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. 2024 Aug 8;14(1):58-67.
doi: 10.1159/000540290. eCollection 2025 Mar.

Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma

Ghassan K Abou-Alfa  1   2   3 , Tim Meyer  4   5 , Richard Kinh Gian Do  1   2 , Sarina A Piha-Paul  6 , Joseph S Light  1 , Scott Sherrin  1 , Amin Yaqubie  1 , Alison Clemens O'Neill  1 , James J Harding  1   2 , Raed Al-Rajabi  7 , Crystal S Denlinger  8 , Pablo Cano  9 , Albert S Cornelius  10 , Eileen M O'Reilly  1   2 , Daniel DiPrimeo  11 , Lisa D Eli  12 , John D Gordan  13 , David B Solit  1   2
Affiliations

Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma

Ghassan K Abou-Alfa et al. Liver Cancer. .

Abstract

Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC.

Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint.

Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0-21.8) and the disease control rate was 13.3% (95% CI: 1.7-40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy.

Conclusion: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

Keywords: Fibrolamellar carcinoma; Neratinib; Pan-HER kinase inhibition; SUMMIT phase 2 basket study.

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Conflict of interest statement

Ghassan K. Abou-Alfa reports institutional research support from Arcus, Agios, AstraZeneca, BioNTech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, and Yiviva, consulting support from Adicet, Alnylam, AstraZeneca, Autem, Bayer, Beigene, Berry Genomics, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Merck, Nerviano, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Surface Oncology, Therabionics, Vector, and Yiviva, and a patent (International Patent Application No. PCT/US2014/031545 filed on March 24, 2014, and priority application Serial No. 61/804,907 filed March 25, 2013). Tim Meyer reports receiving grants from MSD and consulting fees (personal) from Eisai, BMS, Adaptimmune, Ipsen, Roche, AstraZeneca, MSD, and Beigene. Richard Kinh Gian Do, Joseph Light, Amin Yaqubie, Alison Clemens O’Neill, Pablo Cano, and Albert S. Cornelius have no conflicts to declare. Sarina A. Piha-Paul reports receiving clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immorna Biotherapeutics, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, ZielBio, Inc., NCI/NIH, P30CA016672 – Core Grant (CCSG Shared Resources), and consulting fees from CRC Oncology. Scott Sherrin reports stock or stock options in Pfizer, Inc. James J. Harding reports receiving institutional research support from Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Calithera, Eli Lilly, Genoscience, Incyte, Loxo, Novartis, Pfizer, Yiviva, and Zymeworks and has consulted for Adaptimmune, Bristol Myers Squibb, CytomX, Eisai, Eli Lilly, Exelixis, Merck, QED, and Zymeworks. Raed Al Rajabi reports receiving grants or contracts (to institution) from AstraZeneca, Bayer, Exalixis, BioMed Valley Discoveries, and Eureka Therapeutics, participating in a data safety monitoring board or advisory board for AstraZeneca and Taiho, and holding stock or stock options in Seagen and Actinium Pharmaceuticals. Crystal S. Denlinger reports grants or contracts (to institution) from Amgen, AstraZeneca, Agios, Bristol Meyers Squibb, Beigene, Exelixis, Genmab, Zymeworks, Sanofi, and MedImmune, participating in a data safety monitoring board or advisory board for Zymeworks, Beigene, Bristol Meyers Squibb, Merck, and Taiho Oncology, and receipt of medical writing support from Beigene and Amgen. Eileen M. O’Reilly reports receiving research funding to institution from Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, and Pertzye and fees for consulting/data safety monitoring board from Boehringer Ingelheim, BioNTech, Ipsen, Merck, Novartis, AstraZeneca, BioSapien, Astellas, Thetis, Autem, Novocure, Neogene, BMS, Tempus, Fibrogen, Merus, Agios (to spouse), Genentech-Roche (to spouse), and Eisai (to spouse). Daniel DiPrimeo and Lisa D. Eli are employees of and stockholders in Puma Biotechnology, Inc. John D. Gordan reports receiving grants or contracts from the Fibrolamellar Cancer Foundation, support for attending meetings and/or travel from the Fibrolamellar Cancer Foundation and the Cholangiocarcinoma Foundation, patent WO/2021/155004, a leadership or fiduciary role in the Fibrolamellar Cancer Foundation and ASCO; receipt of equipment, drugs, materials, medical writing, gifts or other services from Mirati and eFFECTOR. David B. Solit has consulted/received honoraria from Rain, Pfizer, Fog Pharma, PaigeAI, BridgeBio, Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, and Elsie Biotechnologies, Inc.

Figures

Fig. 1.
Fig. 1.
Flowchart of patients with FLC in the SUMMIT study and Memorial Sloan Kettering Cancer Center compassionate-use program. *Five patients from SUMMIT switched to neratinib-based combination therapy under compassionate use following disease progression on neratinib monotherapy. †Patients were not followed for overall survival after January 4, 2022. ‡Two patients initiated neratinib-based combination therapy under compassionate use. ‖Neratinib in combination with immune checkpoint inhibitors (pembrolizumab or nivolumab) and/or mTOR inhibitors (everolimus or sunitinib). One patient each received pembrolizumab monotherapy and everolimus monotherapy during their treatments. FLC, fibrolamellar carcinoma; mTOR, mammalian target of rapamycin.
Fig. 2.
Fig. 2.
Duration of therapy in patients with FLC who received neratinib monotherapy (SUMMIT) or neratinib-based combination therapy (compassionate use).
See this image and copyright information in PMC

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