334P Lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2- advanced breast cancer patients: Updated phase II results and dose selection

CDK4/6 inhibitors (CDK4/6i) combined with fulvestrant (F) are the established standard of care for HR+/HER2- advanced breast cancer (ABC). Two of the three approved CDK4/6i cause dose-limiting neutropenia requiring a drug holiday, and the third is limited by gastrointestinal (GI) toxicity. Lerociclib is a potent, selective CDK4/6i that is dosed continuously. Initial data presented at SABCS 2019 indicated that lerociclib + F had low rates of GI toxicity and Grade 4 neutropenia, and antitumor activity was comparable with other CDK4/6i + F combinations. This phase I/II study assessed lerociclib with 500 mg F in patients (pts) with HR+/HER2- ABC that had progressed following endocrine therapy. Up to 2 prior chemotherapies in the advanced setting in phase I (dose escalation), and 1 prior in phase II (dose expansion) were allowed. Prior F and CDK4/6i exposure were excluded in phase II. The objectives were to evaluate DLTs, safety, tolerability, PK, preliminary efficacy, and determine the recommended dose of lerociclib when combined with F for future randomized trials. As of Jan 31, 2020, 110 pts had been enrolled across doses of 200–650 mg once daily and 100–250 mg twice daily (BID). Twenty pts received 150 mg BID for a median 6.9 (range 1.7–27.8) months, with median age of 55 years (range 33–84), ECOG of 0 (85%), and median 1 line (range 0–5) of prior anticancer therapy in the advanced setting. The most common lerociclib-related AEs at 150 mg BID were neutropenia (55%), leukopenia (40%), diarrhea (20%), and anemia (20%). Rates of Grade 3 and 4 neutropenia were 30% and 5%, respectively. There were no reports of Grade ≥ 3 nausea, vomiting, or diarrhea. Nineteen pts at 150 mg BID were evaluable for tumor response based on RECIST version 1.1. Six pts (32%) had a confirmed PR; 9 (47%) had SD; 4 (21%) had PD. The CBR (CR+PR+SD ≥ 24 weeks) was 74% (14/19). Subgroup analyses revealed that pts who received no prior chemotherapy in the advanced setting (9/19 pts) had the highest CBR of 89%. Lerociclib 150 mg BID dosed continuously demonstrated a differentiated profile with low rates of GI toxicity and Grade 3/4 neutropenia. Efficacy compares favorably to approved CDK4/6i + F combinations.