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.
SWOG S1115 was a randomized phase 2 study of selumetinib and MK-2206 versus modified FOLFOX in patients who failed gemcitabine-based therapy.
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.
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.
The primary endpoint of the study was overall survival. Secondary objectives included evaluating toxicities, objective tumor response and progression free survival (PFS).
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.
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.