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Tivantinib, erlotinib improve PFS, not OS in advanced NSCLC
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The addition of tivantinib to erlotinib did not improve OS in patients with advanced or metastatic nonsquamous non–small cell lung cancer, according to results of a phase 3 study.
However, the combination increased PFS and appeared well tolerated in the overall patient population, the researchers also reported.
“For patients with locally advanced or metastatic [NSCLC], systemic chemotherapy provides a modest but statistically significant improvement in survival,” Giorgio V. Scagliotti, MD, PhD, professor and chair of medical oncology at the University of Turin in Italy, and colleagues wrote. “In the last 15 years, clinical research efforts with targeted agents have endeavored to improve survival beyond cytotoxic chemotherapy.”
The combination of tivantinib (ARQ 197, ArQule) — a MET receptor tyrosine kinase inhibitor — and erlotinib (Tarceva; Genentech, Astellas Oncology) demonstrated anticancer activity in preclinical and early clinical studies, according to study background.
Scagliotti and colleagues initiated a controlled, double blind phase 3 trial to observe the safety and efficacy of the combination in patients with previously treated NSCLC.
The analysis included data from 1,048 patients (median age, 62 years; 59% men) who had undergone one to two previous systemic treatments, including a platinum doublet.
The researchers randomly assigned patients 1:1 to 150 mg daily erlotinib plus 360 mg twice daily oral tivantinib or placebo until disease progression. Researchers evaluated tumor specimens for EGFR and KRAS mutations, MET expression and MET gene amplification.
OS served as the primary endpoint. Secondary endpoints included PFS, OS in molecular subgroups and safety.
The researchers discontinued the trial at the interim analysis due to futility. Treatment with tivantinib and erlotinib did not improve OS compared with erlotinib and placebo (median OS, 8.5 months vs. 7.8 months; HR = 0.98; 95% CI, 0.84-1.15).
However, patients in the tivantinib arm achieved significantly prolonged median PFS (3.6 months vs. 1.9 months; HR = 0.74; 95% CI, 0.62-0.89).
Exploratory subgroup analyses suggested OS improvements correlated with high MET expression (HR = 0.7; 95% CI, 0.49-1.01).
Ninety-eight percent of patients (n = 1,016) experienced at least one adverse event. The most commonly reported adverse events included rash (tivantinib, 33.1% vs. placebo, 37.3%), diarrhea (34.6% vs. 41%), asthenia or fatigue (43.5% vs. 38.1%) and grade 3 or 4 neutropenia (8.5% vs. 0.8%).
Further, at least one serious adverse event occurred in 410 patients (tivantinib, 42.1%; placebo, 36.9%). Respiratory events comprised the majority of serious adverse events. Patients assigned to tivantinib experienced a higher incidence of pneumonia (3.8% vs. 2.1%) and sepsis (1% vs. 0.4%).
Fifty-nine percent of patients (n = 614) died during the study, primarily due to disease progression (tivantinib, 46%; placebo, 48.4%). The most common reasons for death other than progression included respiratory failure (1.2% vs. 1%), sepsis or septic shock (1% vs. 0.2%) and pneumonia or bronchopneumonia (0.6% vs. 1%).
“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,” Scagliotti and colleagues wrote. – by Cameron Kelsall
Disclosure: Scagliotti reports consultant and speakers bureau roles with and honoraria from AstraZeneca, Clovis Oncology, Eli Lilly, Pfizer and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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