Anticancer agent – motesanib

Published: 11-Mar-2013

Vascular endothelial growth factor, or VEGF, is often targeted to prevent angiogenesis; When it is overexpressed, rapid tumour growth can result

A common target for anticancer agents is the prevention of angiogenesis. Vascular endothelial growth factor, or VEGF, is often targeted as it – and its receptors – plays such a pivotal role in the process. When it is overexpressed, rapid tumour growth can result.

Motesanib is another potential small molecule drug that acts as a VEGF receptor inhibitor, and is being developed by Takeda in partnership with Amgen.1 The orally available nicotinamide derivative has potential in a range of tumour types, and as well as its anti-VEGF activity at various receptors, it is an antagonist of platelet-derived growth factor receptors and the cellular stem cell factor, or Kit, receptor.

One form of tumour it has been tested in is medullary thyroid cancer. In a Phase II trial, 91 patients with locally advanced or metastatic, progressive or symptomatic medullary thyroid cancer were given 125mg/day of the drug for 48 weeks, or until the disease progressed or unacceptable toxicity developed.2 Two patients achieved an objective response, and 81% had stable disease, more than half of which lasted for at least 24 weeks. The median progression-free survival was 48 weeks. The most common treatment-related side-effects were diarrhoea, fatigue, hyperthyroidism, anorexia and hypertension. While the objective response rate was low, the incidence of patients achieving stable disease was significant.

Another potential indication is gastrointestinal stromal tumours. A total of 35 patients with advanced gastrointestinal stromal tumours that had progressed or relapsed after treatment with imatinib were given 125mg of the drug once a day.3 While none of the subjects showed a complete response, one had a partial response, and seven had stable disease for at least 24 months. The median progression free survival time was 16 weeks. Again, hypertension, diarrhoea and fatigue were common.

In a second Phase II trial patients with imatinib-resistant gastrointestinal stromal tumours were again given daily 125mg doses of the drug, this time for 48 weeks or until the disease progressed or its toxicity became intolerable.4 Of the 102 evaluable patients, there was an objective response rate of 3%, with 59% achieving stable disease, and 14% stable disease for at least 24 weeks. Disease progression occurred in 38% of the subjects, and the adverse event profile was similar to previous trials.

In non-squamous non-small cell lung cancer, results were initially promising, with a Phase II trial comparing its efficacy in combination with paclitaxel and carboplatin with that of the monoclonal antibody bevacizumab, showing the two regimes were comparable.5 However, results in a 1,090 patient Phase III study disappointed, with no significant improvement seen over treatment with paclitaxel and carboplatin alone.6 However, in a sub-group analysis of Asian patients, motesanib showed an increase in overall survival, progression-free survival and objective response rates.7

A more recent Phase 1b dose finding study combining motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer, showed promise.8 Subjects were given 50 or 125mg of the drug once a day continuously in combination with paclitaxel or docetaxel chemotherapy cycles. A total of 46 patients were enrolled in the study, and the higher dose was identified as the maximum tolerated. There was an objective response rate of 56% for the combination. Trials continue in various indications.

References

1. A. Polverino et al. Cancer Res.,/i> 2006, 66, 8715

2. M.J. Schlumberger et al. J. Clin. Oncol. 2009, 27, 3794

3. A. Sawaki et al. Cancer Chemother. Pharmacol. 2010, 65, 961

4. R.S. Benjamin et al. Cancer Chemother. Pharmacol. 2011, 68, 69

5. G.R. Blumenschein Jr. et al. Ann. Oncol. 2011, 22, 2057

6. G. Scagliotti et al. J. Clin. Oncol. 2011, 29 (suppl.), Abst. LBA7512

7. Y. Ichinose et al. J. Clin. Oncol. 2011, 30 (suppl.), Abst. 7549

8. R.H. De Boer et al. Breast Cancer Res. Treat. 2012, 135, 241

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