Are we in the ‘era of combinations’ in oncology? Although the hunt continues for profoundly active single agents, it’s increasingly recognized that in many cases, combinations will be critical for significant clinical benefit – by ‘hitting the pathway harder’, ‘hitting adjacent pathways’ or staving off resistance, for example. Even immune-mediated therapies for cancer, which demonstrate sustained response in a subset of patients, are likely to be most potent when combined with each other or agents in other classes. This ‘new reality’ in oncology poses four significant questions for the biopharma industry – and companies that figure out how to answer these questions ahead of their competitors may find themselves with a leg up in the next wave of innovation. In this post I’m going to outline them; in future installments I hope to dive into each in more detail.
What are the best combinations to take into the clinic? There is no shortage of combination hypotheses; the challenge is how to prioritize them before entering clinical trials. Few models can adequately test co-dependence on parallel signaling pathways, let alone more complex co-operative mechanisms like resistance or interplay with the immune system. And for many combinations, it may be just as critical to assess safety as efficacy. To succeed in oncology combinations, companies need to invest in developing, understanding and exploiting animal and cell culture models that predict their clinical behavior.
How can we test the widest possible range of plausible combinations? For many programs, particularly in areas of emerging biology, success will depend on how widely the company can test combination hypotheses in humans. However, traditional clinical trial designs are too costly and slow to support a full matrix of combinations – especially when one also considers potential variations in dosing regimens. Companies will need to become comfortable with adaptive trials, earlier efficacy testing and other ‘non-standard’ trial design methods in order to survive in this environment.
How can we ensure that clinically active combinations succeed in the market? For combinations between two branded agents, the payer hurdle for reimbursement may be far higher than the regulatory approval hurdle. It is not too early for companies to engage payers in discussions of where they’ll set the efficacy bar for reimbursing two drugs in a combination at their monotherapy prices. One possibility is that combinations become fertile ground for experimenting with ‘pay-for-performance’ agreements – e.g., full reimbursement for dramatic clinical effects, and a discount on the combined price otherwise. Any company that aims to succeed with combinations needs to be driving this evolution, not following it.
Should we ‘go at it alone’ or join forces with others? Only rare companies will have both the right / best oncology asset(s) for combinations and sufficient resources to test all of the attractive possibilities. One option is to share risk and reward with a partner to test more or better ideas and increase the overall probability of success. There may be some opportunities for peer-to-peer partnerships in this regard, but a potentially more transformative idea would be securing external financial investors to back individual development programs (illustrated here). Notwithstanding the obvious challenges (not the least of which are valuation and deal structure), companies that figure out how to routinely take on external financing for combination trials will be able to test more clinical hypotheses, increase their probability of success and develop a substantial advantage over competitors.
Pharma can often seem somewhat homogenized in terms of companies’ approaches to drug development, commercialization and strategy – but oncology combinations may allow one or more companies to distinguish themselves from the pack, if they invest effort and resources into solving the problems above.