Lenvatinib is one of the many selective tyrosine kinase inhibitors that is under development for the treatment of cancer. The orally available molecule, being developed by Eisai, acts against multiple tyrosine kinases, notably vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), and platelet-derived growth factor receptors (PDGFR), as well as RET and KIT. By targeting endothelial cells, it is able to inhibit tumour angiogenesis. A number of its targets are also expressed on tumour cells.1
In an open label Phase I sequential, dose escalation study, 27 patients with advanced solid tumours were treated with oral doses of lenvatinib twice a day in a two week on, one week off cycle.2
The dose was escalated from 0.5mg to 1, 2, 4, 6, 9, 13, 16 and 20mg. In the first cycle, no grade 3 or 4 toxicities were seen up to the 13mg twice a day dose level, and this was established as the maximum tolerated dose. Analysis of biomarkers indicated that the antiangiogenic activity of the drug correlated with antitumour activity across a wide range of tumours.
A similar daily dose was tolerated in a single daily dosing regimen in another Phase I study.3 A group of 82 patients with advanced, refractory solid tumours were given escalating doses of 0.2 to 32mg in a once-daily continuous schedule in 28-day cycles. Two patients experienced grade 3 proteinuria at the highest dose, and the maximum tolerated dose thus set at 25mg/day. Seven of the patients achieved a partial response, and a further 38 stable disease. Particularly promising results were seen in patients with melanoma and renal cell carcinoma.
It has also been investigated in combination with carboplatin and paclitaxel in a group of 28 patients with non-small cell lung cancer.4 Subjects were given twice-daily doses of lenvatinib alongside carboplatin and paclitaxel once every three weeks. The initial lenvatinib dose of 6mg was reduced to 4mg because of toxicities including neutropoenia, leukopoenia, thrombocytopoenia and hypertension. With 4mg doses, there was a response rate of 68%, and progression-free survival of nine months.
A different combination, with everolimus, has been investigated in patients with unresectable or metastatic renal cell carcinoma. A total of 20 patients were given 12, 18 or 24mg of lenvatinib plus 5mg of everolimus daily. The highest dose gave an unacceptable toxicity profile. Of the 18 patients given the 12 or 18mg doses, six achieved a partial response, and nine stable disease.
A Phase II trial has been carried out in patients with advanced melanoma. A total of 93 subjects were given 24mg of lenvatinib once a day, with dose reduction for toxicity, until their disease progressed or toxicities became unmanageable.5 Eight patients achieved a confirmed partial response; 46% of the subjects required a dose reduction for toxicity reasons, and 12% withdrew because of toxicity. Common, but largely manageable, toxicities included hypertension, fatigue, nausea, diarrhoea, reduced appetite and vomiting.
In February, Eisai announced top line results of a placebo-controlled Phase III trial in patients with radioiodine-refractory differentiated thyroid cancer via press release. A total of 392 subjects were given 24mg doses of lenvatinib or placebo once a day, and there was a significant increase in progression free survival with the drug. Based on these results, the company plans to submit the drug for approval in this indication later this year.
Further Phase III trials are under way in hepatocellular carcinoma.
References
1. H. Glen et al. BMC Cancer 2011, 11, 309
2. K. Yamada et al. Clin. Cancer Res. 2011, 17, 2528
3. D.S. Boss et al. Br. J. Cancer 2012, 106, 1598
4. M. Nishio et al. Br. J. Cancer 2013, 109, 538
5. S. O’Day et al. J. Clin. Oncol. 2013, 31 (Suppl.), Abst. 9026
