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.
Comparative Emetogenicity Study of Cisplatin Alone and in Combination Regimen on Cancer Patients of Bangladesh