LBA3 SOLTI-1507 IPATHER: Primary results of the phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with trastuzumab and pertuzumab (HP) in patients (pts) with PIK3CA mutant (mut) HER2+ advanced breast cancer (ABC)

In the CLEOPATRA trial, pts with HER2+ PIK3CAmut ABC had a shorter progression-free survival (PFS) than those with PIK3CAwt. We hypothesized that IPAT, an AKT inhibitor with activity in PI3K/AKT-altered tumors, combined with HP was both safe and effective in PIK3CAmut HER2+ ABC. IPATHER is an open-label, single-arm, phase Ib trial that evaluates the safety and efficacy of IPAT + HP in pts with PIK3CAmut HER2+ ABC candidates to maintenance HP following discontinuation of first-line chemotherapy (CT) for reasons other than progressive disease. The primary aim was to determine the maximum tolerated dose (MTD) of IPAT + HP, defined as the highest dose at which ≤1 of the first 6 pts enrolled experienced a dose-limiting toxicity (DLT: grade [G] ≥3 diarrhea >72 hours, G ≥2 diarrhea >5 days [d], other treatment related adverse events [TRAEs] G ≥ 3) during the first 28d of treatment. Initial IPAT dose was 400mg d1-21 in 28d cycles with standard dose HP (de-escalation doses are 300mg and 200mg). Secondary aims included safety, overall response rate (ORR), clinical benefit rate (CBR), and PFS. PIK3CAmut was detected in 24/108 HER2+ tumors (22%). From Feb/2020 to Nov/2023, 17 pts were enrolled, median age 54 (41-78). Most had HR- tumors, visceral metastases, and stage IV disease at diagnosis (59% each). At data cut-off (April 2024), 6 pts (35%) remained on treatment. No DLTs were observed in the first 6 pts and IPAT 400mg + HP was defined as MTD. In the remaining 11 pts, 3 had a DLT (G3 diarrhea, G3 vomiting, and G3 rash). The most common TRAEs were diarrhea (82%), nausea (47%), decreased appetite (35%), and fatigue, rash, and vomiting (29% each). G3/4 TRAEs occurred in 35%; most common were diarrhea and nausea (12% each). With a median follow-up of 19.9 months (m), confirmed ORR was 31%, CBR 69%, and median PFS 15.4m (9.4-NR), with 48% pts progression-free after 18m from enrollment. Maintenance treatment with IPAT 400mg + HP following CT had an acceptable safety profile and showed promising efficacy in pts with PIK3CAmut HER2+ ABC. Combining a PI3K/AKT pathway inhibitor with anti-HER2 treatment in this setting merits further evaluation.