All Times EDT
Keywords: Combination, NMEs, Factorial design, adaptive
Immunotherapy (IO) development is a rapidly evolving field where a single agent activity has been superseded by the activity of a combination with either traditional chemotherapy or another novel IO. In post-IO failure setting where there is a growing unmet need, it is expected that development will gear towards combining a novel IO agent with an existing standard of care or another novel targeted therapy. In such combinations of 2 or more new molecular entity (NME), it is not just adequate to show the superiority of the combination, it may also be required to demonstrate the contribution of the 2NME combination over each single agent. While a full factorial study design might be the most comprehensive design, it may not be always feasible because of larger sample size or absence of single agent activity. Multi-arm adaptive designs involving testing of hypotheses of multiple NME arms over multiple stages and dropping of ineffective NMEs need to be considered. Statistical considerations related to hypothesis testing, control of type 1 error, adequate power for all the hypotheses, targeting meaningful treatment effect, and alpha allocation using graphical gate-keeping procedure play a key role in development of the 2 or more NME designs.