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      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

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          SUMMARY

          Importance

          KRAS mutations are very 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.

          Objective

          SWOG S1115 was a randomized phase 2 study of selumetinib and MK-2206 versus modified FOLFOX in patients who failed gemcitabine-based therapy.

          Design, Setting, and Participants

          Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma who failed gemcitabine-based chemotherapy 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.

          Interventions

          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 5-fluorouracil 2,400 mg/m2 intravenous infusion over 46–48 hours) on days 1 and 15 with each cycle being 28 days.

          Main Outcomes and Measures

          The primary endpoint of the study was overall survival. Secondary objectives included evaluating toxicities, objective tumor response and progression free survival (PFS).

          Results

          Median OS was shorter in the experimental arm (3.9 vs 6.7 months, HR=1.37, p=0.15). PFS was also inferior in the experimental arm (HR=1.61, p=0.02). One vs five patients had a partial response and 12 vs 14 patients had stable disease in the selumetinib plus MK-2206 arm versus (vs) mFOLFOX. Grade 3 or higher toxicities were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients on the experimental arm discontinued therapy due to adverse events, as well.

          Conclusions and Relevance

          Although, dual targeting of MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients who failed gemcitabine-based chemotherapy, this was the first randomized prospective evaluation of mFOLFOX in the U.S. population which showed comparable results to CONKO-003 and PANCREOX.

          Trial Registration

          ClinicalTrials.gov, number NCT01658943

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          Author and article information

          Journal
          101652861
          43608
          JAMA Oncol
          JAMA Oncol
          JAMA oncology
          2374-2437
          2374-2445
          29 October 2017
          01 April 2017
          01 April 2018
          : 3
          : 4
          : 516-522
          Affiliations
          [1 ]City of Hope National Medical Center, Duarte, CA
          [2 ]SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA
          [3 ]Karmanos Cancer Institute, Wayne State University, Detroit, MI
          [4 ]Vanderbilt University Medical Center, Nashville, TN
          [5 ]Washington University in St. Louis, St. Louis, MO
          [6 ]Kaiser Permanente NCORP, Sacramento, CA
          [7 ]University of Rochester, Rochester, NY
          [8 ]University of California, Irvine, Orange, CA
          [9 ]Crossroads Cancer Center/Heartland NCORP, Effingham, IL
          [10 ]St. Joseph Mercy Hospital/Michigan CRC NCORP, Ann Arbor, MI
          [11 ]Cedars-Sinai Medical Center, Los Angeles, CA
          [12 ]Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD
          [13 ]University of California, San Diego, La Jolla, CA
          [14 ]SWOG Group Chair’s Office/Knight Cancer Institute, Oregon Health & Science University, Portland, OR
          [15 ]Yale Cancer Center, New Haven, CT
          Author notes
          Corresponding Author: Vincent Chung, M.D., City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010, Tel: 626-256-4673 ext. 64535, Fax: 626-301-8233, vchung@ 123456coh.org
          Article
          PMC5665683 PMC5665683 5665683 nihpa916085
          10.1001/jamaoncol.2016.5383
          5665683
          27978579
          e96ca8fb-d546-43cf-8ac3-f2d13c6eb317
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