ECC: MET Inhibitor Lung Cancer Trial Stopped Early, but Subgroup Analysis Promising

Chemical structure of tivantinib (ARQ197), a small-molecule MET inhibitor.

A combination regimen of erlotinib and the selective MET inhibitor tivantinib did not improve overall survival compared with erlotinib and placebo among patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) who were previous treated with one or two lines of systemic therapy, according to results of a new phase III study. The study was stopped early because the pre-planned interim analysis crossed the futility boundary.

Results of the MARQUEE double blind, randomized trial were presented by Giorgio Scagliotti, MD, of the University of Turin San Luigi Hospital in Italy, at the European Cancer Congress (ECC) in Amsterdam. The study included 1,048 patients randomized to erlotinib 150 mg once daily plus either placebo (522 patients) or tivantinib 360 mg twice daily (526 patients). Patients could not have been previously treated with an EGFR inhibitor.

The median overall survival was 8.5 months in the tivantinib group and 7.8 months in the placebo group, for a hazard ratio (HR) of 0.98 (95% CI, 0.84–1.15; P = .81). Progression-free survival did show a difference between the groups, at 3.6 months in the tivantinib patients and 1.9 months in the placebo patients for an HR of 0.74 (95% CI, 0.62–0.89; P < .0001). The overall response rate was also improved with tivantinib, at 10.3% compared with 6.5% for placebo (P < .05).

The most common adverse events were rash, diarrhea, and asthenia/fatigue, which occurred at similar rates in each group. Neutropenia of grade 3 or 4 was more common among tivantinib patients (10%) than placebo patients (1%).

According to a press release, MET protein expression levels from tumor samples were available in approximately 40% of patients. In tumors that showed at least 2+ positive MET immunostaining in more than half of cells, the tivantinib combination significantly improved both progression-free survival and overall survival.

“Inhibition of MET, a receptor for hepatocyte growth factor, is a promising therapeutic strategy in several malignancies, lung and gastric cancers in particular,” said Rafal Dziadziuszko, MD, PhD, of the Medical University of Gdansk in Poland; he was not involved in the study. “Based on unfilled promise of this trial, we can no longer ignore the biological measures to identify patients most likely to benefit from MET inhibitor therapy. Although it is unclear which of the several biomarkers are most appropriate to select patients for combined MET and EGFR inhibition therapy, early phase data for tivantinib and other MET inhibitors clearly indicated a possible role of MET protein expression, MET gene copy number, and KRAS mutations.” He noted that the question of biomarker utility should have been resolved prior to initiation of the MARQUEE trial.

Study Details

Study patients had a median age of 62 years, and two-thirds of patients had one prior therapy rather than two. Most patients had an ECOG performance status of 1 (68%); 10.4% of patients had an EGFR mutation, and 27.1% had KRAS mutations. All baseline characteristics were well matched between study arms.