Inavolisib

Bedard P. L, et al. European Journal of Cancer, 2025, 221, 115397.

In this phase 1/1b study, the potent and selective PI3Kα inhibitor inavolisib was evaluated for its therapeutic potential in PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer (LA/mBC). Two experimental treatment regimens were employed: inavolisib (6 mg/9 mg PO QD) plus letrozole (2.5 mg PO QD), and inavolisib (9 mg PO QD) plus fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1, then every 4 weeks), administered until unacceptable toxicity or disease progression. The primary endpoint was safety and tolerability. Paired tumour biopsies and circulating tumour DNA were collected at baseline and Cycle 1 Day 15, facilitating pharmacodynamic and pathophysiologic biomarker analyses. Results demonstrated manageable safety profiles, with treatment-related adverse events primarily low-grade, including hyperglycaemia, stomatitis, nausea, and diarrhoea. In patients previously treated with CDK4/6 inhibitors, inavolisib plus letrozole achieved a 13 % objective response rate with a median progression-free survival of 3.7 months, while inavolisib plus fulvestrant achieved a 25 % response rate with a median progression-free survival of 7.1 months. These findings highlight inavolisib's promising activity when combined with endocrine therapy in this challenging patient population.