Clinical trials designs for combinations are a big topic for the IO field right now. How are industry and regulatory bodies collaborating to get novel trial designs approved?
As an industry, we find ourselves in unprecedented times. Our knowledge of the immune system and how our body fights cancer seems to be growing on a daily basis. In turn, while these are exciting times, they are also challenging. How do we carry out hundreds if not thousands of clinical trials, involving multiple combinations? The number of potential combinations and patients required to initially evaluate these combinations is staggering. In fact, a recent publication by the Cancer Research Institute demonstrates that over 2,000 cancer immunotherapies are entering into pharma/biotech clinical pipelines, with over 3,000 active clinical trials evaluating these agents, and with nearly 500 new PD-1/L1 cancer checkpoint studies launched this year alone (J. Tank, A. Shalabi & V.M. Hubbard-Lucey, Annals of Oncology 0:1-8, 2017)
Carrying out all of these trials using conventional Phase 1b/2 designs would lead to a large number of studies, require huge numbers of patients, and make advancing the most promising combinations exceptionally difficult.
At Roche we have developed MORPHEUS, a Phase 1b/2 adaptive platform to develop combinations of cancer immunotherapies, as a way to overcome some of these hurdles. MORPHEUS allows us to assess multiple combinations against a randomised comparison – giving us the opportunity to compare arms and make decisions about which combination arms to expand or even stop.We have worked closely with regulators to develop MORPHEUS and other companies are having similar conversations to optimize these innovative clinical trial designs. As our understanding of the science develops, these types of innovative trial designs are going to become increasingly important in ensuring that patients receive the best combinations for their disease.
Rational trial design vs. empirical science - can you give us an insight into the pros and cons for each of these two methods?
Many of the innovative clinical trial designs are implementing approaches that incorporate both rational trial design and empirical science. For instance, many of the rational trial design approaches are using earlier randomization, allowing us to better understand the probability of success with further expansion or pivotal trials.In parallel, most of the CIT combinations that are being explored are based on our scientific understanding of the cancer immunity cycle, and the different or overlapping mechanisms of resistance that are observed across different tumor types. Examples of the latter include CIT combinations that attract anti-tumor lymphocytes into tumors that are lacking infiltrative T cells (e.g., ‘immune desert’ or ‘immune excluded’ phenotypes).
Genentech are taking the rational approach to combination therapies, why have you gone down this route and how is it impacting your combination programs? Has there been a positive or negative effect on patient response rates?
We believe our approach is really taking into consideration both approaches to CIT clinical combination development. Our MORPHEUS platform is built upon the rational trial design that gives us enhanced confidence in early clinical signals, while improving on our speed to results, and doing so with an approach to minimize clinical and patient resources. In parallel, our combinations are being developed across a wide variety of tumor phenotypes and indications, using the cancer immunity cycle as our framework to interrogate the scientific hypotheses of immune escape.
Finally, you will be speaking at Phacilitate’s IO Frontiers this coming January. What are you looking forward to at this event and what do you hope to get out of it?
I’m really looking forward to hearing how other pharma and biotech companies are tackling this ‘Tsunami’ of CIT combination potentials, and how we can further work across the pharmaceutical industry, academics, and regulatory agencies, to optimize bringing forward breakthrough CIT combinations to patients in the fastest and most effective manner.