentech, GSK, Janssen, Merck, Pfizer, Puma, Spectrum, and Vaccinex; consulting fees (paid to self) from AbbVie, AstraZeneca, BMS, Eli Lilly, Genentech, Gilead, Gritstone, Janssen, Jazz, Pfizer, Puma, and Regeneron. Dr Martinez Bueno received payments or honoraria from AstraZeneca, GSK, and Seagen; support for attending meetings and/or travel from AstraZeneca, GSK, MSD, and Roche; fees for participating in data safety monitoring or advisory boards from Pfizer. Dr Jhaveri has acted in a consultant or advisory role (payments to self) for AbbVie, AstraZeneca, Biotheranostics, Blueprint Medicines, BMS, Daiichi Sankyo, Genentech, Gilead, Intellisphere, Jounce Therapeutics, Lilly Pharmaceuticals, Novartis, Pfizer, Sanofi, Scorpion Therapeutics, Seattle Genetics, SunPharma Pvt Ltd, Synthon, and Taiho Oncology; research funding (to institution) from ADC Therapeutics, AstraZeneca, Blueprint Medicines, Clovis Oncology, Context Therapeutics, Debio Pharmaceuticals, Genentech, Immunomedics, Lilly Pharmaceuticals, Novartis, Novita Pharmaceuticals, Pfizer, Puma Biotechnology, Scorpion Therapeutics, VelosBio/Merck, and Zymeworks; and travel, accommodation, expenses (to self) from AstraZeneca, Genentech/Roche, Gilead, Intellisphere, Jounce Therapeutics, Lilly Pharmaceuticals, Pfizer, and Taiho Pharmaceutical. Dr Piha-Paul received grants or contracts (to institution) from AbbVie, Inc., ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Chugai Pharmaceutical Co., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix, Five Prime Therapeutics, F-Star Beta, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, GlaxoSmithKline, Helix BioPharma, Hengrui Pharmaceuticals, HiberCell, Immunomedics, Incyte Corp, Jacobio Pharmaceuticals, Jazz Pharmaceuticals, Jiangsu Simcere Pharmaceutical Co, Loxo Oncology, Lytix Biopharma, Medimmune, Medivation, Merck Sharp and Dohme, Nectin Therapeutics, Novartis Pharmaceuticals, Nurix, OncoNano Medicine, Pieris Pharmaceuticals, Pfizer, Phanes Therapeutics, Principia Biopharma, Puma Biotechnology, Purinomia Biotech, Rapt Therapeutics, Replimune, Roche/Blueprint, Seattle Genetics, Silverback Therapeutics, Shasqi, Synlogic Therapeutics, Taiho Oncology, Tallac Therapeutics, Tesaro, Theradex Oncology, Toragen Therapeutics, TransThera Bio, Xencor, ZielBio, Inc.; core grant P30CA016672 (CCSG Shared Resources; to institution) from the NIH/NCI; and fees for consulting from CRC Oncology and Lilly USA. Dr Unni received consulting fees from Biotheranostics, Eli Lilly, Macrogenics, Novartis, and Pfizer Inc. Dr Zick received grants or contracts (to institution) from the Israel Science Foundation and Monsa Memorial Fund; and consulting fees (to institution) from IMEL. Dr Mahipal received consulting fees from AstraZeneca and Guardant; and payments or honoraria from AstraZeneca, Exelexis, and Taiho Oncology. Dr Naltet received consulting fees (to self) from AstraZeneca, MSD, and Pfizer; payments or honoraria (to self) from Amgen, AstraZeneca, BMS, Janssen, and Sanofi; payment for expert testimony (to self) from Amgen, AstraZeneca, Janssen, Pfizer, Sanofi, and Takeda; and support for attending meetings or travel (to self) from AstraZeneca, BMS, Roche, and Sanofi. Dr Antoñanzas received payments or honoraria from AstraZeneca, MSD, Sanofi, and Takeda; and support for attending meetings, and/or travel from MSD, Sanofi, and Takeda. Professor Crown received grants or contracts (to institution) from Puma Biotechnology; payments or honoraria (to self) from Novartis; support for attending meetings or travel (to self) from AstraZeneca, MSD Oncology, Novartis, Pfizer, Regeneron, and Roche; has a patent (pending; WO2020011770 [A1] - A method of predicting response to treatment in cancer patients); has participated on data safety monitoring boards (payments to self) from AstraZeneca, Immunocore, and MSD; has a leadership or fiduciary role in The Cancer Clinical Research Trust (unpaid role); and received stock or stock options (payments to self) in Akkure and OncoAssure. Drs Bebchuk, Eli, and Lowenthal are employed by and have stock or stock options in Puma Biotechnology. Dr Mahalingam received grants or contracts (to institution) from Acepodia, Actuate Therapeutics, ADC Therapeutics, Amgen, AVEO, Bayer, BioNTech, BMS, Dialectic Therapeutics, Epizyme, Fujifilm, ImmuneSensor, Immune-Onc Therapeutics, Leap Therapeutics, Merck, Millennium, NGM Biopharmaceuticals, Novartis, Oncolytics, Orana Med, Puma Biotechnology, Qurient, Rafael, Repare Therapeutics, Triumvira Therapeutics, Vigeo Therapeutics, and Werewolf Therapeutics; payment or honoraria for speaker bureaus from Amgen, BMS, Eisai, Exelixis; participated in a drug safety monitoring board and advisory board for Actuate; and participated in a scientific advisory board for OncoOne and Qurient. Dr Dooms, Dr de Miguel, and Dr Suga have no conflicts to report.
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