INAVO122: A phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients (pts) with PIK3CA-mutated, HER2-positive advanced breast cancer (HER2+ aBC).

TPS1124 Background: The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2+ BC and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Jhaveri KL, et al. SABCS 2023; GS03-13, Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line (1L) induction treatment in pts with PIK3CA-mutated, HER2+ aBC. Methods: INAVO122 (NCT05894239) is a multicenter, randomized, international, double-blind, placebo-controlled study. Pts will be enrolled for: 1L induction treatment if they are receiving/will receive PH + a taxane; or for maintenance treatment if they completed induction treatment per standard of care. In the maintenance phase, pts will be randomized 1:1 to receive inavolisib (9 mg orally once daily; 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression (PD), unacceptable toxicity, death, consent withdrawal, or at the investigator’s (INV) discretion. Enrolled pts must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥6 months from completion of neoadjuvant/adjuvant HER2-targeted treatment. They must not have received any non-hormonal treatment for aBC prior to induction, and, at screening, fasting glucose must be <126 mg/dL and HbA1c <6.4%. To be randomized, pts must have completed induction therapy without PD and show left ventricular ejection fraction ≥50%. The primary endpoint is INV-assessed progression-free survival. Secondary endpoints are overall survival; INV-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. An independent data monitoring committee will be in place for safety. Target randomization is ~230 pts; this study is currently recruiting (15 pts enrolled). Encore from SABCS 2023 (PO2-19-09). Clinical trial information: NCT05894239 .