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
Open accessAbstract
IMPORTANCE: 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. OBJECTIVE: To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. DESIGN, SETTING, AND PARTICIPANTS: 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. 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 fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01658943.
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The poorer results in the selumetinib plus MK-2206 arm are probably partly attributable to the combination's toxicity.
“This outcome is likely due, in part, to the toxicity of the drug combination as the combination arm had a higher fraction of patients that experienced grade 3 or higher toxicity and discontinued treatment (94).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [94]
A phase II trial in metastatic pancreatic cancer compared selumetinib plus MK-2206 with mFOLFOX chemotherapy; patients on the drug combination had slightly worse outcomes than controls.
“In a phase II study combining the MEK inhibitor selumetinib with the AKT inhibitor MK-2206 in patients with metastatic pancreatic cancer, those receiving the drug combination actually did slightly worse than the control group receiving the mFOLFOX chemotherapy (94).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [94]
In that trial, a greater proportion of patients in the combination arm had grade 3 or higher toxicity and stopped treatment.
“the combination arm had a higher fraction of patients that experienced grade 3 or higher toxicity and discontinued treatment (94).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [94]
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Self-citation
- Authors
- Chung, V., McDonough, S., Philip, P. A., Cardin, D., Wang-Gillam, A., Hui, L., Tejani, M. A., Seery, T. E., Dy, I. A., Al Baghdadi, T., Hendifar, A. E., Doyle, L. A., Lowy, A. M., Guthrie, K. A., Blanke, C. D., & Hochster, H. S.
- Affiliations
- City Of Hope National Medical Center (US)
- Fred Hutch Cancer Center (US)
- Wayne State University (US)
- Vanderbilt University Medical Center (US)
- Washington University in St Louis, St Louis, Missouri
- Kaiser Permanente (US)
- University of Rochester (US)
- University of California, Irvine (US)
- Heartland Cancer Research (US)
- St Joseph Mercy Hospital/Michigan CRC NCORP, Ann Arbor
- Cedars-Sinai Medical Center (US)
- National Cancer Institute (US)
- University of California San Diego (US)
- Oregon Health & Science University (US)
- Yale Cancer Center, New Haven, Connecticut
- Corresponding author
- Chung, Vincent
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2017-04-01
- Volume
- 3
- Issue
- 4
- Pages
- 516
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC5665683
- OpenAlex
- W2563361316
- Cited by
- 176
- References
- 33
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 22 · 2023: 14 · 2022: 26 · 2021: 29 · 2020: 16 · 2019: 24 · 2018: 19 · 2017: 10
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Cancer Institute (U10CA004919, UG1CA189822, UG1CA189821, UG1CA189953, UG1CA189808, U10CA180820, U10CA180833, U10CA180828, UG1CA189960, U10CA180846, N01 CA004919, UG1CA189853, U10CA046368, U10CA180835, U10CA180888, UG1CA189830, UG1CA189954, U10CA011083, U10CA180819, UG1CA189804, UG1CA189971, U10CA180801, U10CA180798, U10CA046113, U10CA180818, UG1CA189858, UG1CA189809, U10CA180821, U10CA180847)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- selumetinib, MK-2206, oxaliplatin, 5-fluorouracil, FOLFOX, metastatic pancreatic adenocarcinoma, KRAS mutation, MEK inhibition, PI3K/AKT inhibition, targeted therapy, oral combination therapy, overall survival, progression-free survival, liver metastasis, gemcitabine
- MeSH terms
- Oxaliplatin, Adenocarcinoma, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Female, Fluorouracil, Heterocyclic Compounds, 3-Ring, Humans, Male, Middle Aged, Organoplatinum Compounds, Pancreatic Neoplasms, Proportional Hazards Models, Salvage Therapy, Disease-Free Survival, Kaplan-Meier Estimate
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