Abstract PD7-09: A phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib in patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) who had progressed after endocrine therapy (ET)
Authors: Jhaveri Komal , Juric Dejan , Cresta Sara , Yap Yoon-Sim , Duhoux Francois P , Terret Catherine , Layman Rachel , Kundamal Nicole , Liao Serena , Ji Yan , Crystal Adam , Curigliano Giuseppe 
Published: March 2020

Abstract
Background: The combination of ribociclib (an oral CDK4/6 inhibitor) and ET improved survival outcomes in patients (pts) with ER+ ABC in comparison to single-agent ET. In preclinical models, LSZ102 (an experimental oral SERD) demonstrated synergistic activity with ribociclib. This phase 1/1b, open-label study evaluates single-agent LSZ102 (Arm A) and LSZ102 in combination with ribociclib (Arm B) or alpelisib (Arm C) in pts with ER+ ABC who had progressed after ET. Here we present preliminary data from dose escalation of Arm B. Methods: Dose-escalation evaluated daily (QD) LSZ102 at different doses plus ribociclib starting at 300 mg QD either in a 3-week on/1-week (3w/1w) off or in continuous regimen. Pts (aged ≥18 years; ECOG PS 0-1) with histologically confirmed ER+ ABC and progression after ET were enrolled. Prior fulvestrant and/or CDK4/6 inhibitor therapy were permitted. The primary objective was to characterize the safety and tolerability of LSZ102 and ribociclib in combination and identify a recommended dose for expansion (RDE). Secondary objectives included preliminary antitumor activity and characterization of pharmacokinetics. Results: As of 30-Nov-2018, 76 pts were enrolled. The median age of pts was 59 years, 78% (n=59) were Caucasian, 75% (n=57) had an ECOG PS of 0, 63% (n=48) had received prior fulvestrant, and 43% (n=33) a prior CDK4/6 inhibitor; the median number of prior lines of therapy (metastatic setting) was 4 (range 0-10). Pts received LSZ102 QD in combination with ribociclib QD either in a 3w/1w (n=42) or continuous (n=24) regimen, fasted, fed or without regard to food. LSZ102 twice daily (BID) was also explored with a ribociclib BID continuous regimen (n=10). Doses of LSZ102 ranged from 200-600 mg QD and 200-300 mg BID. Doses of ribociclib ranged from 200-600 mg and 200-400 mg in the 3w/1w and continuous regimens, respectively. At data cut-off, 47 pts had discontinued treatment, 42 due to disease progression. Three dose-limiting toxicities were reported: decreased appetite (1 pt) and febrile neutropenia and sepsis (1 pt), all in the 3w/1w regimen. The most common treatment-related adverse events (AEs) were nausea (48.7%), diarrhea (31.6%), fatigue (26.3%), and neutropenia (25.0%). The most common treatment-related grade 3 or 4 AE was neutropenia (10.5%). Four pts (5.3%) required dose reduction due to an AE. Median PFS was 6.0 months. Of 71 evaluable pts, 11% (n=8) had a PR, 39% (n=28) had a best overall response of SD and 16% (n=11) had non-CR/non-PD. ORR, DCR and CBR ≥6 months (includes non-CR/non-PD) were 11% (n=8), 66% (n=47) and 21% (n=15), respectively. The RDE is 450 mg QD LSZ102 with 400 mg QD ribociclib for both ribociclib regimens. Preliminary PK showed the exposure of LSZ102 and ribociclib in combination at the RDE were largely comparable with exposure of the corresponding single agents. Conclusion: The combination of LSZ102 and ribociclib was well-tolerated and demonstrated antitumor activity in heavily pre-treated pts with ER+ ABC many of whom had progressed after fulvestrant and/or CDK4/6 inhibitor therapy.
Citation Format: Komal Jhaveri, Dejan Juric, Sara Cresta, Yoon-Sim Yap, Francois P Duhoux, Catherine Terret, Rachel Layman, Nicole Kundamal, Serena Liao, Yan Ji, Adam Crystal, Giuseppe Curigliano. A phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib in patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) who had progressed after endocrine therapy (ET) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-09.