INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2–), PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC).
Authors: Juric Dejan , Kalinsky Kevin , Im Seock-Ah , Ciruelos Eva , Bianchini Giampaolo , Barrios Carlos H. , Jacot William , Schmid Peter , Loi Sherene , Rugo Hope S. , Craine Veronica , Hutchinson Katherine E. , Flechais Aulde , Thanopoulou Eirini , Harbeck Nadia 
Published: June 2024

TPS1136 Background: Standard-of-care (SoC) endocrine therapy (ET) for pts with HR+, HER2–, PIK3CAmut LA/mBC was transformed by combinations with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is); a CDK4/6i-based combination is approved in high-risk, early BC. However, in most pts, mechanisms of resistance that emerge during or after treatment with a CDK4/6i and ET combination lead to relapse/disease progression. Dysregulating mutations in PIK3CA, occurring in ~40% of HR+, HER2– BCs, represent a common mechanism of resistance to CDK4/6is and ET combinations. ALP, a selective PI3Kα inhibitor (PI3Kαi) + FUL is approved for pts with HR+, HER2–, PIK3CAmut LA/mBC, but its widespread implementation in clinical practice has been challenging. As such, there is a significant need to develop PI3Kαis with a better therapeutic index. INAVO is a highly potent and selective PI3Kαi that also facilitates the degradation of mutated PI3Kα isoform. INAVO has demonstrated manageable safety/tolerability, alone and in combination with SoC treatments in HR+, HER2–, PIK3CAmut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including in pts pretreated with a CDK4/6i-based regimen. Methods: INAVO121 is a Phase III, randomized, open-label study. Pts are randomized 1:1 to receive INAVO (9 mg oral daily [PO QD]) + FUL (500 mg intramuscularly on Days [D] 1 and 15 of Cycle 1, then D1 of subsequent cycles) or ALP (300 mg PO QD) + FUL. Randomization is stratified by visceral disease (yes vs. no) and prior CDK4/6i therapy (adjuvant vs. metastatic setting). Pts will receive treatment until disease progression or unacceptable toxicity. Pts have HR+, HER2–, PIK3CAmut LA/mBC (confirmed by circulating tumor DNA or tumor tissue), adequate hematologic and organ function, and disease progression after or during treatment with a CDK4/6i-based regimen. Up to two prior lines of systemic therapy in LA/mBC, including one line of chemotherapy, are allowed. The primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival, BICR-objective response rate, BICR-best overall response, BICR-duration of response, BICR-clinical benefit rate, safety, tolerability, pt-reported outcomes, and pharmacokinetics. A stratified log-rank test at an overall 0.05 significance level (two-sided) will be used for the primary endpoint analysis. Median PFS will be estimated using Kaplan–Meier methodology. An independent data monitoring committee will be in place for safety and efficacy. The study is open for enrollment and has randomized 159 pts; the study is targeting 400 pts at ~200 sites globally. Clinical trial information: NCT05646862 .