Investigational c-Met inhibitor shows early promise in NSCLC

By Joanna Lyford, Senior medwireNews Reporter

A first-in-class drug that inhibits c-Met, a receptor tyrosine kinase, has demonstrated good tolerability when combined with erlotinib in the treatment of Japanese patients with advanced/metastatic non-small-cell lung cancer (NSCLC).

The drug, tivantinib, will now be studied in phase II trials at individualized dosages guided by genotyping of CYP2C19, the drug’s key metabolic enzyme.

In two phase I studies, 25 patients were genotyped and classified as extensive metabolizers (EMs) or poor metabolizers (PMs) based on the presence of specific CYP2C19 polymorphisms.

Guided by findings from an earlier study, the 16 EMs received oral tivantinib at a maximum dose of 360 mg twice daily while the nine PMs received doses up to 240 mg twice daily, taken with or just after meals; all patients also received erlotinib 150 mg once a day.

Treatment was given for a median of 71.5 days in EMs and 134.0 days in PMs.

Safety data were available for 24 of the 25 patients. There was no dose-limiting toxicity during the study and the combination of tivantinib plus erlotinib was generally well tolerated, according to the study authors.

The most common adverse events were rash, diarrhea, dry skin, nausea, and stomatitis, all of which were experienced by more than 25% of EMs and PMs. The most common grade 3 adverse events were hematologic toxicities, such as leukopenia, anemia, and neutropenia, which tended to occur concurrently. All adverse events were resolved by appropriate therapy or study drug interruption.

One patient, a PM, developed sepsis that was considered to be a serious adverse event related to the investigational drug. Treatment was stopped and the patient recovered from the sepsis after 14 days.

In terms of efficacy, three patients had a partial response, 10 had stable disease, and nine had progressive disease. The overall response rate was 12% and the disease control rate was 52%.

Of the six patients with meaningful clinical efficacy (ie, a partial response or long-term stable disease), three were EMs and three were PMs. Of the three patients with a partial response, one possessed wild-type EGFR with high c-Met expression, while the other two possessed mutated EGFR with variable c-Met expression.

Writing in the British Journal of Cancer, Nobuyuki Yamamoto (Shizuoka Cancer Center, Sunto-gun, Japan) and colleagues conclude that tivantinib at doses of up to 240 mg twice daily in PMs or 360 mg twice daily in EMs, in combination with erlotinib, is “tolerable and manageable” in Japanese patients with NSCLC.

“These results warrant further investigation of this combination in phase II NSCLC studies conducted in the Japanese/Asian population,” the authors write.

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