cfDNA analysis from phase I/II study of lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2-advanced breast cancer patients

Abstract

Background: Despite significant improvements in progression-free survival for patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with approved CDK4/6 inhibitors combined with fulvestrant, treatment is limited by neutropenia and gastrointestinal (GI) side effects. Lerociclib, dosed twice daily (BID) with no drug holiday in combination with fulvestrant, has a favorable safety profile with low rates of GI adverse events and Grade 3/4 neutropenia, as well as encouraging antitumor activity in pts with HR+/HER2- ABC (NCT02983071). Cell-free DNA (cfDNA) analysis in peripheral blood was conducted to characterize mechanisms of response and resistance in pts that received lerociclib and fulvestrant. Methods: Pts with pretreated ABC were enrolled across doses of lerociclib 200e650 mg once daily and 100e250 mg BID in combination with fulvestrant 500 mg. Peripheral blood samples were drawn and cfDNA was isolated at baseline, cycle 1 day 15, each time point when tumor assessments were performed during the treatmentperiod, and at the end of treatment. Samples were analyzed using the Guardant360 platform. Results: Currently, 58 pts have been evaluated at baseline, with 44 pts (75.9%) harboring at least one somatic single nucleotide variant (mutation) in the genes evaluated. Seventeen pts (29.3%) harbored mutations in PIK3CA, with H1047R being the most common (8/17, 47.1%). Seven pts (12.1%) harbored mutations in ESR1, with D583G being the most common (4/7, 57.1%). No pts had mutations in both ESR1 and PIK3CA at baseline. Additionally, 3 pts (5.2%), 2 pts (3.4%), and 1 pt (1.7%) had mutations in genes at baseline associated with CDK4/6 resistance (RB1, CCND1, and CCNE1, respectively). Additional analyses of cfDNA (cycle 1 day 15 and end of treatment) along with correlation of cfDNA dynamics with clinical response are ongoing and will be presented. Conclusions: The most common baseline mutations detected were PIK3CA and ESR1. Additional analyses, including cycle 1 day 15 change from baseline and correlation with clinical response, are anticipated to help elucidate predictors of response and/or resistance to the combination of lerociclib and fulvestrant in patients with HR+ ABC.