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With some of the recently developed drugs showing unprecedented response rates and consistent improvement in overall survival in some indications, we face the dawn of a new era in anticancer research. New therapeutic targets, novel classes of products, booming and competing pipelines, innovative statistical methods, and a changing regulatory environment are all features of this new era.
More than ever, we need clinical trials that can incorporate the required innovations into their design, conduct, infrastructure and analysis. Fortunately, specialist CROs stand ready to take what they have learned from the past 10 years of oncology drug development and apply it to the new world in which we find ourselves.
These CROs already know how to meet the challenges of segmented study populations and an increasingly competitive development landscape, how to implement complex and adaptive designs, and how to squeeze every ounce of value out of data – skills that pharmaceutical and biotech companies will increasingly require going forward.
Immunotherapy reigns supreme
Immunotherapy is a contemporary approach to cancer treatment using an old idea: eliciting the immune system to fight cancer. Although it dates back at least 120 years, immunotherapy only emerged as a clearly effective modality 10 years ago. In 2011, the FDA approved Bristol Myers Squibb’s ipilimumab to treat unresectable and metastatic malignant melanoma, shifting the dial on cancer treatment. This monoclonal antibody was the first in a series of checkpoint inhibitors (CPIs). Its approval was soon followed by that of CPIs targeting programmed death 1 (PD-1) and PD-1 ligand (PD-L1), such as atezolizumab (Genentech), avelumab (EMD Serono/Pfizer), cemiplimab (Regeneron), durvalumab (Medimmune/AstraZeneca), nivolumab (Bristol Myers Squibb), and pembrolizumab (Merck).
In addition to CPIs, the immunotherapy class includes other antibodies with various immunological targets. Examples include cell-based products such as genetically engineered T-cell therapies (CAR-T cells), small molecules, oncolytic viruses, vaccines and cytokines. Some of these types of immunotherapy are in earlier phases of development, whereas others are already represented by approved products. Some of those products have led to unprecedented responses in clinical settings marked by resistance to conventional treatments. Moreover, CPIs have led to improvements in overall survival in many cases, including difficult-to-treat tumors such as melanoma, non-small-cell lung cancer without driver mutations and triple-negative breast cancer. Thus, immunotherapy will likely reign supreme in the foreseeable future as the mainstay or backbone treatment across indications.
New challenges require innovation
The benefit derived from immunotherapy has generated an unprecedented number of trials competing for the same limited pool of patients in research centers. Moreover, the availability of approved immunotherapy in many settings has influenced the choice of control arms in late-phase trials and led to the need to be flexible in such a choice, given expected changes in the standard of care during trial conduct. Likewise, the need to include a backbone of approved immunotherapy in early-phase trials can, in some cases, create constraints on the experimental product itself since its administration will, in some instances, piggyback that of the approved drug. Likewise, the need to assess combinations early on will likely become more frequent in drug development.
In addition to the design and logistic constraints highlighted above, immunotherapy has opened the floodgates to several methodological issues that had been of lesser concern with previous modalities. Three of the most salient among such issues are the dynamics of tumor responses and disease progression during immunotherapy, particularly CPIs, the revival of overall survival as the most reliable long-term endpoint, and the need to consider specific statistical issues in trial design and analysis. Non-proportional hazards are the most important of such statistical issues, which plagues the analyses of progression-free and overall survival.
For all the above reasons, developing novel immunotherapy products has become a highly specialized field of activity. The field requires scientific and operational expertise, an innovative mindset in trial design and analysis, and the adherence to time-tested methodologies accepted and expected from regulatory authorities.
What does the future hold?
In a certain way, immunotherapy reverses some trends in oncology that had become relevant for targeted agents. Such trends include the need to define predictive biomarkers, which considerably shrink the eligible population for a given trial; the reliance on progression-free survival as the primary endpoint in Phase 3; and a generally limited concern with adverse events. With immunotherapy, predictive biomarkers are not necessarily a requirement. Even though target expression and tumor mutational burden may select patients more likely to respond, true predictive biomarkers remain elusive in the case of CPIs. Likewise, overall survival has often been the primary endpoint in pivotal Phase 3 trials of immunotherapy, whereas progression-free survival appears to be less predictive of treatment benefit in this setting. Finally, concern with a whole new type of toxicity — immune-related adverse events — has replaced the typical adverse events observed with chemotherapy and some well-known targeted agents.
These trends pose new challenges for drug development, but also open the door to immense opportunities for sponsors who can leverage the right resources and tap from efficient research networks. In that sense, expert oncology CROs with experience in immune-oncology and advanced capabilities in data collection and analysis are vital partners in the journey to successful development. This capability will only become more critical going forward. Intelligent and efficient drug development must take all of this into account while remaining agile enough to respond to the current revolution in cancer therapy.
Elisabeth (Els) Coart, Ph.D., is director, consulting services IDDI. She is IDDI’s expert in analytical and clinical validation of IVDs. She has a strong background in assay development combined with 10 years’ experience as a statistician for the biotech and diagnostic industries. In addition, she has a longstanding interest in Alzheimer’s disease (AD) biomarkers and presents IDDI’s work in this field at AD symposia.
Serge Bodart has worked in the pharmaceutical industry for 20 years. He co-founded SYMFO, a European-based electronic Patient Reported Outcome (ePRO) provider, where he has been involved in all aspects of the electronic Clinical Outcome Assessments (eCOA) life cycle from concept to commercialization. He acted as the eCOA subject matter expert and scientific advisor for companies such as Biomedical Systems, mProve, Bracket Global and Signant Health. In his career, he also gained extensive international expertise in business development. He currently proudly serves as chief commercial officer at IDDI.