No Survival Benefit of Adding MET Inhibitor Tivantinib to Erlotinib in Previously Treated Advanced Nonsquamous NSCLC


Key Points

  • The addition of tivantinib to erlotinib improved progression-free but not overall survival.
  • Exploratory analysis suggested benefit of tivantinib in patients with high MET expression.

In a phase III trial reported in the Journal of Clinical Oncology, Scagliotti et al found that the addition of the MET receptor tyrosine kinase inhibitor tivantinib to erlotinib (Tarceva) did not improve overall survival in previously treated patients with locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC).

Study Details

In this double-blind trial, 1,048 patients from Europe, Russia, the United States, Latin America, Canada, and Australia with stage IIIB to IV disease who had received one to two systemic treatments including a platinum doublet were randomly assigned between January 2011 and July 2012 to receive tivantinib at 360 mg twice daily plus erlotinib at 150 mg daily (n = 526) or erlotinib plus placebo (n = 522). The primary endpoint was overall survival.

Patients in the tivantinib and placebo groups were generally balanced for baseline characteristics, including age (median, 62 and 61 years), sex (59% male in both), race (82% and 85% white), smoking status (81% ever in both), Eastern Cooperative Oncology Group performance status (0 or 1 for > 99% in both), tumor stage (IV in 95% and 96%), and MET expression status (high in 20% and 21%, low in 20% and 24%, and unknown in 58% and 51%).

No Improvement in Overall Survival

The trial was discontinued for futility at a planned interim analysis. Median overall survival was 8.5 months in the tivantinib group vs 7.8 months in the placebo group (hazard ratio [HR] = 0.98, P = .81). Median progression-free survival was prolonged in the tivantinib group (3.6 vs1.9 months, HR = 0.74, P < .001). A prespecified exploratory analysis indicated improved median overall survival (9.3 vs 5.9 months, HR = 0.70, 95% confidence interval [CI] = 0.49–1.01) and progression-free survival (3.7 vs1.9 months, HR = 0.72, 95% CI = 0.52-0.99) in patients with high MET expression.

After discontinuation of study treatment, 37% of patients in the tivantinib group and 44% of patients in the placebo group received subsequent therapy, primarily chemotherapy (30% and 39%).

Adverse Events

The most common adverse events of any grade in the tivantinib group were fatigue/asthenia (44% vs 38% in the placebo group), diarrhea (35% vs 41%), and rash (33% vs 37%). The most common grade ≥ 3 adverse events were fatigue/asthenia (9.0% vs 7.9%), dyspnea (8.8% vs 7.4%), neutropenia (8.5% vs0.8%), and anemia (6.3% vs 2.9%).

The investigators concluded: “[Erlotinib plus tivantinib] was well tolerated and increased [progression-free survival] but did not improve [overall survival] in the overall nonsquamous NSCLC population.”

Giorgio V. Scagliotti, MD, of University of Torino, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by ArQule and Daiichi Sankyo. For full disclosures of the study authors, visit

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