Selumetinib Fails to Improve PFS With Docetaxel in Advanced NSCLC

The combination of selumetinib and docetaxel did not improve progression-free survival (PFS) among patients with advanced or metastatic non–small-cell lung cancer (NSCLC) over placebo plus docetaxel, according to the phase II SELECT-2 trial. There was a higher response rate with selumetinib, but this did not translate into clinical benefit.

Earlier studies have shown promising outcomes with selumetinib in patients with advanced KRAS-mutant NSCLC. “Selumetinib has also demonstrated activity in preclinical KRAS wild-type models, which suggested that selumetinib plus docetaxel may provide clinical benefit to patients with NSCLC with activation of the RAS-ERK pathway, independent of a KRAS mutation,” wrote study authors led by Jean-Charles Soria, MD, PhD, of Gustave Roussy Cancer Campus in Villejuif, France.

The SELECT-2 trial included 212 patients with advanced or metastatic NSCLC; the initial trial design included patients regardless of KRAS mutation status, but this was amended to include only those with KRAS wild-type NSCLC. Sixty-nine percent of the final cohort were patients who had KRAS wild-type tumors. Patients were randomized to one of three groups, receiving either selumetinib 75 mg twice per day plus docetaxel at either a 60-mg/m² dose (SEL+DOC 60) or a 75-mg/m² dose (SEL+DOC 75), or to placebo plus the higher docetaxel dose (PBO+DOC 75). Results were published in Annals of Oncology.

Neither of the selumetinib groups showed significant PFS improvement over placebo. Compared with the PBO+DOC 75 group, the SEL+DOC 60 group had a hazard ratio (HR) for PFS of 1.12 (90% CI, 0.8–1.61; P = .584). The SEL+DOC 75 group had an HR of 0.92 (90% CI, 0.65–1.31; P = .690). The median PFS was 3.0 months with SEL+DOC 60, 4.2 months with SEL+DOC 75, and 4.3 months with PBO+DOC 75.

When restricted to just the KRAS wild-type patients, the results were no different, with non-significant HRs for each dosing group. The number of KRAS-mutant patients was too small for an efficacy analysis, the authors wrote.

Overall survival was also not improved with selumetinib. The median overall survival was 5.7 months with SEL+DOC 60, 7.7 months with SEL+DOC 75, and 11.5 months with PBO+DOC 75.

The response rate, however, was better with the study drug. The objective response rates in the full cohort were 33% with the higher selumetinib dose, 18% with the lower dose, and 14% with placebo. Response durations were similar in the SEL+DOC 75 and PBO+DOC 75 groups (133 and 127 days, respectively), but shorter in the SEL+DOC 60 group (87 days).

No new safety signals emerged in this trial, and toxicity was similar to previously published studies. The most common grade 3 or higher adverse event was neutropenia.

The authors noted that there was no common factor found among a group of patients with a long duration of response and at least a 30% decrease in tumor size, suggesting that “the importance of assessing novel biomarkers to identify patient subgroups that may benefit from treatment with MEK inhibitors is highlighted.” At this point though, “selumetinib currently does not have a role as a second-line treatment for patients with advanced NSCLC.”