Abstract PO2-19-08: INAVO121: Phase III study of inavolisib + fulvestrant vs alpelisib + fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer

Abstract BACKGROUND Standard-of-care (SoC) endocrine therapy (ET) for patients (pts) with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer (HR+, HER2–, PIK3CA-mut 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. Alpelisib (ALP; a selective PI3Kα inhibitor; PI3Kαi) + fulvestrant (FUL) is approved for pts with HR+, HER2–, PIK3CA-mut 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. Inavolisib (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–, PIK3CA-mut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including a CDK4/6i-based regimen. TRIAL DESIGN 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. ELIGIBILITY CRITERIA Pts have HR+, HER2–, PIK3CA-mut 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. AIMS 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. STATISTICAL METHODS 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. ACCRUAL The study is open for enrollment and has randomized four pts; the study is targeting 400 pts at ~200 sites globally. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05646862. This abstract was originally presented at ASCO 2023 (TPS1123). Citation Format: Dejan Juric, Kevin Kalinsky, Seock-Ah Im, Eva Ciruelos, Giampaolo Bianchini, Carlos Barrios, William Jacot, Peter Schmid, Sherene Loi, Hope Rugo, Veronica Craine, Katherine Hutchinson, Aulde Flechais, Eirini Thanopoulou, Nadia Harbeck. INAVO121: Phase III study of inavolisib + fulvestrant vs alpelisib + fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-08.