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

Vincent Chung, Shannon McDonough, Philip A. Philip, Dana Cardin, Andrea Wang-Gillam, Laifong Hui, Mohamedtaki A. Tejani, Tara E. Seery, Irene A. Dy, Tareq Al Baghdadi, Andrew E. Hendifar, L. Austin Doyle, Andrew M. Lowy, Katherine A. Guthrie, Charles Blanke, Howard S. Hochster

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)516-522
Number of pages7
JournalJAMA oncology
Volume3
Issue number4
DOIs
StatePublished - 2017

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oxaliplatin
Pancreatic Neoplasms
Fluorouracil
Randomized Controlled Trials
gemcitabine
Therapeutics
Survival
Poisons
Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositol 3-Kinases
Drug Therapy
MK 2206
AZD 6244
Disease-Free Survival
Adenocarcinoma

ASJC Scopus subject areas

  • Medicine(all)

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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. / Chung, Vincent; McDonough, Shannon; Philip, Philip A.; Cardin, Dana; Wang-Gillam, Andrea; Hui, Laifong; Tejani, Mohamedtaki A.; Seery, Tara E.; Dy, Irene A.; Al Baghdadi, Tareq; Hendifar, Andrew E.; Doyle, L. Austin; Lowy, Andrew M.; Guthrie, Katherine A.; Blanke, Charles; Hochster, Howard S.

In: JAMA oncology, Vol. 3, No. 4, 2017, p. 516-522.

Research output: Contribution to journalArticle

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, C & Hochster, HS 2017, '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', JAMA oncology, vol. 3, no. 4, pp. 516-522. https://doi.org/10.1001/jamaoncol.2016.5383
Chung, Vincent ; McDonough, Shannon ; Philip, Philip A. ; Cardin, Dana ; Wang-Gillam, Andrea ; Hui, Laifong ; Tejani, Mohamedtaki A. ; Seery, Tara E. ; Dy, Irene A. ; Al Baghdadi, Tareq ; Hendifar, Andrew E. ; Doyle, L. Austin ; Lowy, Andrew M. ; Guthrie, Katherine A. ; Blanke, Charles ; Hochster, Howard S. / 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. In: JAMA oncology. 2017 ; Vol. 3, No. 4. pp. 516-522.
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abstract = "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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TY - JOUR

T1 - Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy

T2 - SWOG S1115 study randomized clinical trial

AU - Chung, Vincent

AU - McDonough, Shannon

AU - Philip, Philip A.

AU - Cardin, Dana

AU - Wang-Gillam, Andrea

AU - Hui, Laifong

AU - Tejani, Mohamedtaki A.

AU - Seery, Tara E.

AU - Dy, Irene A.

AU - Al Baghdadi, Tareq

AU - Hendifar, Andrew E.

AU - Doyle, L. Austin

AU - Lowy, Andrew M.

AU - Guthrie, Katherine A.

AU - Blanke, Charles

AU - Hochster, Howard S.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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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