Background: CDK4/6 inhibition has demonstrated significant improvements in PFS when combined with fulvestrant (F) in patients with breast cancer (BC). G1T38 (38) is a potent, selective oral CDK4/6 inhibitor with best-in-class potential. Continuous daily dosing in preclinical models inhibits tumor growth and leads to a dose-dependent ANC decline and subsequent plateau. A completed Phase 1 trial supports this Phase 1b/2a trial (NCT02983071) in BC patients. Methods: Patients with metastatic or locally advanced HR+ HER2(-) BC who had progressed following endocrine therapy are eligible. Patients receive 38 QD or BID continuously with 500 mg F. Primary objectives are to evaluate DLTs, safety, and tolerability and to determine the RP2D and schedule of 38 administered with F. Results: To date, 24 patients (median age 55.5) have enrolled and received 38 doses ranging from 200-500 mg QD and 100-150 mg BID for up to 367 days. Dose escalation is ongoing. 38 is well tolerated: no 38-related SAEs have been reported and no patient has withdrawn due to an AE. 1 DLT of Grade 4 neutropenia occurred at 200 mg QD. The most common 38-related TEAEs are cytopenias and GI AEs. There have been no reports of VTE, QT prolongation, or DILI. Incidence/severity of diarrhea is less than abemaciclib, and similar to palbociclib and ribociclib. The degree of neutropenia is consistent with effective CDK4/6 inhibition with 79% all-grade neutropenia. Following an initial decline, ANCs plateau beginning at Week 5, which is consistent with preclinical findings. The % ANC change at Week 5 ranges from -48% (200 mg QD) to -74% (500 mg QD). Confirmed PR rate is 20% in evaluable patients, with a median time to response of 12 weeks. The CBR (CR + PR + SD ≥ 24 weeks) is 57%. Conclusions: G1T38 is a potential best-in-class CDK4/6 inhibitor. Continuous daily dosing with G1T38 + F is well tolerated with non-dose-limiting ANC decrease that plateaus at week 5, thus eliminating the need for a drug holiday. Early efficacy results are encouraging, and data support continued dose escalation and dose expansion. Combinations of G1T38 in other indications are anticipated; a Phase 1/2a trial of G1T38 + Tagrisso in EGFRm NSCLC will initiate in March 2018. Clinical trial information: NCT02983071