Tivantinib plus erlotinib may benefit high MET expression non–small cell lung cancers



AMSTERDAM – A subset of patients with inoperable, locally advanced, or metastatic, nonsquamous non–small cell lung cancer, and high MET expression appear to benefit from a combination of tivantinib and erlotinib, according to research presented at the multidisciplinary European cancer congresses.

"Tivantinib did improve overall survival in the subgroup of tumors with high MET expression suggesting the potential for efficacy in a biomarker-selected population," said Dr. Giorgio Scagliotti of the University of Turin, San Luigi Hospital, Italy, who presented the findings.

Another trial would be needed to confirm the finding, which was the result of an exploratory analysis. The overall findings were negative in the interim results of the phase III MARQUEE (MET Inhibitor ARQ 197 plus Erlotinib vs. Erlotinib plus Placebo in NSCLC) trial. Those results were first revealed in October 2012 and prompted the study’s sponsors, ArQule and Daiichi Sankyo, to halt the trial after its independent data monitoring committee noted that the primary endpoint would not be met with further follow-up.

Sara Freeman/IMNG Medical Media

Dr. Giorgio Scagliotti

Overall survival according to MET expression could be determined in 445 patients in the trial, with 211 (47%) exhibiting high expression and 234 (53%) exhibiting low expression. In the subgroup with high expression of MET, median overall survival was 9.3 months with tivantinib plus erlotinib (n = 104) and 5.9 months with placebo plus erlotinib (n = 107). The hazard ratio (HR) of 0.70 (P = .03) for this difference was clearly in favor of the combination treatment. Progression-free survival in this subgroup of patients was 3.6 months and 1.6 months (HR, 0.7; P = .014), respectively, with overall response rate (ORR) of 10.6% vs. 6.5%.

In the MET low expression subgroup, overall survival was not significantly different comparing the combination approach (n = 107) with erlotinib alone (n = 127), at a median of 8.5 months vs. 7.7 months (HR, 0.90; P = .53). Progression-free survival (3.7 vs. 1.9 months; HR, 0.66; P = .006) and ORR (11.2% vs. 5.2%) were improved, however.

Based on data from the entire MARQUEE study group, the dual treatment was associated with a nonsignificant difference in median overall survival of 8.5 months vs. 7.8 months vs. erlotinib alone (HR, 0.98; P = .81).

Progression-free survival was improved, however, at a median of 3.6 vs. 1.9 months (HR, 0.7; P less than .001), respectively. There was also a higher ORR in patients given the dual therapy (10.3% vs. 6.5%; P less than .05).

The rationale for using tivantinib in combination with erlotinib is that the addition of the MET inhibitor might help to overcome the known resistance to drugs that target the epidermal growth factor receptor (EGFR). Dr. Scagliotti noted that in a prior phase II study (J. Clin. Oncol. 2011;29:3307-15), both progression-free and overall survivals were improved by the dual therapy vs. erlotinib alone in patients with nonsquamous histology, a population enriched for MET overexpression.

A total of 1,048 patients with inoperable, locally advanced or metastatic nonsquamous non–small cell lung cancer were recruited. Patients had been previously treated with one or two lines of systemic therapy, including a platinum doublet, but had not received any prior EGFR-targeting treatment. After stratification by the number of prior therapies, sex, smoking history, as well as EGFR and KRAS mutation status, patients were randomized to treatment with tivantinib at a dose of 360 mg twice daily or matching placebo in addition to erlotinib at a dose of 150 mg once daily. Patients were treated until disease progression (Clin. Lung Cancer 2012;13:391-5).

The most common grade 3 or higher side effect seen with the combination treatment arm was neutropenia, affecting 10% of patients (n = 520). The rate of neutropenia in the patients who received placebo plus erlotinib was 1% (n = 517). Other notable side effects that were higher in the combination vs. control arm were fatigue, occurring in 9% and 7.9% of patients, respectively; and anemia (6.5% vs. 2.9%). Conversely there were lower rates of rash (1.9% vs. 3.9%), nausea (0.8% vs. 1.7%), and diarrhea (2.5% vs. 3.7%).

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