NO BENEFIT OF MEK INHIBITORS IN KRAS MUTANT NSCLC

A targeted combination therapy for patients with KRAS-mutant non-small cell lung cancer (NSCLC) did not improve overall survival (OS) or progression-free survival (PFS), researchers reported.

The phase III, randomized SELECT-1 trial compared the experimental MEK inhibitor selumetinib, in combination with docetaxel (Taxotere), with docetaxel and placebo as second-line therapy in patients who failed a previous line of therapy, explained Pasi Jänne, MD, PhD, of the Dana Farber Cancer Institute in Boston, and colleagues.

After a follow-up of approximately 1 year, median OS in the selumetinib combination group was 8.7 months versus 7.9 months in the docetaxel plus placebo group (hazard ratio 1.05, 95% CI 0.85-1.30, P=0.64), they wrote in JAMA.

Median PFS was 3.9 months in the combination group versus 2.8 months in the docetaxel-placebo group (HR 0.93, 95% CI 0.77-1.12, P=0.44). The objective response rate (ORR) was 20.1% in the combination group and 13.7% in the docetaxel-placebo group (odds ratio 1.61, 95% CI 1.00-2.62, P=0.05).

The results are especially puzzling, because a phase II clinical trial with the same design found that the combination therapy with selumetinib significantly improved PFS and ORR, and numerically improved OS, the authors noted.

"Genotype-directed targeted therapy is the standard of care for patients with advanced NSCLC. However, there are currently no targeted therapies specifically approved for patients with lung cancers related to a mutation in the KRAS gene, which are detected in approximately 25% of lung adenocarcinoma patients. Such patients have a worse prognosis and may derive less clinical benefit from chemotherapy than the overall population of patients with NSCLC," they wrote.

"The development of pharmacological strategies to directly target KRAS has proven challenging," they said. "As such, therapeutic development has focused on inhibiting KRAS effector proteins downstream, including MEK. To our knowledge, SELECT-1 is the largest randomized trial for patients with KRAS-mutant NSCLC performed to date. However, not all KRAS mutations are functionally the same, and the genomic context in which KRAS mutations occur may also influence therapeutic efficacy."

In an accompanying editorial, Jacob Kaufman, MD, of Duke University, and Thomas Stinchcombe, MD, of the Duke Cancer Institute, both in Durham, N.C., said, "This trial had a compelling preclinical rationale, because MEK signaling is downstream from KRAS, and selumetinib demonstrated activity in KRAS-mutant NSCLC xenograft models."

"The oncology community will be left seeking an explanation for these nonsignificant trial results and wondering what next investigational path should be pursued in this population. One possibility is that clinical benefit may only occur in a subset of tumors that exhibits a favorable genetic or signaling environment," they suggested.

The study included 510 patients with locally advanced or metastatic NSCLC (stage IIIB-IV) who had failed one previous line of therapy. All patients had a centrally confirmed KRAS-mutant tumor and at least 1 lesion suitable for measuring. Their mean age was 61 and 41% were women.

The patients were randomized 1:1 to receive either selumetinib-docetaxel or docetaxel-placebo. The median duration of treatment was 74 days in the combination group and 85 days in the docetaxel-placebo group. The median number of treatment cycles was 4 for both groups.

Tumors were evaluated by CT or MRI at baseline, and every 6 weeks thereafter. Patients were followed for survival every 8 weeks after treatment. The study's primary endpoint was PFS, with secondary endpoints of OS and ORR.

At the end of the study period, 447 patients (88%) had experienced a progression event, specifically 218 (86%) in the combination group and 229 (89%) in the placebo=docetaxel group. When the investigators analyzed the results by KRAS mutation subtypes, they found no differences in PFS.

In terms of study limitations, "Although the present trial was a randomized study, and hence should lead to a minimization of any imbalances, it is possible that differences in the distribution of concomitant genomic alterations, alongside KRAS mutations, contribute to the findings and to the differences observed between the phase 2 and phase 3 trials," the authors wrote.

"The approach of using molecular testing and treating with a corresponding targeted therapy has ushered advances in the treatment of NSCLC as well as other cancers," Kaufman and Stinchcombe said. "Molecular testing has helped identify the patients most and least likely to benefit from therapy and accelerated the speed of drug development.

"However, progress appears to be slowing," they noted. "This is in part because many of the remaining molecular alterations susceptible to targeted therapies have lower prevalence, which makes identification and performing trials challenging."

The study was funded by AstraZeneca. Some co-authors were company employees.

Jänne disclosed relevant relationships with Boehringer-Ingelheim, Pfizer, Ariad Pharmaceuticals, Genentech/Roche, Chugai, Merrimack, Ignyta, LOXO Oncology, and ACEA Biosciences. Co-authors disclosed multiple relevant relationships with industry.

Kaufman and Stinchcombe disclosed no relevant relationships with industry.