Targeting G(1)/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor–based regimens

BACKGROUND: Although CDK4/6 inhibitors are an established treatment for hormone receptor–positive, HER2-negative metastatic breast cancers, their benefit in other malignancies remains limited. METHODS: We investigated factors associated with clinical outcomes from CDK4/6 inhibitor–based therapy among patients with G(1)/S phase cell-cycle alterations (CDK4/6 amplifications, CCND1/2/3 amplifications, or CDKN2A/B alterations). RESULTS: Overall, 2457 patients with diverse solid tumors that underwent clinical-grade, next-generation sequencing (182–465 genes) and therapy outcome of (non–breast cancer) patients treated with matched CDK4/6 inhibitors were analyzed. G(1)/S phase cell-cycle alterations occurred in 20.6% (507 of 2457) of patients; 99% of those patients (n = 501) harbored ≥1 characterized co-alteration (median, 4; range, 0–24). In 40 patients with G(1)/S phase cell-cycle alterations given CDK4/6 inhibitors as part of their regimen, significantly longer median progression-free survival (PFS) was observed when CDK4/6 inhibitor–based therapies matched a larger proportion of tumor alterations, often because CDK4/6 inhibitors were administered together with other drugs that were matched to genomic co-alterations, hence achieving a high matching score (high vs. low [≥50% vs. <50%] matching score, PFS, 6.2 vs. 2.0 months, P < 0.001 [n = 40] [multivariate]) and higher rate of stable disease ≥6 months or an objective response (57% vs. 21%, P = 0.048). CONCLUSION: In summary, in cell-cycle–altered cancers, matched CDK4/6 inhibitors, as part of an individualized regimen targeting a majority of genomic alterations, was independently associated with longer PFS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02478931. FUNDING: Joan and Irwin Jacobs Fund, National Cancer Institute (P30 CA023100, R01 CA226803), and the FDA (R01 FD006334).