Abstract PS17-07: Interim analysis of giredestrant + inavolisib in MORPHEUS Breast Cancer: a Phase Ib/II study of giredestrant treatment combinations in estrogen receptor-positive, HER2-negative, locally advanced/metastatic breast cancer

Abstract BACKGROUND Patients with estrogen receptor-positive metastatic breast cancer (ER+ mBC) almost always progress on first-line endocrine therapy (ET), which is usually combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Finding effective ET combinations after progression following CDK4/6is remains a challenge. Giredestrant (GIR) is a highly potent, nonsteroidal, oral, selective ER antagonist and degrader. Inavolisib (INAVO) is a highly potent PI3Kα-selective inhibitor that promotes degradation of mutated p110α. After first-line treatment (tx) with a CDK4/6i, PIK3CA mutations (mut), which are common, persist and remain a sensitive oncogenic target in these patients. We present a 16-week interim analysis of GIR vs GIR + INAVO in MORPHEUS BC (NCT04802759). METHODS Patients whose tumors harbored a PIK3CAmut and who had disease progression on up to two lines of endocrine-based therapy (including at least one prior line of CDK4/6i) for locally advanced (LA)/mBC were randomized 1:6 to receive GIR (30 mg orally daily [PO QD]) or GIR + INAVO (9 mg PO QD) tx until disease progression or unacceptable toxicity. Given the small numbers, the GIR arm is presented for overall safety. Primary endpoints are safety and objective response rate (ORR). Other endpoints include progression-free survival (PFS), disease control rate (DCR), and pharmacokinetics. Genetic alterations were identified centrally in baseline circulating tumor DNA using the FoundationOne Liquid CDx assay. In cases where PIK3CAmut could not be determined centrally, local blood or tissue results are used. RESULTS As of April 18, 2023, seven and 15 patients were enrolled in the GIR and GIR + INAVO arms, respectively; 71% (n = 5) and 67% (n = 10) received one prior line of therapy in the LA/mBC setting; 14% (n = 1) and 33% (n = 5) received two prior lines; and one GIR-arm patient received four prior lines. Prior fulvestrant (FUL) was received by 53% of patients in the GIR + INAVO arm (n = 8). For GIR + INAVO, the ORR was 47% (n = 7); the complete response rate was 7% (n = 1); and the partial response (PR) rate was 40% (n = 6). The DCR at 12 weeks was 80% (12/15 patients). The median PFS was 10.3 months (95% confidence interval = 6.5, not evaluable) with 47% of patients (n = 7) having events. In the GIR + INAVO arm, 5/6 patients with an ESR1mut had a PR (83%) and one (17%) had stable disease. No clinically relevant drug–drug interaction was observed. Safety data are presented in the table. Two patients experienced grade 3 hyperglycemia, one of whom had baseline elevated HbA1c and has been on insulin therapy since the event. The other patient received a single day of insulin treatment. In the GIR + INAVO arm, the incidence of rash and stomatitis (all grade 1) was 13% each. CONCLUSIONS An encouraging efficacy signal was observed with GIR + INAVO when compared cross-trial with BYLieve arm A (PMID: 33794206). ORRs were 47% in MORPHEUS BC vs 21% in BYLieve for patients with measurable disease (although no prior FUL was allowed in BYLieve). Safety of GIR + INAVO was aligned to the individual safety profiles of each of the drugs, with no new safety signals identified and a favorable tolerability profile for a PI3Kα inhibitor-based combination. Table. Safety summary Data are % of patients. AE, adverse event; GIR, giredestrant; INAVO, inavolisib; TRAE, treatment-related adverse event; tx, treatment. Citation Format: Hope Rugo, Maria Gion, Cristina Hernando, Kyung Hae Jung, Mafalda Oliveira, Melinda Telli, Gregory Vidal, Sina Vatandoust, Jing Zhu, Richard Schwab, Huy Ngo, Erika Ferreira, Ann Collier, Vanessa Breton, Einav Gal-Yam. Interim analysis of giredestrant + inavolisib in MORPHEUS Breast Cancer: a Phase Ib/II study of giredestrant treatment combinations in estrogen receptor-positive, HER2-negative, locally advanced/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 PS17-07.