Abstract PD1-08: Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 for estrogen receptor-positive (ER+) advanced breast cancer (ABC) with progression on endocrine therapy (ET)
Authors: Jhaveri K , Curigliano G , Yap Y-S , Cresta S , Duhoux FP , Terret C , Takahashi S , Ulaner GA , Kundamal N , Baldoni D , Liao S , Crystal A , Juric D 
Published: May 2019

Background: LSZ102 is an orally bioavailable SERD that inhibits ER gene transcription, induces receptor degradation, and blocks ER-dependent cell growth in preclinical models. This study is evaluating LSZ102 as a single agent and in combination with the CDK 4/6 inhibitor ribociclib (LEE011) or the PI3K inhibitor alpelisib (BYL719) in patients (pts) with ER+ ABC. The LSZ102 single agent data are presented below; combination data are not discussed.

Methods: In the dose-escalation phase evaluating single-agent LSZ102 (Arm A), pts (age ≥18 years; ECOG PS 0-1) with histologically confirmed ER+ ABC and progression on endocrine therapy (ET) received LSZ102. The starting dose was 200 mg once daily. The primary objective of Arm A was to characterize the safety and tolerability of LSZ102 and identify a recommended dose for expansion (RDE). Secondary objectives included preliminary antitumor activity and pharmacokinetics (PK).

Results: As of January 22, 2018, 57 pts were enrolled to Arm A (LSZ102 200 mg, n=4; 400 mg, n=6; 450 mg fasted, n=15; 450 mg with food, n=6; 600 mg, n=20; 900 mg, n=6). Median age was 60 years, 75% (n=43) of pts had an ECOG PS of 0, 56% (n=32) had received prior fulvestrant, and 58% (n=33) had received prior CDK4/6 inhibitors; median number of prior lines of therapy (all settings) was 6. At data cut-off, 48 pts had discontinued treatment, most (n=45, 94%) due to disease progression. Dose-limiting toxicities across treatment groups included diarrhea (2 pts in the 900-mg group), vomiting (1 pt in the 600-mg group), and AST and ALT elevation (1 pt in the 450-mg with food group). The most common treatment-related adverse events (AEs) in the treatment period were diarrhea (60%), nausea (56%), and vomiting (30%). In the treatment period, treatment-related grade 3 AEs (12%) were infrequent, and there were no such grade 4 events. Six pts (11%) required dose reduction due to AEs (nausea, vomiting or diarrhea); 4/6 of the dose reductions occurred at 900 mg. Preliminary PK assessment showed rapid absorption and dose-proportional increases in LSZ102 exposure; trough concentrations were above the predicted tumorostatic concentrations at doses of ≥400 mg. Based on PK results for the 450-mg fasted and fed cohorts, LSZ102 exposure does not appear to be affected by dosing with a regular meal. Evidence of ER modulation by immunohistochemistry was observed in paired baseline and on-treatment biopsies. 18F-fluoroestradiol positron emission tomography (FES-PET) analysis (n=6) demonstrated abrogation of FES-PET signal for pts in the 450-mg and 600-mg dose groups. Seventeen pts (29.8%) had a best response of stable disease, and 1 pt, who happened to be in the 600-mg group, achieved a partial response.

Conclusion: In heavily pretreated pts, LSZ102 was well tolerated, demonstrated antitumor activity, and achieved effective exposure levels based on PK and pharmacodynamics. Food intake did not appear to significantly alter the PK profile of LSZ102. Dose escalation for LSZ102 in combination with ribociclib or alpelisib is ongoing and will be reported in a future analysis. An update on the recommended single agent dose and schedule will be presented.

Citation Format: Jhaveri K, Curigliano G, Yap Y-S, Cresta S, Duhoux FP, Terret C, Takahashi S, Ulaner GA, Kundamal N, Baldoni D, Liao S, Crystal A, Juric D. Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 for estrogen receptor-positive (ER+) advanced breast cancer (ABC) with progression on endocrine therapy (ET) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-08.