Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced non-small cell lung cancer
Mené sur 89 patients atteints d'un cancer avancé du poumon non à petites cellules (dont 41 avec un gène KRAS muté), cet essai évalue l'efficacité, du point de vue de la survie sans progression et du taux de réponse objective, et la toxicité du sélumetinib, seul ou en combinaison avec l'erlotinib
Background KRAS mutations in NSCLC are associated with a lack of response to EGFR inhibitors. Selumetinib (AZD6244; ARRY-142886) is an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway. Patients and Methods Advanced NSCLC patients failing 1-2 prior regimens underwent KRAS profiling. KRAS wild-type patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily). KRAS-mutant patients were randomized to selumetinib (75 mg BID) or the combination. The primary endpoints were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Biomarker studies of ERK phosphorylation and immune subsets were performed. Results From March 2010 to May 2013, 89 patients were screened; 41 KRAS mutant and 38 KRAS wild-type patients were enrolled. Median PFS in the KRAS wild-type arm was 2.4 months (95% CI: 1.3 to 3.7) for erlotinib alone and 2.1 months (95% CI: 1.8 to 5.1) for the combination. The ORR in the KRAS mutant group was 0% (95% CI: 0.0% to 33.6%) for selumetinib alone and 10% (95% CI: 2.1% to 26.3%) for the combination. Combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation (8%). PD-1 expression on regulatory T-cells (Tregs), Tim-3 on CD8+ T-cells, and Th17 levels were associated with PFS and OS in patients receiving selumetinib. Conclusions This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies.
Annals of Oncology 2016