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.

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. T...

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Detalles Bibliográficos
Autores: Bedard, PL, Jhaveri, KL, Accordino, MK, Cervantes, A, Gambardella, V, Hamilton, E, Italiano, A, Kalinsky, K, Krop, IE, Oliveira, M, Schmid, P, Saura, C, Turner, N, Varga, A, Cheeti, S, Dey, A, Hilz, S, Hutchinson, KE, Jin, YL, Royer-Joo, S, Peters, U, Shankar, N, Schutzman, JL, Aimi, J, Song, K, Juric, D
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p19983
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/19983
Access Level:acceso abierto
Palabra clave:Breast
Fulvestrant
Letrozole
Metastatic
Phase I
Descripción
Sumario: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 PI3Ka inhibitor that promotes mutated p110a 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.

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