Giredestrant (G) with atezolizumab (ATEZO), and/or abemaciclib (ABEMA) in patients (pts) with ER+/HER2– locally advanced/metastatic breast cancer (LA/mBC): Interim analysis (IA) from the phase I/II MORPHEUS Breast Cancer study.

Abstract

1061 Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a therapeutic mainstay for first-line treatment (tx) of ER+ mBC, but selection of effective ET combinations after progression remains a challenge. G is a highly potent, non-steroidal, oral (PO), selective ER antagonist and degrader shown to be well tolerated and to achieve robust ER occupancy. Immune checkpoint inhibition has shown a trend towards activity in a number of ER+ BC studies. Additionally, ABEMA (a CDK4/6i) has immunomodulatory activity, making its inclusion a compelling therapeutic approach. Here, we present a 24-week IA of the G + ATEZO ± ABEMA arms and a 22-week IA of the G + ABEMA arm from MORPHEUS BC (NCT04802759). Methods: Eligible pts had ER+, HER2– LA/mBC and had received prior tx with a CDK4/6i and 1–2 lines of ET. Pts were randomized to G (30 mg PO QD) alone (previously reported), G + ATEZO (840 mg IV Q2W), G + ATEZO + ABEMA (150 mg PO BID), or G + ABEMA until loss of clinical benefit/unacceptable toxicity. Investigational drug doses were identical across all arms. Primary endpoints were safety and objective response rate (ORR). Exploratory analyses included evaluation of circulating tumor DNA alterations and tumor gene expression using RNAseq. Results: As of Apr 24, 2024, 15 pts in the G + ATEZO arm, 30 in the G + ATEZO + ABEMA arm and, as of Jan 9, 2023, 15 in the G + ABEMA arm, were efficacy/safety evaluable. Many pts had prior fulvestrant (60%, 43%, and 27%, respectively) and prior CDK4/6i duration ≥12 mo (73%, 77%, and 53%). Safety data are shown in the Table. In the triplet arm, the most common grade ≥3 adverse event (AE) was neutropenia/neutrophil count decreased (20%). No grade 5 AEs were reported. Confirmed ORR (all partial responses) were 20%, 33%, and 7% in the G + ATEZO, G + ATEZO + ABEMA, and the G + ABEMA arms, respectively. 7/9 confirmed responses (in ESR1 -evaluable pts) in the G + ATEZO + ABEMA arm were in pts with ESR1 -mutated disease. Data with longer follow-up, including progression-free survival, detailed safety, and exploratory biomarker analyses, will be presented. Conclusions: The combinations of G + ATEZO, G + ATEZO + ABEMA, and G + ABEMA were tolerable, with no unexpected safety signals including no high-grade interstitial lung disease/pneumonitis and low rates of high-grade liver toxicity. Clinical activity was observed, with a trend towards improved ORR with G + ATEZO + ABEMA, particularly in tumors with ESR1 mutations. Clinical trial information: NCT04802759 . n (%) G + ATEZO(n = 15) G + ATEZO + ABEMA (n = 30) G + ABEMA (n = 15) Any AE 14 (93) 30 (100) 15 (100) AE: highest grade 3 8 (53) 15 (50) 8 (53) AE: highest grade 4 0 (0) 0 (0) 1 (7) Any-grade tx-related AE (TRAE) 12 (80) 30 (100) 13 (87) TRAE leading to discontinuation of any tx 3 (20) 5 (17) 0 (0)