Tivantinib With Erlotinib Fails to Improve OS in NSCLC

Adding tivantinib to erlotinib improved progression-free survival (PFS) but not overall survival (OS) in patients with previously treated non–small-cell lung cancer (NSCLC), according to a new phase III trial. The trial was discontinued for futility at an interim analysis.

“The involvement of MET in multiple signal transduction pathways affecting tumor-cell proliferation, mobilization, and angiogenesis makes it an interesting potential target for cancer therapy,” wrote study authors led by Giorgio V. Scagliotti, MD, of the University of Torino in Italy. Tivantinib is a selective inhibitor of the MET receptor tyrosine kinase, helping to slow cell proliferation and induce apoptosis in cancer cells that express MET.

The new study compared erlotinib plus tivantinib to erlotinib plus placebo in 1,048 patients with advanced nonsquamous NSCLC. All patients had been previously treated with one or two systemic regimens, including a platinum doublet. Results were published online ahead of print in the Journal of Clinical Oncology.

A total of 976 patients (93%) subsequently discontinued treatment after a mean of 16.2 weeks, and two were lost to follow-up; most patients (295 in combination group, 350 in placebo group) discontinued due to progressive disease.

The primary endpoint of OS did not differ significantly between the groups on an intention-to-treat analysis, and thus the trial was stopped for futility at an interim analysis. The median OS was 8.5 months with erlotinib and tivantinib and 7.8 months with erlotinib and placebo, for a hazard ratio (HR) of 0.98 (95% confidence interval [CI], 0.84–1.14; P = .81). OS was also similar in an EGFR wild-type subgroup.

The addition of tivantinib did improve PFS, however. The median PFS was 3.6 months with tivantinib and 1.9 months without it, for an HR of 0.74 (95% CI, 0.64–0.85; P < .001). This was also true in the EGFR wild-type subgroup.

The researchers did see a trend toward improved OS in a subgroup of 211 patients with high MET tumor expression, with a median OS of 9.3 months with tivantinib and 5.9 months without, for an HR of 0.70 (95% CI, 0.49–1.01). PFS was significantly better with tivantinib in this subgroup.

Almost all patients in both groups experienced at least one treatment-emergent adverse event (AE). Myelosuppression-related AEs, which are known to be related to tivantinib, were more common in that group; this included anemia (16% vs 9.9%), neutropenia (11.9% vs 1.9%), leukopenia (5.8% vs 1%), and febrile neutropenia (3.3% vs 0.4%).

“Further investigation of tivantinib in patients with nonsquamous NSCLC with high MET expression is warranted, as is exploration of the most relevant tumor biomarkers to select patients for combined MET and EGFR inhibition therapy,” the authors concluded.