Reference Detail

Ref Type

Journal Article

PMID

(27978579)

Authors

Chung V, McDonough S, Philip PA, Cardin D, Wang-Gillam A, Hui L, Tejani MA, Seery TE, Dy IA, Al Baghdadi T, Hendifar AE, Doyle LA, Lowy AM, Guthrie KA, Blanke CD, Hochster HS

Title

Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JAMA oncology	3	4	2017 Apr 01	516-522	JAMA Oncol

URL

Abstract Text

KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer.To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed.SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases.Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle.The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival.There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients).Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX.clinicaltrials.gov Identifier: NCT01658943.

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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