MEK and PI3K/AKT Inhibition Ineffective in Pancreatic Cancer

MEK and PI3K/AKT inhibition with selumetinib and MK-2206 does not improve survival of patients with KRAS-mutant, metastatic pancreatic adenocarcinoma, according to a study published in JAMA Oncology.¹

This phase 2 trial (ClinicalTrials.gov Identifier: NCT01658943) was conducted to determine whether inhibiting mutant RAS downstream signaling pathways would be an effective substitute for KRAS inhibition, which has not been efficacious for patients with pancreatic cancer. The goal was to compared the efficacy of selumetinib—an MEK 1/2 inhibitor—plus MK-2206—an AKT inhibitor—with that of modified FOLFOX (cytotoxic oxaliplatin plus fluorouracil [mFOLFOX]).

In this randomized trial, 58 patients were randomized to receive selumetinib and MK-2206, while 62 patients received mFOLFOX. For the experimental arm and mFOLFOX arm, the progression-free survival rates were 1.9 months and 2.0 months, respectively, and the overall survival rates were 3.9 months and 6.7 months, respectively.

One patient on the experimental arm had a partial response; 4 had a partial response with mFOLFOX. There were no complete responses.

Grade 3 or worse toxic events were more common in the experimental arm than with mFOLFOX (67% vs 37%).

The authors speculated that insufficient understanding of signaling networks driving the cancer progression contributed to the study’s failure. Other limitations included insufficient serial biopsies during treatment, though, according to the authors, liquid biopsies may mitigate this issue.

Reference

1. Chung 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: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2016 Dec 15. doi: 10.1001/jamaoncol.2016.5383 [Epub ahead of print]