Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With <i>KRAS</i>-Mutant Advanced Non–Small Cell Lung Cancer
Authors: Pasi A. Jänne, Michel M. van den Heuvel, Fabrice Barlesi, Manuel Cobo, Julien Mazieres, Lucio Crinò, Sergey Orlov, Fiona Blackhall, Juergen Wolf, Pilar Garrido, Artem Poltoratskiy, Gabriella Mariani, Dana Ghiorghiu, Elaine Kilgour, Paul Smith, Alexander Kohlmann, David J. Carlile, David Lawrence, Karin Bowen, Johan Vansteenkiste
Journal: JAMA (2017)

<h3>Importance</h3> There are no specifically approved targeted therapies for the most common genomically defined subset of non–small cell lung cancer (NSCLC),<i>KRAS</i>-mutant lung cancer. <h3>Objective</h3> To compare efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced<i>KRAS</i>-mutant NSCLC. <h3>Design, Setting, and Participants</h3> Multinational, randomized clinical trial conducted at 202 sites across 25 countries from October 2013 through January 2016. Of 3323 patients with advanced NSCLC and disease progression following first-line anticancer therapy tested for a<i>KRAS</i>mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016. <h3>Interventions</h3> Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel. <h3>Main Outcomes and Measures</h3> Primary end point was investigator assessed progression-free survival. Secondary end points included overall survival, objective response rate, duration of response, effects on disease-related symptoms, safety, and tolerability. <h3>Results</h3> Of 510 randomized patients (mean age, 61.4 years [SD, 8.3]; women, 207 [41%]), 505 patients (99%) received treatment and completed the study (251 received selumetinib + docetaxel; 254 received placebo + docetaxel). At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5-5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4-5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77-1.12];<i>P</i> = .44). Median overall survival was 8.7 months (IQR, 3.6-16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8-20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85-1.30];<i>P</i> = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00-2.62];<i>P</i> = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7-4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8-5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%). <h3>Conclusions and Relevance</h3> Among patients with previously treated advanced<i>KRAS-</i>mutant non–small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone. <h3>Trial Registration</h3> clinicaltrials.gov:NCT01933932