The proto-oncogene c-MET plays many roles in the propagation of tumours, including cancer cell proliferation and survival, invasion and metastasis, and even angiogenesis. Thus, blocking its activity has great potential. One developmental drug that acts in this way is ArQule’s tivantinib, which is being developed in conjunction with Daiichi Sankyo and Kyowa Hakko Kogyo.1
In a Phase I open label dose escalation study, 79 patients with advanced or metastatic solid tumours that were refractory to standard therapy were given doses of 10–360mg twice a day for 14 days of a 21-day cycle.2 Treatment was continued until unacceptable toxicity, tumour progression, withdrawal or death occurred. The drug was well tolerated and three patients achieved a partial response, while a further 40 maintained stabled disease for a median of 20 weeks. Dose-limiting grade 3 or higher toxicities included leucopoenia, neutropoenia, thrombo-cytopenia, vomiting and dehydration.
A Phase Ib trial was carried out in 20 cirrhotic patients with hepatocellular carcinoma who had received up to two prior systemic chemotherapy regimens. Subjects were given 360mg of the drug orally twice a day until disease progression or unacceptable toxicity.3 Of the 15 evaluable patients, five had achieved stable disease for at least four months, one with a minor radiographic response. There was no drug related worsening of liver function.
It has also been investigated in combination with erlotinib.4 A total of 167 patients with previously treated non-small cell lung cancer were given either 150mg oral erlotinib a day plus 360mg oral tivantinib twice a day, or erlotinib plus placebo. Median progression-free survival was 3.8 months for the combination, compared with 2.3 months for erlotinib alone. An objective response was seen in 10% of the patients on the combination, 7% of the erlotinib only group, and also in two patients who crossed over to the tivantinib group after progression.
It has also been investigated in a Phase II trial in 27 patients with relapsed or refrac-tory germ cell tumours.5 Twice-daily doses of 360mg were given in continuous 28-day cycles until disease progression or unacceptable toxicity. In the majority, the primary tumour was in the testis. Of the 25 evaluable patients, the best response was stable disease in seven subjects, with the rest progressing. It did not demonstrate activity as a single agent in this group of patients, but may be of benefit in combination with other chemotherapy agents.
references
1. N. Munshi et al. Mol. Cancer Ther. 2010, 9, 1544
2. L.S. Rosen et al .Clin. Cancer Res. 2011, 17, 7754
3. P. Zucali et al. J. Clin. Oncol. 2010, 28 (suppl.), Abst 4137
4. L.V. Sequist et al. J. Clin. Oncol. 2011, 29, 3307
5. D.R. Feldman et al. J. Clin. Oncol. 2011, 29 (suppl.), Abst 4638