I-SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant amcenestrant +/- abemaciclib +/- letrozole in molecularly selected patients (pts) with HR+ HER2- stage 2/3 breast cancer (BC).

person Amy Jo Chien University of California, San Francisco, San Francisco, CA info_outline Amy Jo Chien, Rita A. Mukhtar, Karthik Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Christos Vaklavas, Anthony D. Elias, Mei Wei, Matthew P. Goetz, Laura van 't Veer, Silver Alkhafaji, Hope S. Rugo, Nan Chen, W. Fraser Fraser Symmans, Alexander D. Borowsky, Lamorna Brown Swigart, Natsuko Onishi, Douglas Yee, Nola Hylton, Laura Esserman

Authors person Amy Jo Chien University of California, San Francisco, San Francisco, CA info_outline Amy Jo Chien, Rita A. Mukhtar, Karthik Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Christos Vaklavas, Anthony D. Elias, Mei Wei, Matthew P. Goetz, Laura van 't Veer, Silver Alkhafaji, Hope S. Rugo, Nan Chen, W. Fraser Fraser Symmans, Alexander D. Borowsky, Lamorna Brown Swigart, Natsuko Onishi, Douglas Yee, Nola Hylton, Laura Esserman Organizations University of California, San Francisco, San Francisco, CA, Mayo Clinic, Rochester, MN, University of Chicago Medical Center, Chicago, IL, Winship Cancer Institute of Emory University, Atlanta, GA, Hunstman Cancer Institute at the University of Utah, Salt Lake City, UT, University of Colorado Cancer Center, Aurora, CO, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, University of Chicago, Chicago, IL, The University of Texas MD Anderson Cancer Center, Alliance for Clinical Trials in Oncology, Houston, TX, University of California, Davis, Davis, CA, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, Department of Surgery, University of California, San Francisco, San Francisco, CA Abstract Disclosures Research Funding Quantum Leap Healthcare Collaborative and NCI (P01CA210961) Background: EOP is an I-SPY2 neoadjuvant sub-study designed to test the tolerability and impact of novel endocrine-based strategies in stage 2/3 BC pts predicted to have lower benefit from chemotherapy. Amcenestrant (A) is an oral selective estrogen receptor degrader (SERD) with activity in hormone receptor positive (HR+) HER2- metastatic BC. Methods: EOP eligibility included pts screened for the main I-SPY2 trial with HR+ HER2-, MammaPrint (MP) low risk Stage 2/3 BC. Pts with MP High risk tumor signatures were eligible if clinically node-negative (cN-). Pts were stratified by SET index and menopausal status. Pts were randomized to 3 arms: A 200 mg qd (A), A + abemaciclib 150 mg bid (AA), A + letrozole 2.5 mg qd (AL). Premenopausal pts received concurrent ovarian function suppression. Treatment was for 6 mos followed by surgery. Baseline (BL) and 3-wk biopsies were performed. Breast MRIs were conducted at BL (T0), 3 wks (T1), 12 wks (T2), 6 mos (T3). The primary endpoint was feasibility, defined as >75% of pts completing >75% study therapy. Results: Between May 2021 and Aug 2022, 74 pts were randomized: 31 A, 21 AA, 22 AL. Median age 50 years, 54% premenopausal, 38% clinically node-positive (cN+). 41% pts had ductal, 38% lobular, 11% mixed ductal/lobular histology. Mean BL tumor Ki67 (central testing) was 16.9%, 88% MP low, 76% SET index Hi. Pt and tumor characteristics were balanced across the 3 arms. Treatment in all 3 arms was feasible with 95% of pts completing >75% study therapy. Most common AEs include grade 1-2 hot flashes (69%) and fatigue (66%). Grade 3 AEs include neutropenia (2 pts) and diarrhea (1 pt) in AA. Table summarizes key response endpoints, which were similar between pre- and postmenopausal pts. Of 28 cN+ pts, 2 (7%) were pathologically node-negative (pN-). Mean MRI Functional Tumor Volume (cc) change between T0->T1, T1->T2, T2->T3, T0->T3 was -6.06 (-34.2%), -3.55 (-29.2%), -0.829 (-20.1%), -11.3 (-68.4%), respectively, similar across arms (p=0.396).ctDNA was detected in 10/59 (17%) pts at T0. ctDNA became undetectable in 6 pts, decreased in 4 pts, and went from ctDNA undetectable at baseline to detectable at T3 in 2 pts. Conclusions: Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy. Clinical trial information: NCT01042379. A (n = 31) AA (n = 21) AL (n = 22) Total (n=74) 3 wk mean Ki67 (%) 4.7 2.26 3.33 3.64 3 wk Ki67 <10% 28 (90.3%) 18 (85.7%) 16 (72.7%) 62 (83.8%) 3 wk Ki67 <2.7% 12 (38.7%) 16 (76.2%) 9 (40.9%) 37 (50%) 3 wk median % ER H-score Δ -70.3% -59.7% -57.5% -65% Modified PEPI 0 6 (19.4%) 3 (14.2%) 1 (4.5%) 10 (13.5%) RCB 0/1 0 1 (4.8%) 0 1 (1.4%) cN- pN+ 5 (16.1%) 3 (14.3%) 7 (31.8%) 15 (20.3%) cN+ pN- 0 (0%) 1 (4.8%) 1 (4.5%) 2 (2.7%)

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