Inavolisib plus letrozole or fulvestrant in PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer (GO39374): An open-label, multicentre, dose-escalation and dose-expansion phase 1/1b study
- PMID: 40203765
- DOI: 10.1016/j.ejca.2025.115397
Inavolisib plus letrozole or fulvestrant in PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer (GO39374): An open-label, multicentre, dose-escalation and dose-expansion phase 1/1b study
Abstract
Background: A variety of treatment options continue to be explored in the post-cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) setting for hormone receptor (HR)-positive, HER2-negative locally advanced/metastatic breast cancer (LA/mBC), and optimal sequencing of therapies remains to be determined. This phase 1/1b study examined inavolisib, a potent and selective PI3Kα inhibitor that promotes mutated p110α degradation, alone and in combination with endocrine therapy (ET) ± palbociclib, in PIK3CA-mutated, HR-positive, HER2-negative LA/mBC. We report data on inavolisib plus ET, including in patients who had previously received a CDK4/6i.
Methods: Women age ≥ 18 years received inavolisib (6 mg/9 mg orally once daily [PO QD]) plus letrozole (2·5 mg PO QD), or inavolisib (9 mg PO QD) plus fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1 then every 4 weeks), until unacceptable toxicity/disease progression.
Primary endpoint: safety and tolerability.
Findings: Thirty-seven and 60 patients were enrolled in the inavolisib plus letrozole and inavolisib plus fulvestrant arms, respectively. Overall, treatment-related adverse events (mostly low grade) occurred in 94·6 % and 93·3 % of patients, respectively; the most frequent (≥10 % of patients in either arm) were hyperglycaemia, stomatitis, nausea, and diarrhoea. Confirmed objective response rates in patients with measurable disease were 9·7 % and 25·9 %, respectively; median progression-free survival was 3·7 and 7·3 months. Among patients with previous CDK4/6i therapy (29/37 and 58/60 patients, respectively), confirmed objective response rates were 13·0 % and 25·0 %; median progression-free survival was 3·7 and 7·1 months. No drug-drug interactions were observed for any study treatment. Paired baseline and Cycle 1 Day 15 tumour biopsies and circulating tumour DNA analyses demonstrated the impact of study treatment on pharmacodynamic/pathophysiologic biomarkers of response.
Interpretation: Inavolisib plus ET demonstrated a manageable safety profile and encouraging preliminary anti-tumour activity in patients with PIK3CA-mutated, HR-positive, HER2-negative LA/mBC, including those in the post-CDK4/6i setting.
Keywords: Breast; Fulvestrant; Letrozole; Metastatic; Phase I.
Copyright © 2025. Published by Elsevier Ltd.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.L. Bedard reports research funding from AstraZeneca, Bayer, Bicara Therapeutics, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Gilead, LegoChem, Lilly, Medicenna, Merck, Novartis, Seagen, Takeda, and Zymeworks; and a consulting/advisory role for Amgen, Gilead, Lilly, Merck, Repare, Seattle Genetics, and Zymeworks. K.L. Jhaveri reports a consulting/advisory role for Novartis, Pfizer, Taiho Oncology, Genentech, AbbVie, Eisai, AstraZeneca, Blueprint Medicines, Seattle Genetics, Olema Pharmaceuticals, Daiichi Sankyo, Sun Pharma Advanced Research Company Ltd, Menarini/Stemline, Merck Pharmaceuticals, Gilead, Scorpion Therapeutics, Lilly/Loxo Oncology, Bicycle Therapeutics, and Zymeworks; and institutional research funding from Novartis, Genentech, AstraZeneca, Pfizer, Lilly/Loxo Oncology, Zymeworks, Immunomedics/Gilead, PUMA Biotechnology, Merck Pharmaceuticals, Eisai, Scorpion Therapeutics, and Blueprint Medicines. M.K. Accordino reports honoraria from Incrowd; institutional research funding from Novartis, Genentech, and Roche; and other relationships with Disney. Cervantes reports institutional research funding from Genentech, Merck-Serono, Bristol Myers Squibb, MSD, Roche, BeiGene, Bayer, Servier, Eli Lilly, Natera, Novartis, Takeda, Astellas, and Fibrogen; and advisory board or speaker fees from Merck-Serono, Roche, Servier, Takeda, and Astellas. V. Gambardella reports a consulting/advisory role for Boehringer Ingelheim; institutional research funding from Genentech, Merck Serono, Roche, BeiGene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas Pharma, FibroGen, Amcure, Natera, Sierra Oncology, AstraZeneca, MedImmune, Bristol Myers Squibb, and MSD; and travel/accommodation/expenses from Boehringer Ingelheim. E. Hamilton reports institutional research funding from Abbvie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Cascadian Therapeutics, Clovis, Compugen, Context Therapeutics, Cullinan, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon Pharmaceuticals, FujiFilm, G1 Therapeutics, Gilead Sciences, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, Inspirna, InventisBio, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, Leap Therapeutics, Lilly, Loxo Oncology, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Mersana, Merus, Millennium, Molecular Templates, Myriad Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Oncothyreon, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Prelude Therapeutics, Profound Bio, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, StemCentRx, Stemline Therapeutics, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Zenith Epigenetics, and Zymeworks; and a consulting/advisory role for Accutar Biotechnology, Arvinas, AstraZeneca, Circle Pharma, Daiichi Sankyo, Entos, Gilead Sciences, IQVIA, Janssen, Jazz Pharmaceuticals, Jefferies LLC, Johnson and Johnson, Lilly, Medical Pharma Services, Mersana Therapeutics, Olema Pharmaceuticals, Pfizer, Roche/Genentech, Shorla Pharma, Stemline Therapeutics, Tempus Labs, Theratechnologies, Tubulis, and Zentalis Pharmaceuticals. Italiano reports institutional research funding from Genentech, Merck-Serono, Bristol Myers Squibb, MSD, Roche, BeiGene, Bayer, Servier, and Novartis; and advisory board or speaker fees from Merck-Serono, Roche, Bayer, MSD, and Daiichi Sankyo. K. Kalinsky reports a consulting/advisory role for Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Immunomedics, Merck, Seattle Genetics, Cyclocel, Biotheranostics, Regor, Gilead, Prelude Therapeutics, RayzeBio, eFFECTOR Therapeutics, and Cullinan Oncology; and stocks/shares (spouse) in Grail, Array BioPharma, and Pfizer. I.E. Krop reports institutional research funding from Genentech/Roche, Pfizer, and Macrogenics; a consulting/advisory role for Genentech/Roche, Daiichi Sankyo, AstraZeneca, and SeaGen; Data and Safety Monitoring Committee participation for Merck, Novartis, and SeaGen; and employment and stocks/shares in PureTech (spouse). M. Oliveira reports institutional grant/research support from AstraZeneca, Ayala Pharmaceuticals, Boehringer Ingelheim, Genentech, Gilead, GlaxoSmithKline, Novartis, Roche, Seagen, and Zenith Epigenetics; a consulting/advisory role for AstraZeneca, Daiichi Sankyo/AstraZeneca, Gilead, iTEOS, Lilly, MSD, Pierre-Fabre, Relay Therapeutics, Roche, and Seagen; honoraria from AstraZeneca, Eisai, Gilead, Libbs, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen; and travel/accommodation/expenses from AstraZeneca, Eisai, Gilead, and Pierre-Fabre. P. Schmid reports honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma Biotechnology, Roche, Eisai, Celgene, Genentech, Gilead Sciences, Sanofi, and Stemline Therapeutics; a consulting/advisory role for Genentech/Roche, AstraZeneca, Merck, Boehringer Ingelheim, Bayer, Pfizer, Novartis, Eisai, Celgene, and Biontech; and institutional research funding from AstraZeneca, Astellas Pharma, Genentech, Novartis, and Roche. C. Saura reports a consulting/advisory role for AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly MediTech, Novartis, Pint Pharma, Pfizer, PharmaLex, Philips Healthcare, Pierre Fabre, Puma Biotechnology, Roche, SeaGen, Synthon, and Zymeworks; research funding from AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, Novartis, Pfizer, Puma Biotechnology, and Roche; and travel/accommodation/expenses from AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, Novartis, Pfizer, Puma Biotechnology, and Roche. N.Turner reports advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GlaxoSmithKline, Repare Therapeutics, Relay Therapeutics, Gilead, Inivata, Guardant, and Exact Sciences; and research funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis, and Natera. Varga reports employment by AstraZeneca/MedImmune and stocks/shares in AstraZeneca/MedImmune. S. Cheeti, A. Dey, S. Hilz, K.E. Hutchinson, S. Royer-Joo, U. Peters, N. Shankar, J.L. Schutzman, J. Aimi, and K. Song report employment by Genentech, Inc. and stocks/shares in F. Hoffmann-La Roche Ltd. Y. Jin reports employment at Hoffmann-La Roche Ltd and stocks/shares in F. Hoffmann-La Roche Ltd. D. Juric reports stocks/shares in Relay Therapeutics, PIC Therapeutics, and Vibliome Therapeutics; a consulting/advisory role for Novartis, Eisai, Genentech, MapKure, Vibliome Therapeutics, PIC Therapeutics, Relay Therapeutics, AstraZeneca, Lilly, and Pfizer; and institutional research funding from Novartis, Genentech, Takeda, Eisai, Amgen, Syros Pharmaceuticals, InventisBio, Infinity Pharmaceuticals, Takeda, Pfizer, Arvinas, Blueprint Medicines, AstraZeneca, Ribon Therapeutics, and Scorpion Therapeutics. All authors received research support in the form of third-party medical writing assistance, furnished by Katie Wilson, PhD, of Nucleus Global (an Inizio Company), from F. Hoffmann-La Roche Ltd.
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