Dataset Information

CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors.

ABSTRACT: Cyclin-dependent kinases (CDK) 4/6 inhibitors, namely abemaciclib, palbociclib, and ribociclib, interfere with cell cycle progression, induce cell senescence and might promote cancer cell disruption by a cytotoxic T cells-mediated effect. Phase III randomized clinical trials have proven that CDK4/6 inhibitors (CDK4/6i) in combination with several endocrine agents improve treatment efficacy over endocrine agents alone for hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (MBC). Based on such results, these combinations have been approved for clinical use. Preclinical studies in cell cultures and mouse models proved that CDK4/6i are active against a broad spectrum of solid tumors other than breast cancer, including liposarcoma, rhabdomyosarcoma, non-small cell lung cancer, glioblastoma multiforme, esophageal cancer, and melanoma. The role of CDK4/6i in monotherapy in several solid tumors is currently under evaluation in phase I, II, and III trials. Nowadays, abemaciclib is the only of the three inhibitors that has received approval as single agent therapy for pretreated HR+ HER2- MBC. Here we review biological, preclinical and clinical data on the role of CDK4/6 inhibitors as single agents in advanced solid tumors.

SUBMITTER: Schettini F

PROVIDER: S-EPMC6315195 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors.

Schettini Francesco F De Santo Irene I Rea Carmen G CG De Placido Pietro P Formisano Luigi L Giuliano Mario M Arpino Grazia G De Laurentiis Michelino M Puglisi Fabio F De Placido Sabino S Del Mastro Lucia L

Frontiers in oncology 20181212

Cyclin-dependent kinases (CDK) 4/6 inhibitors, namely abemaciclib, palbociclib, and ribociclib, interfere with cell cycle progression, induce cell senescence and might promote cancer cell disruption by a cytotoxic T cells-mediated effect. Phase III randomized clinical trials have proven that CDK4/6 inhibitors (CDK4/6i) in combination with several endocrine agents improve treatment efficacy over endocrine agents alone for hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast can ...[more]

PMID: 30631751

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Project description:Objective response rate (ORR) is an increasingly important end point for accelerated development of highly active anticancer therapies, yet its relationship to regulatory approval is not well characterized.To identify circumstances in which a high ORR is associated with regulatory approval, and therefore might be an appropriate end point for definitive single-arm studies of anticancer therapies.A database of all oncology clinical trials registered at clinicaltrials.gov between October 1, 2007, and September 30, 2010.Trials of palliative systemic therapies for 4 measurable solid tumor types, limited to those with trial arms of at least 20 patients reporting ORR per Response Evaluation Criteria in Solid Tumors (RECIST).A systematic search was used to identify the reported ORR for each eligible treatment arm that had been presented publicly.For each treatment regimen, defined as a single-agent or unique combination of agents for 1 cancer type, the mean ORR and the maximum ORR statistically exceeded were calculated, and their association with regulatory approval was studied. A regimen was considered approved for a specific cancer type if it had received regulatory approval in any country for treatment of advanced cancer of that type.From 1800 trials, 874 eligible trial arms in 578 eligible trials were identified; 542 arms had ORR data available for 294 regimens. Maximum ORR and mean ORR were significantly associated with regulatory approval (??=?0.27, P?<?.001; ??=?0.12, P?=?.01); this relationship was stronger for single-agent therapies (??=?0.49; ??=?0.41) than for combination regimens (? = 0.28; ? = 0.17). Evaluation of ORR thresholds between 20% and 60% as potential trial end points demonstrated that ORR statistically exceeding 30% with a single agent had 98% specificity and 89% positive predictive value for identifying regimens achieving regulatory approval.For single-agent regimens, high ORR was associated with regulatory approval; this relationship was less strong for combination regimens. Our data suggest that high ORR (eg, statistically exceeding an ORR of 30%) is an appropriate end point for single-arm trials aiming to demonstrate breakthrough activity of a single-agent anticancer therapy.

Dataset Information

CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors.

Publications

CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors.

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