In light of recent positive data, regorafenib (Bayer HealthCare) and perifosine (Keryx Biopharmaceuticals/AEterna Zentaris/Yakult Honsha) are poised for FDA approval as third-line therapies for patients with metastatic colorectal cancer (mCRC), a current area of high unmet need. Currently, there are limited treatment options in the third-line setting for patients with mCRC, as a large proportion of patients exhaust all treatment options in earlier lines. This is particularly relevant for patients with mutations in the KRAS gene, who are non-responsive to anti-epidermal growth factor receptor treatments, commonly used agents in later lines of therapy.

A multinational Phase III clinical trial (CORRECT trial) for regorafenib was initiated in April 2010, evaluating regorafenib in combination with best supportive care compared to best supportive care alone, as a third-line treatment in patients with mCRC. In a press release from Bayer on October 26, 2011, it was announced that a pre-planned interim analysis showed a significant benefit in overall survival in patients receiving regorafenib. The study has since been unblinded and patients in the placebo arm will be offered treatment with regorafenib. Although the completion date for the trial was initially estimated as June 2013, Bayer are in discussions with health authorities worldwide, including the FDA and the European Medicines Agency, regarding the next steps in filing for approval of regorafenib in the treatment of mCRC. Considering the fast track designation granted by the FDA for regorafenib (for the treatment of patients with mCRC who have progressed after approved standard therapies) and the positive results from the Phase III study, we anticipate an approval for regorafenib in the U.S. nearing the end of 2012.

Should regorafenib meet the requirements of the FDA, it would be the first small molecule tyrosine kinase inhibitor to gain approval in CRC, an unexpected triumph against the backdrop of high profile failures of small molecule tyrosine kinases in CRC, such as Pfizer's sunitinib and AstraZeneca's cediranib, which both failed in Phase III first-line studies and were discontinued in June 2009 and May 2010, respectively. Indeed, experts interviewed by Decision Resources just a few months ago were skeptical that a small molecule tyrosine kinase inhibitor could be successful in CRC in light of previous failures; therefore the promising data for regorafenib comes as pleasant surprise.

The Phase III X-PECT trial for perifosine in mCRC was initiated in April 2010 and is comparing perifosine in combination with capecitabine to capecitabine alone in heavily pretreated, refractory, mCRC patients. On August 31, 2011, a press release from AEterna Zentaris announced the completion of a pre-specified interim analysis for safety and efficacy. These interim Phase II data were recently published in the Journal of Clinical Oncology on November 20, 2011 (Bendell JC, 2011). In response to these results, the Data Safety Monitoring Board has recommended that the Phase III X-PECT study continue to completion, as planned. The trial is expected to complete in February 2012 and we anticipate an approval for perifosine in the third quarter of 2012 in the U.S.

Thought leaders interviewed by Decision Resources welcome new agents into the third-line setting. With the anticipated launch of two new agents, the proportion of patients receiving a third-line treatment is set to increase, particularly for patients with mutations in the KRAS gene. Given that both regorafenib and perifosine have the convenience of being orally administered agents and are expected to launch in close succession, final efficacy and safety data are likely to determine which agent will garner increase patient share in this setting. Although regorafenib and perifosine will not have a significant impact on the overall CRC market, considering the size of the third-line patient population, these two emerging agents will undoubtedly be well-received by physicians and will provide treatment options in a setting with a high current unmet medical need.

Bendell JC et al. Randomized Placebo-Controlled Phase II Trial of Perifosine Plus Capecitabine As Second- or Third-Line Therapy in Patients With Metastatic Colorectal Cancer. J Clin Oncol. 2011 Nov 20;29(33):4394-400. Epub 2011 Oct 3.

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