MEK Inhibitor Adds No Value in Treatment of KRAS-Mutant NSCLC

Adding selumetinib to docetaxel does not provide any significant benefit over docetaxel alone for patients previously treated for advanced KRAS-mutant non–small-cell lung cancer (NSCLC), according to a new study.

KRAS mutations can be detected in about one-quarter of lung adenocarcinoma patients, who have a worse prognosis and may not respond as well to chemotherapy as the general population of NSCLC patients. KRAS mutations lead to tumor development and growth by activating downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway involving MAPK kinase (MEK), stated researchers led by Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

The researchers published their results in JAMA.

In a previous randomized phase II study, selumetinib, a MEK 1 and 2 inhibitor, in combination with docetaxel as a second-line treatment for 87 patients with KRAS-mutant advanced NSCLC significantly improved median progression-free survival (PFS) and the objective response rate (ORR), and numerically improved overall survival (OS). These encouraging results led to the development of the phase III Selumetinib Evaluation as Combination Therapy (SELECT-1) trial.

This multicenter, randomized trial included 510 patients, mean age 61.4 years; 251 patients received selumetinib plus docetaxel and 254 patients received placebo plus docetaxel.

The results show that median PFS and OS were not significantly different in the two groups. Median PFS was 3.9 months with selumetinib plus docetaxel and 2.8 months with placebo plus docetaxel. Median OS was 8.7 months with selumetinib plus docetaxel and 7.9 months with placebo plus docetaxel.

ORR was 20.1% with selumetinib plus docetaxel and 13.7% with docetaxel alone. Median duration of response was 2.9 months with the two-drug combination and 4.5 months with docetaxel alone.

Adverse events of grade 3 or higher were more frequent with selumetinib plus docetaxel (67%) as compared with docetaxel alone (45%).

The researchers explained the better performance of patients receiving placebo plus docetaxel in their study as compared with the phase II trial may be due to the administration of prophylactic G-CSF to all patients in the SELECT-1 trial. This is not routine clinical practice for docetaxel monotherapy in this patient population, they noted.

In an editorial accompanying the journal article, Drs. Jacob Kaufman, MD, PhD, and Thomas E. Stinchcombe, MD, of Duke University in Durham, North Carolina, note that the discrepancy in the results from the earlier phase II trial and current phase III trial may be that “clinical benefit may only occur in a subset of tumors that exhibits a favorable genetic or signaling environment.” Also, the presence of other mutations or the relative activity of various signaling pathways may also influence response to MEK inhibition.

“MEK inhibition may be a viable strategy in this tumor subset but other drug candidates may be more effective than selumetinib,” they stated. “Alternatively, combination of MEK inhibition with other targeted therapies may have more synergy than was observed with docetaxel.”

They added: “The development of a targeted therapy is critical to the future management of patients with KRAS-mutant NSCLC and may provide a path forward for other solid tumor malignancies that harbor KRAS mutations.”