Abstract GS03-13: Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis

Abstract Background: More effective treatments for patients (pts) with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative breast cancer (HR+, HER2– BC) that prevent or overcome resistance are needed. Previous phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα) inhibitors have a limited therapeutic window. Inavolisib is a highly potent and selective inhibitor of the PI3K catalytic subunit α isoform protein (p110α; encoded by the PIK3CA gene). In addition, inavolisib promotes the degradation of mutated p110α, which may limit toxicity. Prior preclinical data suggested substantial synergy between PI3K and cyclin-dependent kinase 4/6 inhibition plus endocrine therapy. The inavolisib first-in-human study (NCT03006172) showed that the triplet had a manageable safety profile, lack of drug–drug interactions, and promising preliminary antitumor activity. Methods: The Phase III, randomized, double-blind INAVO120 trial (NCT04191499) recruited 325 pts with PIK3CA-mutated, HR+, HER2– locally advanced/metastatic BC (LA/mBC) who relapsed during or within 12 months of adjuvant endocrine therapy completion, and who had no prior therapy for advanced BC. PIK3CA mutations were identified by central circulating tumor DNA (ctDNA) or local tissue/ctDNA analysis. Pts were randomized to inavolisib (9 mg orally once a day [PO QD] on Days 1–28 of each cycle) or placebo (PO QD) in combination with palbociclib (125 mg PO QD on Days 1–21 of each cycle) and fulvestrant (500 mg intramuscularly on Cycle 1 Days 1 and 15, and on Day 1 of each subsequent cycle). This is the first study to assess the triplet combination at maximum dose (inavolisib) or per-label dose/schedule (palbociclib/fulvestrant). The primary endpoint was investigator-assessed progression-free survival (INV-PFS). Secondary endpoints included overall survival (OS) and confirmed objective response rate (ORR). Adverse events (AEs) were graded per NCI-CTCAE v5. Results: After 21.3 months median follow-up, median INV-PFS was 15.0 months (95% confidence interval [CI] = 11.3, 20.5) with inavolisib + palbociclib + fulvestrant, and 7.3 months (95% CI = 5.6, 9.3) with placebo + palbociclib + fulvestrant (hazard ratio 0.43; 95% CI = 0.32, 0.59). Landmark INV-PFS event-free rates at 6, 12, and 18 months were 82.9%, 55.9%, and 46.2% with inavolisib, and 55.9%, 32.6%, and 21.1% with placebo. OS showed a trend in favor of inavolisib (hazard ratio 0.64; 95% CI = 0.43, 0.97; p = 0.0338 [boundary 0.0098 or hazard ratio 0.592]), with follow-up ongoing. Landmark OS event-free rates at 12 and 18 months were 85.9% and 73.7% with inavolisib, and 74.9% and 67.5% with placebo. Confirmed ORRs were 58.4% with inavolisib and 25.0% with placebo. Rates of selected Grade 3–4 AEs with inavolisib and placebo were: neutropenia at 80.2% and 78.4%; hyperglycemia at 5.6% and 0%; diarrhea at 3.7% and 0%; stomatitis and mucosal inflammation at 5.6% and 0%; and rash at 0% and 0%. The rate of discontinuation due to AEs was 6.2% for inavolisib and 0.6% for placebo. There were no treatment-related Grade 5 AEs. Conclusions: Inavolisib + palbociclib + fulvestrant demonstrated a statistically significant and clinically meaningful improvement in INV-PFS vs. placebo + palbociclib + fulvestrant in this high-risk population, and a favorable OS trend in favor of the inavolisib combination at the first interim analysis. Inavolisib + palbociclib + fulvestrant had a manageable safety profile consistent with the known safety profiles of the individual drugs (reflective of α isoform selectivity of inavolisib), and no new safety signal was identified. Inavolisib + palbociclib + fulvestrant could represent a new standard of care for pts with PIK3CA-mutated, HR+, HER2– LA/mBC. Citation Format: Komal L. Jhaveri, Seock-Ah Im, Cristina Saura, Dejan Juric, Sibylle Loibl, Kevin Kalinsky, Peter Schmid, Sherene Loi, Eirini Thanopoulou, Noopur Shankar, Guiyuan Lei, Thomas Stout, Katherine E. Hutchinson, Jennifer Schutzman, Chunyan Song, Nicholas C. Turner. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis [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 GS03-13.