Reference Detail

Ref Type

Journal Article

PMID

(26187616)

Authors

Gupta S, Argilés G, Munster PN, Hollebecque A, Dajani O, Cheng JD, Wang R, Swift A, Tosolini A, Piha-Paul SA

Title

A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	23	2015 Dec 01	5235-44	Clin Cancer Res

URL

Abstract Text

The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth.This phase I study assessed dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of oral ridaforolimus plus oral MK-2206 in patients with advanced solid tumors. Efficacy was evaluated in patients with biomarker-identified estrogen receptor-positive breast cancer (low RAS gene signature and high Ki67 index) or castration-resistant prostate cancer (PTEN deficiency) with PI3K pathway addiction.Thirty-five patients were enrolled: 11 patients in part A (three breast cancer) and 24 biomarker-eligible patients in part B (16 breast cancer, eight prostate cancer). One patient with breast cancer from part A was also found to be biomarker-eligible when tested after she had clinical response. The MTD was 10 mg/d ridaforolimus 5 d/wk + 90 mg/wk MK-2206; 1 of 17 patients experienced DLT (grade 3 rash) at this dose. The most common adverse events at MTD were rash (44.4%), stomatitis (38.9%), diarrhea (27.8%), and decreased appetite (27.8%). By investigator assessment, 2 of 16 (12.5%) evaluable patients with breast cancer had partial response; by central assessment, 2 of 14 (14.3%) evaluable patients had complete response. Two patients had durable stable disease (SD) for 416 and 285 days, respectively. No patients with prostate cancer responded; one patient had SD for ≥ 6 months.Combination ridaforolimus and MK-2206 showed promising activity and good tolerability in heavily pretreated patients with hormone-positive and -negative breast cancer exhibiting PI3K pathway dependence.

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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
PIK3CA act mut	breast cancer	predicted - sensitive	MK2206 + Ridaforolimus	Phase I	Actionable	In a Phase I clinical trial, Ridaforolimus in combination with MK-2206 demonstrated clinical activity in breast cancer patients expressing a PI3K pathway dependent gene expression signature, with complete response in 14.3% (2/14), partial response in 12.5% (2/16), and 2 patients achieving stable disease (PMID: 26187616).	26187616
PTEN loss	prostate cancer	no benefit	MK2206	Phase I	Actionable	In a Phase I clinical trial, 8 patients with metastatic, castration-resistant prostate cancer harboring a loss of PTEN did not respond to MK-2206 therapy, but prolonged stable disease was observed in 2 patients (PMID: 26187616).	26187616