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Ref Type Journal Article
PMID (30647837)
Authors Gopalan PK, Villegas AG, Cao C, Pinder-Schenck M, Chiappori A, Hou W, Zajac-Kaye M, Ivey AM, Kaye FJ
Title CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition.
Journal Oncotarget
Vol 9
Issue 100
Date 2018 Dec 21
URL
Abstract Text Aberrant activation of CDK4/6 kinase is the most common somatic event in non-small cell lung cancer (NSCLC). Palbociclib is a highly specific CDK4/6 inhibitor shown to inhibit cell cycle progression and promote cellular senescence. We conducted a phase 2 clinical trial of palbociclib in 19 previously-treated patients with advanced NSCLC. Only patients with p16-null staining by immunohistochemistry and documented tumor progression were eligible. The primary endpoint was tumor response rate. Palbociclib therapy alone was well-tolerated. Of 16 evaluable patients who received > 1 month of therapy, there were no objective responses. However, 8 patients (50%) with previously progressive NSCLC had stable disease (SD) lasting a range of 4-10.5 months. Median overall survival (OS) for all cases was 5.1 months, and median overall survival for the subset of patients with SD was 16.6 months. We also performed preclinical testing of palbociclib in combination with 13 different targeted or cytotoxic chemotherapeutic agents using a cell viability assay. Only the combination of palbociclib and mTOR inhibitors resulted in synergistic growth inhibition, particularly in tumors carrying RAS mutations. Our findings warrant further clinical investigation of the combination of palbociclib and mTOR inhibitors, especially in patients carrying activated RAS mutations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CDKN2A negative lung non-small cell carcinoma sensitive Palbociclib + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, Ibrance (palbociclib) and Rapamune (sirolimus) synergisticaly inhibited growth of Cdkn2a-null non-small cell lung cancer cell lines in culture (PMID: 30647837). 30647837
CDKN2A negative lung non-small cell carcinoma sensitive Everolimus + Palbociclib Preclinical - Cell culture Actionable In a preclinical study, Ibrance (palbociclib) and Afinitor (everolimus) synergisticaly inhibited growth of Cdkn2a-null non-small cell lung cancer cell lines in culture (PMID: 30647837). 30647837
CDKN2A negative lung non-small cell carcinoma predicted - sensitive Palbociclib Phase II Actionable In a Phase II trial, Ibrance (palbociclib) treatment resulted in no objective response (0/16) and stable disease in 50% (8/16) of patients with advanced Cdkn2a-null (by IHC) non-small cell lung cancer, with a median overall survival (mOS) of 5.1 months for all patients and a mOS of 16.6 months in patients achieved stable disease (PMID: 30647837; NCT01291017). 30647837
CDKN2A negative lung non-small cell carcinoma sensitive Palbociclib + PF-04691502 Preclinical - Cell culture Actionable In a preclinical study, Ibrance (palbociclib) and PF-04691502 synergisticaly inhibited growth of Cdkn2a-null non-small cell lung cancer cell lines in culture (PMID: 30647837). 30647837