MEK Inhibitor Selumetinib and Docetaxel in KRAS-Mutant Advanced NSCLC
A phase III trial (SELECT-1) has shown no improvement in progression-free survival with the addition of the MEK inhibitor selumetinib to docetaxel in the second-line treatment of patients with KRAS-mutant non–small cell lung cancer (NSCLC). Trial results were reported by Jänne et al in JAMA. KRAS mutations are associated with tumorigenesis via activation of downstream pathways including the MAPK pathway, which involves MEK and ERK kinases.
Study Details
In the double-blind trial, 510 patients with previously treated locally advanced or metastatic disease from 202 sites in 25 countries were randomized between October 2013 and January 2016 to receive oral selumetinib at 75 mg twice daily on a continuous schedule plus docetaxel at 75 mg/m2 intravenously on day 1 of every 21-day cycle (n = 254) or matched placebo plus docetaxel at the same schedule (n = 256). The primary endpoint was investigator-assessed progression-free survival. The cutoff date for analysis was June 2016. Overall, patients had a median age of 62 years, 41% were women, 95% were white, 92% were current (22%) or former smokers, 95% had metastatic disease, 94% had KRAS codon 12 or 13 mutations, and 91% had adenocarcinoma histology.
Progression-Free Survival
At the time of data cutoff, median progression-free survival was 3.9 months (interquartile range [IQR] = 1.5–5.9) in the selumetinib group vs 2.8 months (IQR = 1.4–5.5) in the control group (difference = 1.1 months; hazard ratio [HR] = 0.93, P = .44). Subgroup analyses showed no significant interactions of treatment by subgroup. Median overall survival was 8.7 months vs 7.9 months (difference = 0.9 months, HR = 1.05, P = .64). The objective response rate was 20.1% vs 13.7% (odds ratio = 1.61, P = .05), and the median duration of response was 2.9 months vs 4.5 months.
Adverse Events
The most common adverse events of any grade in the selumetinib group were diarrhea (61%), nausea (38%), rash (34%), and peripheral edema (30%); the most common adverse events in the control group were diarrhea (35%) and fatigue (31%). Adverse events of grade ≥ 3 occurred in 67% of the selumetinib group vs 45% of the control group, with the most common in the selumetinib group being asthenia (9%), dyspnea (8%), diarrhea (7%), and neutropenia (7%). Febrile neutropenia occurred in 2% vs 1%.
The investigators concluded: “Among patients with previously treated advanced KRAS-mutant non–small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone.”
The study was funded by AstraZeneca.
Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, is the corresponding author of the JAMA article.
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