Abstract PD10-08: Interim safety in the inavolisib + ribociclib or abemaciclib + fulvestrant or letrozole arms of MORPHEUS-pan breast cancer: A Phase 1b/2 study of efficacy and safety of multiple treatment combinations in patients with advanced breast cancer

Abstract BACKGROUND Recommended first-line therapy for patients (pts) with hormone receptor-positive, HER2-negative advanced breast cancer (HR+, HER2- aBC) is endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Estrogen receptor-CDK4/6-PI3K pathway crosstalk may promote resistance. PIK3CA mutations are linked to poorer outcomes and are predictive of response to PI3Kis. In INAVO120 (NCT04191499), adding inavolisib (INAVO), a highly potent, oral, selective PI3Kαi, to fulvestrant (FULV) + palbociclib significantly improved progression-free and overall survival vs placebo in pts with PIK3CA-mutated, HR+, HER2-, endocrine-resistant aBC. However, data on the safety and combinability of other CDK4/6is with INAVO + ET are lacking. We present updated interim safety data from the INAVO + abemaciclib (ABEMA) + FULV, INAVO + ribociclib (RIBO) 400 mg + FULV, and INAVO + RIBO 600 mg + FULV / letrozole (LET) arms of the MORPHEUS-pan breast cancer (NCT03424005) umbrella study. METHODS Eligible pts had previously treated PIK3CA-mutated, HR+, HER2- aBC. Pts were randomized to receive INAVO (9 mg orally PO daily, days D1-28) + ABEMA (150 mg PO twice daily, D1-28) + FULV (500 mg intramuscularly on D1 + 15 of Cycle 1, then D1 of each subsequent cycle); INAVO + RIBO 400 mg (PO daily, D1-21) + FULV; or INAVO + RIBO 600 mg + physician’s choice of FULV or LET (2.5 mg PO daily, D1-28). Data from the INAVO + RIBO 600 mg + FULV / LET arms are combined due to later opening, resulting in smaller sample sizes and shorter follow-up. Adverse events (AEs) were assessed per National Cancer Institute Common Terminology Criteria for AEs v4.0. RESULTS At clinical cutoff (Mar 31, 2025), 7 / 16 pts in the INAVO + ABEMA + FULV arm and 8 / 19 in the INAVO + RIBO 400 mg + FULV arm had discontinued study treatment due to disease progression or symptomatic deterioration (11 / 11 were still on treatment in the INAVO + RIBO 600 mg + FULV / LET arms). Two of the 19 pts in the INAVO + RIBO 400 mg + FULV arm had discontinued the study due to death, assessed as related to progressive disease. Median safety follow-up was 5.7, 4.9, and 2.4 months in the respective arms. Fourteen of 16 pts in the INAVO + ABEMA + FULV arm, 7 / 19 in the INAVO + RIBO 400 mg + FULV arm, and 7 / 11 in the INAVO + RIBO 600 mg + FULV / LET arms had grade 3 AEs. No grade 4 or fatal AEs were reported. Six serious AEs were reported across 2 / 16 pts in the INAVO + ABEMA + FULV arm and 3 / 19 in the INAVO + RIBO 400 mg + FULV arm (none in the RIBO 600 mg arms). Of these, one was assessed as related to INAVO (hyperglycemia). One pt discontinued study treatment due to an AE (grade 2 asthenia in the INAVO + ABEMA + FULV arm; related to INAVO + ABEMA). Dose interruptions of any treatment due to AEs occurred in 13 / 16, 8 / 19, and 5 / 11 pts in the three arms, respectively; dose modifications of any treatment due to AEs, in 13 / 16, 5 / 19, and 6 / 11. Eight of 16 pts in the INAVO + ABEMA + FULV arm had ≥ 1 AE of special interest for INAVO (grade ≥ 3 hyperglycemia in 6 / 16, grade ≥ 2 pneumonitis in 1 / 16, and grade ≥ 3 stomatitis and mucosal inflammation in 1 / 16), as did 3 / 19 in the INAVO + RIBO 400 mg + FULV arm (all grade ≥ 3 hyperglycemia), and 4 / 11 in the INAVO + RIBO 600 mg + FULV / LET arms (all grade ≥ 3 hyperglycemia). CONCLUSIONS AEs observed with INAVO-containing triplet regimens in PIK3CA-mutated, HR+, HER2-, endocrine-resistant aBC were consistent with the known safety profiles of the individual agents. The combinations were tolerable, supporting further investigation. Updated data, including pharmacokinetics and data from additional pts, including those treated with INAVO + ABEMA + LET, will be presented. Citation Format: E. Gal-Yam, Y. Park, A. Sonnenblick, S. Breuer, R. Yerushalmi, S. Loi, K. Lee, H. Martin, J. Soong, K. Kallapur, R. Schwab, C. Cahuzac, T. Fisher, J. Sohn. Interim safety in the inavolisib + ribociclib or abemaciclib + fulvestrant or letrozole arms of MORPHEUS-pan breast cancer: A Phase 1b/2 study of efficacy and safety of multiple treatment combinations in patients with advanced breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD10-08.