BGB-43395 (selective CDK4 inhibitor) + letrozole shows high early ORR with low neutropenia in 1L HR+/HER2− mBC

BGB-43395 is an oral, highly selective CDK4 inhibitor (designed to spare CDK6) combined with the aromatase inhibitor letrozole in an open-label Phase 1a/1b safety-expansion (cohort 2) for CDK4/6i-naive metastatic/advanced HR+/HER2− breast cancer (n=58; NCT06120283; data cut Nov 11, 2025). Investigator-assessed unconfirmed ORR was 58% (240 mg BID; n=19), 68% (400 mg BID; n=19), and 40% (600 mg BID; n=20), with disease control rates 95%–100% and mPFS not reached at a short median follow-up of 6.8 months. Safety was GI-forward and dose-dependent—G≥3 TEAEs rose from 32%/37% to 65% at 600 mg, driven by diarrhea (any-grade 79%/95%/90%; G3 5%/11%/30%), while hematologic toxicity was comparatively low vs SOC CDK4/6 inhibitors (e.g., palbociclib + letrozole mPFS ~24.8 months in PALOMA-2, but with substantially higher neutropenia rates than seen here); discontinuations were 3% and median relative dose intensity fell to 69% at 600 mg (vs 97%–100% at 240–400 mg).