The addition of selumetinib to docetaxel failed to improve progression-free and overall survival in patients with KRAS-mutated locally advanced or metastatic NSCLC.
The addition of the oral MEK inhibitor selumetinib to docetaxel failed to improve progression-free survival (PFS) and overall survival (OS) in patients with KRAS-mutated locally advanced or metastatic non–small-cell lung cancer (NSCLC), according to a phase III trial (abstract LBA47_PR).
“KRAS-mutant lung cancer is the largest genomically defined subset of lung cancer where we do not have effective targeted therapies,” said the study’s principal investigator Pasi JÃ¤nne, MD, PhD, of Dana-Farber Cancer Institute in Boston, in a press release. He presented the study at the European Society for Medical Oncology (ESMO) 2016 Congress in Copenhagen.
An earlier phase II study showed a significant PFS advantage and numerical OS advantage with selumetinib and docetaxel compared with docetaxel alone. The new trial, called SELECT-1, included 510 patients with KRAS-mutant NSCLC, randomized to either selumetinib plus docetaxel (254 patients) or placebo plus docetaxel (256 patients).
At the time of data cutoff, 447 patients (88%) had progressed and 346 (68%) had died. In contrast to the phase II study, the PFS was no better with selumetinib (3.9 months) than without it (2.8 months), with a hazard ratio (HR) for progression of 0.93 (95% CI, 0.77–1.12; P = .44).
The median OS was 8.7 months with the study drug, and 7.9 months without it, for an HR of 1.05 (95% CI, 0.85–1.30; P =.64). The objective response rate was slightly better with selumetinib, at 20.1%, compared with 13.7% with placebo, for an odds ratio of 1.61 (95% CI, 1.00–2.62; P = .051).
Almost all patients in the selumetinib group (99%) and placebo group (95%) experienced at least one adverse event. Grade 3 or higher adverse events were more common with selumetinib (67% vs 45%), as were serious adverse events (49% vs 32%) and events that led to hospitalization (46% vs 30%).
JÃ¤nne concluded that selumetinib does not provide clinical benefit in these patients. “Hence it is not a treatment approach that should be adapted moving forward, and there remains a desperate need and an opportunity to develop new treatments for this subset of NSCLC patients,” he said.
Alex Adjei, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, who discussed the study at ESMO, noted that phase II trials of the size that SELECT-1 was based on historically have often led to negative phase III trials, and that the preclinical rationale for studying this drug in this malignancy was “weak, at best.” MEK inhibitors have demonstrated some cytotoxic synergy with docetaxel in various tumor types; that synergy has been independent of KRAS mutation status.