Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities

Abstract

Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials.

Enhancing global access to cancer medicines

“…For instance, the optimum, cost-effective doses have not been determined for many approved immune checkpoint inhibitors. 53 Although flat dosing is feasible for immune checkpoint inhibitors because there is no clear relationship between dose response or dose toxicity, weight-based doses continue to be approved for some. While treatment with ipilimumab is usually limited to 4 doses, the optimal treatment duration for other immune checkpoint inhibitors is not defined.…”

“…Table 6 outlines some strategies to increase clinical trial efficiency. 53,74,79,[81][82][83][84][85][86][87][88][89] An international body representing the governments of all countries and working in partnership with academic research groups, cancer clinical trial networks (eg, the National Cancer Institute, the Institute of Cancer Research, the European Society for Medical Oncology, the American Society of Clinical Oncology), the World Health Organization, the pharmaceutical industry, not-for-profit organizations, and patient advocate groups could be responsible for setting the global research priorities for developing cancer medicines. It is not a responsibility that should be fragmented or left to one sector alone.…”

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

“…In fact, Baik et al reported the limitations, challenges and opportunities in the immuno‐oncology clinical trial design. They found that due to the rapidity of development, competition, and race for FDA approval, the optimal dosing and schedule of ICIs are still not fully defined and continue to be under study …”

“…They found that due to the rapidity of development, competition, and race for FDA approval, the optimal dosing and schedule of ICIs are still not fully defined and continue to be under study. 85 Importantly, Kleef's protocol consists only of approved drugs and treatments. Therefore, our prediction that low-dose ICI-induced autoimmune T cells are powerful therapeutic tools can be confirmed or refuted in prospective, controlled clinical trials.…”

The Challenge for Development of Valuable Immuno-oncology Biomarkers

“…In addition, many early phase immunotherapy studies have not requested or mandated these biopsies, a potential shortcoming. In part due to the restricitive nature of clinical trial eligibility (55), many patients who must receive immunotherapy as standard of care may have limited opportunities to participate in research directed at studies of resistance, as such studies may be infrequent or under-resourced. A creative solution to this has been the efforts of patient advocacy groups to begin international tissue bank consortia, for instance in melanoma (56).…”