3623 Background: Although CDK4/6 inhibitors are established as a standard treatment option for hormone receptor-positive, HER2-negative metastatic breast cancer patients, its benefit in other solid tumors is unclear. Moreover, no clear biomarker exists that predicts the response to CDK4/6 inhibitors. Herein, we investigated the factors associated with clinical outcomes from CDK4/6 inhibitor-based therapy, used alone or in combination with other therapies targeting genomic co-alterations, among diverse cancer patients with potentially sensitizing alterations in G1-S phase cell-cycle alterations (defined as CDK4/6 amplifications, CCND1/2/3 amplifications or CDKN2A/ B alterations). Methods: We interrogated molecular profiles of 2,457 patients with diverse solid tumors for G1-S phase cell-cycle alterations and co-altered genes using clinical-grade next generation sequencing (182-465 genes). Results: G1-S phase cell-cycle alterations occurred in 20.6% (507/2,457) of patients with 99% of those with cell cycle alterations (N = 501/507) harboring at least one characterized co-alteration (median, 4; range, 0-24). Significant improvement in median PFS was observed when CDK4/6 inhibitor-based therapies matched a larger proportion of tumor alterations, often by being given together with other drugs that were matched to genomic co-alterations, hence achieving a high Matching Score (high Matching Score [≥50%] vs. low Matching Score [ < 50%]: all cohorts including breast cancer [N = 58]: PFS: 6.2 vs. 3.2 months, P = 0.001; non-breast cancer cohort [N = 40]: PFS 6.2 vs. 2.0 months, P < 0.001 [multivariate]). (Matching Score roughly equivalent to number of alterations targeted divided by total number of characterized alterations). In contrast, targeting CDK4/6 alone in patients harboring cell-cycle pathway alterations along with other co-alterations, without targeting the genomic co-alterations, did not improve PFS even in patients who received matched CDK4/6 inhibitors as part of a combination regimen. Representative cases that were successfully treated with a matched combination strategy will also be presented. Conclusions: Most patients with G1-S phase cell-cycle alterations harbored co-genomic alterations. Our current study suggests that targeting co-alterations along with cell cycle molecular alterations may be necessary to achieve better clinical outcome. Further clinical investigation with larger numbers of patients are required.