The addition of selumetinib to erlotinib failed to improve objective response rate or progression-free survival compared with erlotinib monotherapy in KRAS mutation-positive and KRAS wild-type advanced non-small cell lung cancer (NSCLC), a study published in the journal Annals of Oncology has shown.1
Because KRAS mutations in NSCLC are associated with a lack of response to EGFR kinase inhibitors, researchers sought to evaluate the safety and efficacy of erlotinib plus selumetinib, an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway.
For the phase 2 trials, researchers enrolled 79 KRAS mutant or wild-type patients with advanced NSCLC who had failed 1 or 2 prior regimens. The 38 KRAS wild-type patients were randomly assigned to receive erlotinib 150 mg daily or selumetinib 150 mg daily plus erlotinib 100 mg daily, while the 41 KRAS mutant patients received selumetinib 75 mg or the combination.
Results showed that median progression-free survival in the KRAS wild-type arm was 2.4 months (95% CI, 1.3 – 3.7) for erlotinib alone and 2.1 months (95% CI, 1.8 – 5.1) for erlotinib plus selumetinib.
Researchers found that the objective response rate in the KRAS mutant group was 0% (95% CI, 0.0 – 33.6) for selumetinib alone compared with 10% (95% CI, 2.1 – 26.3) for the combination.
In regard to safety, combination therapy was associated with increased toxicities, requiring dose reductions in 56% of patients and treatment discontinuation in 8%.
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The study also demonstration that PD-1 expression on regulatory T-cells, Tim-3 on CD8+ T-cells, and Th17 levels were associated with progression-free and overall survival in patients receiving selumetinib, suggesting that further studies on the association of immune subsets and immune checkpoint receptor expression with selumetinib may be warranted.
- Carter CA, Rajan A, Keen C, et al. Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced non-small cell lung cancer [published online ahead of print January 22, 2016]. Ann Oncol. doi: 10.1093/annonc/mdw008.