Abstract P5-21-04: Phase I/Ib study of the SERD LSZ102 alone or in combination with ribociclib in ER+ breast cancer

Background: LSZ102 is an orally bioavailable selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) gene transcription, induces receptor degradation, and blocks ER-dependent cell growth in preclinical models. This Phase I/Ib, open-label study is evaluating LSZ102 as a single agent and in combination with the CDK4/6 inhibitor ribociclib (LEE011) or the PI3K inhibitor alpelisib (BYL719) in patients (pts) with locally advanced/metastatic ER-positive (ER+) breast cancer (BC). Methods: The primary objective is to characterize the safety and tolerability, and identify a recommended dose and regimen of LSZ102 alone (Arm A) or in combination with ribociclib (Arm B) or alpelisib (Arm C). Secondary objectives include evaluation of preliminary antitumor activity and pharmacokinetics (PK). Eligible pts (aged ≥18 yrs; ECOG PS 0-1) have histologically confirmed ER+ BC that has progressed after endocrine therapy. Results: As of March 14, 2017, dose escalation evaluating 16 pts in Arm A (LSZ102 200 mg [n=4], 400 mg [n=6], and 600 mg [n=6]) had completed (median age 57.5 yrs; 81% ECOG PS 0; 63% received prior fulvestrant). Five pts (median age 59.0 yrs; 80% ECOG PS 0; 60% received prior fulvestrant) had enrolled in the first cohort of Arm B (LSZ102 200 mg QD + ribociclib 300 mg 3 weeks on/1 week off) with evaluation ongoing. Arm C (LSZ102 + alpelisib) had yet to open. As of March 14, 2017, 9/16 (56%) pts in Arm A had discontinued treatment, all due to progressive disease (PD); in Arm B all pts were still receiving treatment. There were no dose-limiting toxicities in either arm at the dose levels evaluated; dose escalation is ongoing. The most common drug-related adverse events (AEs) were diarrhea (Grade [Gr] 1: 7/16; Gr 2: 2/16 pts), nausea (Gr 1: 6/16; Gr 2: 2/16 pts), and vomiting (Gr 1: 3/16 pts) in Arm A, and hot flush, nausea, vaginal discharge (all Gr 1: 2/5 pts), thrombocytopenia (Gr 1: 1/5; Gr 2: 1/5 pts), and neutropenia (Gr 2: 1/5, Gr 3: 1/5 pts) in Arm B. There were no drug-related Gr 3/4 AEs reported in Arm A; in Arm B, Gr 3 neutropenia, leukopenia, and lymphopenia each occurred in 1/5 pts. Preliminary PK assessment showed single-agent LSZ102 exposure increased dose-proportionally from 200 to 600 mg QD. In combination with ribociclib, exposures were consistent with those of the single agent at the same dose. In Arm A, preliminary evidence of antitumor activity was observed. Efficacy data for Arms B and C were not available as of March 14, 2017. One pt, whose tumor harbored an ESR1 D538G mutation, had been treated with multiple prior therapies in the metastatic setting, including letrozole, exemestane, tamoxifen, exemestane + everolimus, and anastrozole, as well as fulvestrant for 120 days prior to PD, and letrozole + palbociclib for 94 days prior to PD. As of March 14, 2017, this pt had been on LSZ102 treatment (400 mg QD) for 167 days, with a best response of stable disease (14% reduction in sum of diameter of target lesions). Conclusions: Oral single-agent LSZ102 appears well-tolerated, with a manageable safety profile. Preliminary data also suggest tolerability when combined with ribociclib. Preliminary evidence of single-agent antitumor activity was seen in heavily pretreated pts with ER+ BC in a post-fulvestrant setting. Citation Format: Juric D, Curigliano G, Cresta S, Yap Y-S, Terret C, Duhoux FP, Takahashi S, Kundamal N, Bhansali S, Liao S, Crystal A, Jhaveri K. Phase I/Ib study of the SERD LSZ102 alone or in combination with ribociclib in ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-04.