LAUSR

Abstract Background Lerociclib (lero) is a potent, selective oral CDK4/6 inhibitor (CDK4/6i). Preclinical and early clinical data have demonstrated that lero is differentiated based on its favorable safety/tolerability profile and ability to be dosed continuously with less dose-limiting neutropenia. Encouraging preliminary efficacy has been observed in HR+/HER2- breast cancer in combination with fulvestrant (NCT#02983071). Several putative mechanisms of resistance to EGFR TKIs are upstream of the CDK4/6 pathway, and in vitro and in vivo studies with CDK4/6i + EGFR TKIs have demonstrated enhanced efficacy and delayed time to resistance. These data provide strong rationale to investigate lero + osimertinib (osi) in the clinic. Methods Patients with metastatic NSCLC, confirmed EGFR mutation associated with EGFR TKI sensitivity, ECOG of 0 or 1, and treatment with ≤2 lines of chemo or any EGFR TKI including osi are eligible for this phase Ib study. Patients receive lero QD or BID continuously in combination with 80 mg osi QD until disease progression. The objectives are to evaluate DLTs, safety, tolerability, PK, and anti-tumor efficacy, and to determine the dose for the randomized phase II portion of the study. Results Currently, 18 patients (mean age 63 years) have been enrolled and received lero doses of 200, 300, or 400 mg QD; the longest duration being 317 days. BID enrollment is ongoing. Lero is well tolerated; no lero-related SAEs have been reported, and no patient has withdrawn due to an AE. One DLT of Grade 4 neutropenia occurred at 400 mg QD. The most common lero-related TEAEs are neutropenia and diarrhea. The incidence of diarrhea with lero + osi is similar to single agent osi (FLAURA study). There have been no reports of VTE, QT prolongation, or DILI. No clinically relevant drug-drug interaction has been observed. Conclusions The combination of continuously administered lero + osi in patients with EGFRmut NSCLC (treatment naive or previously treated) is well tolerated with only one DLT event to date. Updated safety, anti-tumor efficacy, and cfDNA data will be presented (NCT#03455829). Clinical trial identification NCT03455829. Legal entity responsible for the study G1 Therapeutics, Inc. Funding G1 Therapeutics. Disclosure D. Berz: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Genentech; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Tempus; Honoraria (self): Biocept; Shareholder / Stockholder / Stock options, Major Owner: Valkyrie Therapeutics. A. Spira: Advisory / Consultancy: G1 Therapeutics. J.W. Goldman: Honoraria (self), Research grant / Funding (institution): AstraZeneca. Y.L. Pritchett: Full / Part-time employment: G1 Therapeutics. C.G. Cisneros: Full / Part-time employment: G1 Therapeutics. C. Li: Full / Part-time employment: G1 Therapeutics. J.A. Sorrentino: Full / Part-time employment: G1 Therapeutics. R. Malik: Full / Part-time employment: G1 Therapeutics. A.P. Beelen: Full / Part-time employment: G1 Therapeutics. All other authors have declared no conflicts of interest.