Onartuzumab Falters in Late-Stage NSCLC Trial

A phase III study exploring the MET inhibitor onartuzumab (MetMab) as a treatment for patients with non-small cell lung cancer (NSCLC) is being stopped, following an interim analysis that suggested a lack of clinically meaningful efficacy. Genentech, the company developing the drug, made the announcement on March 3.

The phase III METLung study, randomized 499 patients with previously treated MET-positive advanced NSCLC to onartuzumab plus erlotinib or erlotinib and placebo. The primary endpoint of the study was overall survival (OS) with secondary endpoints of progression-free survival (PFS), objective response rate, and safety. Genentech announced that adverse events were similar between the two arms and that full data were submitted for presentation at an upcoming meeting.

"These results are disappointing because new options are needed for people with lung cancer, the most common and deadly cancer worldwide,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a release. "We remain committed to helping people with lung cancer and are studying several investigational medicines in this disease.”

In the phase II trial, treatment with onartuzumab plus erlotinib significantly improved PFS and OS for patients who tested positive for MET. The median OS for patients treated with the combination was 12.6 months compared with 3.8 months in the placebo plus erlotinib arm (hazard ratio [HR] = 0.37; 95% CI, 0.20-0.71; P = .002). The median PFS was 2.9 months versus 1.5 months, for onartuzumab and placebo, respectively (HR=0.53; 95% CI, 0.26-0.85; P = .04). However, in the overall population of all MET expression, the combination did not show a statistically significant advantage.

The METLung findings represent the most recent data in a series of unsuccessful phase III clinical trials in NSCLC. Each of these investigations has sought to add on to the established therapeutic strategy of EGFR inhibition for patients with NSCLC, though none have produced positive results.

Following recruitment of 1048 patients, the phase III MARQUEE trial examining tivantinib plus erlotinib was halted early, as it failed to meet its primary objective of OS. However, the secondary endpoint of PFS was significantly extended in favor of the tivantinib combinations by a median of 1.7 months (3.6 months versus 1.9 months; HR = 0.74; P <.0001).

In addition to MARQUEE, the phase III ATTENTION trial exploring tivantinib plus erlotinib in Asian patients with advanced EGFR wild-type non-squamous NSCLC failed to show a statistically significant improvement in the primary endpoint of OS. In this analysis, the median OS with tivantinib was 12.9 months versus 11.2 months with placebo (HR = 0.89, P = 0.4). ArQule Inc., the company developing tivantinib along with Daiichi Sankyo, announced these findings in mid-January 2014.

In January 2014, Pfizer announced that two phase III trials investigating the pan-HER inhibitor dacomitinib were unable to meet their primary endpoints. In the first of these trials, labeled ARCHER 1009, dacomitinib failed to improve PFS in comparison to erlotinib in the second- and third-line setting for patients with NSCLC. Notably, EGFR status was not in the inclusion criteria for this trial. In the second study, known as NCIC CTG BR.26, dacomitinib failed to improve OS versus placebo, following progression on standard therapies, including EGFR inhibitors.

The ongoing phase III ARCHER 1050 trial looks to compare dacomitinib with gefitinib as a first-line treatment for patients with EGFR-positive, advanced NSCLC. The primary outcome measure is PFS.

A second phase III study exploring onartuzumab plus erolotinib in patients with MET/EGFR-positive advanced NSCLC remains open (NCT02031744). In a press release, Genentech said it was evaluating the possible implications of the METLung results on the overall onartuzumab development program.