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
Mené sur 97 patientes atteintes d'un cancer du sein HR+ HER2- avec mutation au niveau du gène PIK3CA et de stade avancé ou métastatique, cet essai multicentrique de phase I/IB détermine la dose maximale tolérée de l'inavolisib en combinaison avec le létrozole ou le fulvestrant puis évalue l'efficacité de ces combinaisons du point de vue du taux de réponse objective
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 PI3K
α 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.