If you have not visited the ESMO conference for some years, you might be astonished by the rapid growth this conference has seen. This year’s attendance was well over 20,000 persons and therefore not only the largest ESMO ever, but also the largest conference ever to be held in Denmark. As of now, ESMO conferences will be held every year, instead of alternating with the joint ESMO-ECCO-ESTRO conferences in odd numbered years. The scientific program of ESMO 2016 had many breakthrough, and potentially game changing, results, especially in the field of immune oncology. After prior two waves of oncological innovations, cytotoxic drugs and targeted therapies, respectively, immune oncology is the third big wave of breakthroughs. These are exciting times for oncology research, with many promising new therapies for patients.
As expert oncology CRO it is good to take a step back from the individual trial results and to look at the greater themes in oncology drug development. One observation is that drug development timelines are decreasing. This is apparent from the fact that the annual ESMO has become the second large outlet for phase III trial results. In the past, the time from a first-in-man study to marketing authorization was 10 years. Nowadays, 4 years is no exception, with several drugs being approved straight from a randomized phase II trial. This means that standards of care can shift rapidly, which should be noted when designing a new study. By the time a study is underway, the comparator arm or background therapy may have already become yesterday’s news, thereby potentially jeopardizing recruitment.
The types of early phase trials are also shifting. The classic phase I – II – III progression is rapidly becoming obsolete and replaced by combined phase trials. The design of those early phase trials is also shifting. As many new therapies do not follow a linear dose-toxicity curve, the standard 3+3 dose escalation design is not applicable any longer. Slowly, adaptive or accelerated designs are finding their way into the development programs. These designs require good oversight and rapid communication lines with sites to adjust individual patient treatment.
The newest generation of (immune) oncology therapies is particularly suitable to be combined with other drugs. With each available new compound, the number of potential combinations rises exponentially, whereas development budgets do not. Difficult choices have to be made, but the experts at ESMO agreed that single agent activity of each compound should be known before combinations are tested.
It may be obvious to state that predictive biomarkers (once that can predict which patients will respond to treatment) are a holy grail for oncology drug development. Even though much attention is paid to biomarker development, it is often difficult to find a suitable biomarker or to distinguish it from a prognostic biomarker. For anti-PD-1 therapy, the use of PD-L1 as a biomarker is not as straightforward as it seems. There are numerous technical challenges. The first one is whether a single tumor location or a liquid biopsy is representative for all other locations. Several studies suggested this was not the always the case: primary tumors may have a different molecular build than circulating tumor cells or a metastasis. In one session on the topic of biomarkers it was advised not to exclude biomarker-negative patients in early phase studies, but to include all patients and test biomarkers as a secondary endpoint.
Progression-free survival (PFS) is used as a primary endpoint in many oncology trials. With many immune oncology drugs showing a flare effect or pseudo-progression, it is not known how PFS should be tested or whether it is still a meaningful endpoint at all for these types of drugs. Various studies were presented where PFS was not different between treatment arms, but overall survival was. Immune-related response criteria may improve the usefulness of PFS, but other endpoints may need to be considered.
Not only does the nature of immune oncology treatments change the design or endpoints of trials, also the type of toxicities that are observed. Immune-related adverse events (AE) have a different pattern than classic cytotoxic drugs. Cytokine release syndrome, colitis, pneumonitis and the difficult to treat hypophysitis are a couple of examples. Patients should preferably be treated at sites with experience in the use of these drugs. Pharmacovigilance experts and medical monitors should be aware that these AEs can occur.
At SMS-oncology we’re on top of this shifting landscape in oncology drug development and our oncology experts can assist you with study design and study conduct in these areas.