Why attend the TAT Congress series that focuses on phase 1 trials in oncology? There are several reasons, but probably the most important one is that a revolution is ongoing which has changed and will continue to change the role of phase 1 studies in drug development considerably.
Thus, the TAT Congress (“The Home of Phase 1 in Oncology”) is no longer the exclusive domain of highly-specialized phase 1 investigators and their translational research scientists. It has become an event of prime interest to a much broader population. It is also the place for industry’s drug development specialists – from pharma and biotech – to discuss with the academic phase 1 community how the path to initial regulatory approval may be shortened and for regulators to see what is coming their way, often already in the near future, not 8 to 10 years down the road like in the old days.
First-in-human phase 1 studies have historically been “human toxicology” studies aimed at describing the drug’s toxicity, establishing the MTD, a recommended dose for phase 2 studies and, in several cases, describing the pharmacokinetics of the new drug.
In their Editorial “Phase I trials in oncology: a new era has started” (Ann Oncol 2015;26:7-9), Postel-Vinay and Soria have made it clear that the role of early-phase trials in oncology drug development has changed due to:
- The advent of precision medicine and molecular targeted agents
- Trial enrichment and increased response rates
- Immuno-stimulatory antibodies
- Open attitude of regulators (breakthrough designation and conditional approval)
Safety/toxicity is no longer the only focus of phase 1 studies. The goals and the design of phase 1 studies have changed. Their focus has broadened and now includes clinical activity/response and biomarker research in addition to safety. Molecular enrichment of the patient population has become a common feature of phase 1 studies.
This new phase 1 paradigm has already led to rapid (conditional) approval of several new cancer therapeutics showing outstanding clinical activity in early-phase studies with only a few hundred patients: e.g., crizotinib, ceritinib, nivolumab, pembrolizumab, and atezolizumab. Oncology phase 1 studies are no longer a necessary hurdle on the way to pivotal phase 3 trials, they themselves can provide sufficient evidence of antitumor efficacy for regulatory approval.This new role of phase I trials is currently debated by regulatory agencies, such as the FDA, which has tried to provide some new guidance.