Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial

Abstract

Importance: There are no specifically approved targeted therapies for the most common genomically defined subset of non-small cell lung cancer (NSCLC), KRAS-mutant lung cancer.

Objective: To compare efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced KRAS-mutant NSCLC.

Design, setting, and participants: 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 KRAS mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016.

Interventions: Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel.

Main outcomes and measures: 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.

Results: 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]; P = .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]; P = .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]; P = .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%).

Conclusions and relevance: 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.

Trial registration: clinicaltrials.gov: NCT01933932.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jänne reports receiving personal fees from Boehringer-Ingelheim, Pfizer, Ariad Pharmaceuticals, Genentech/Roche, Chugai, Merrimack, Ignyta, LOXO Oncology, and ACEA Biosciences; grant funding from Puma Biotechnology and Astellas; being a shareholder of Gatekeeper Pharmaceuticals and LOXO Oncology; and receiving postmarketing royalties from a Dana-Farber Cancer Institute–owned patent on EGFR mutation licensed to Lab Corp. Dr Barlesi reports receiving consultancy fees from Bristol-Myers Squibb, Boehringer-Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann-La Roche, Novartis, Merck, Merck Sharp & Dohme, Pierre Fabre, and Pfizer and payment for lectures including service on speaker bureaus from Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche, Novartis, Pierre Fabre, and Pfizer. Dr Wolf reports receiving board membership fees from Bristol-Myers Squibb, Boehringer-Ingelheim, Merck Sharp & Dohme, Clovis Oncology, Novartis, Pfizer, and Roche, and grants from Bayer, Boehringer-Ingelheim, Novartis, Pfizer, and Roche. Dr Garrido reports receiving personal fees from Bristol-Myers Squibb, Roche, Pfizer, Novartis, Merck Sharp & Dohme, and Boehringer-Ingelheim and grant funding from Boehringer-Ingelheim.

Figures

Figure 1.. Flow of Patients Through Randomization and Treatment

KRAS indicates v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homologue. To convert creatinine clearance to mL/s/m2, multiply by 0.0167. The full analysis set included all randomized patients; the safety analysis set included all patients who received at least 1 dose of randomized investigational product (selumetinib or placebo). aPatients could be prescreened if the investigator considered it appropriate for the patient to consent to central KRAS mutation status screening of archival tumor material prior to consenting to the main study. bSpecific reasons for exclusion of 2457 prescreened patients are not available. cAn individual patient could have had more than 1 reason for exclusion. dSevere noncompliance was based on the Case Report Form categories. The choices were patient decision, adverse event, severe noncompliance to protocol, condition under investigation worsened, and other. eIneligible due to cardiac conditions as specified in the protocol and World Health Organization performance status higher than 1. fAt the time of data cutoff (June 7, 2016).

Figure 2.. Estimated Progression-Free Survival in the Selumetinib Plus Docetaxel and Placebo Plus Docetaxel Groups

HR indicates hazard ratio; IQR, interquartile range. The dotted line indicates median survival. In this full analysis set (performed using stratified log-rank test with factors for World Health Organization Performance Status), 88% patients had a progression event (447 of 510 events). Data cutoff was June 7, 2016. The crosses indicate censored observations. Median duration of follow-up for progression-free survival: selumetinib + docetaxel, 2.7 months (IQR, 0.6-5.6); placebo + docetaxel, 4.2 months (IQR, 0.03-11.1).

Figure 3.. Estimated Overall Survival in the Selumetinib Plus Docetaxel and Placebo Plus Docetaxel Groups

HR indicates hazard ratio. The dotted line indicates median survival. In this full analysis set (performed using stratified log-rank test with factors for World Health Organization Performance Status), 68% of patients had a death event (346 of 510 events). Data cutoff was June 7, 2016. The crosses indicate censored observations. Median duration of follow-up for overall survival: selumetinib + docetaxel, 13.5 months (IQR, 7.4-17.3); placebo + docetaxel, 12.2 months (IQR, 8.1-16.8).