Clinical development of 2NME-based oncology treatment regimens.

Over the past decade many signaling pathways have been identified and implicated in cancer development. This has lead to rational drug development of many new molecules that target specific nodes on one or more signaling pathways. It is now believed that targeting key parallel or compensatory pathways may require combining two or more new molecular entities (2NMEs). This approach to drug development differs from the classic case where a single component of a new combination regimen has yet to receive FDA approval. The approach presents numerous challenges to both regulatory authorities and industry sponsors. Of course, the key challenge is the usual demonstration of both safety and efficacy of the proposed combination. In addition, however, superiority of the 2NME-based regimen over both of the individual NME-based regimens and the standard of care (SOC) must be demonstrated. If the individual NME-based regimens are not very effective, then it is desirable to demonstrate the superiority of the 2NME-based regimen as early as possible in the clinical development program so that the number of patients exposed to an ineffective regimen is minimized. In this manuscript we present several strategies for clinical development programs for a 2NME-based oncology regimen. We make recommendations regarding settings where the proposed development strategies are most well suited.