Selumetinib + MK-2206 Fails to Improve Survival vs mFOLFOX in Pancreatic Cancer
Blocking pathways downstream of the KRAS protein was thought to be an effective strategy for pancreatic cancer.
Seluminitinib, a MEK inhibitor, plus MK-2206, an AKT inhibitor, failed to improve overall survival compared with modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) in patients with previously treated metastatic pancreatic cancer, a study published in JAMA Oncology has shown.1
Patients with pancreatic cancer often harbor KRAS mutations; however, targeting the KRAS protein in this population has not been successful. As an alternate treatment strategy to slow cancer growth and improve survival, researchers hypothesized that blocking the MEK and PI3K/AKT pathways downstream of the KRAS protein could be effective.
Therefore, researchers sought to compare the efficacy and safety of selumetinib and MK-2206 with mFOLFOX in patients with metastatic pancreatic cancer who had failed prior gemcitabine-based chemotherapy.
For the open-label, phase 2 study (ClinicalTrials.gov Identifier: NCT01658943), investigators enrolled 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based therapy had failed. Participants were randomly assigned 1:1 to receive selumetinib 100 mg orally daily plus MK-2206 135 mg orally once weekly, or modified FOLFOX on days 1 and 15 of each 28-day cycle.
Results showed no significant difference in overall survival between the 2 treatments arms (hazard ratio [HR], 1.37; 95% CI, 0.90-2.08; P = .15). Median overall survival was 3.9 months with the investigational agents and 6.7 months with mFOLFOX.
Investigators found that progression-free survival was significantly shorter for patients who received selumetinib plus MK-2206 vs those given mFOLFOX (HR, 1.61; 95% CI, 1.07-2.43; P = .02); median progression-free survival was 1.9 months and 2.0 months, respectively.
One patient in the experimental arm achieved a partial response vs 5 in the mFOLFOX arm; 12 and 14 patients had stable disease, respectively.
The study further demonstrated that treatment with selumetinib and MK-2206 was associated with higher rates of grade 3 or higher toxicities, and more patients in that arm discontinued therapy due to adverse events.The findings ultimately suggest that dual inhibition of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib and MK-2206 is not efficacious for patients with metastatic pancreatic adenocarcinoma who have failed prior gemcitabine therapy.
ReferenceChung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy. JAMA Oncol. 2016 Dec 15. doi: 10.1001/jamaoncol.2016.5383. [Epub ahead of print]