Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	9	100	2018 Dec 21	37352-37366	Oncotarget

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	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
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	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