Design and conduct of early clinical studies of immunotherapy agent combinations: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies

Abstract

The Methodology for the Development of Innovative Cancer Therapies Task Force considered aspects of the design and conduct of early studies of combinations of immunotherapy agents during their 2018 meeting. The Task Force defined the relevant data to justify combination clinical trials, which includes a robust hypothesis for the combination, pre-clinical data with evidence of efficacy and an understanding of the pharmacodynamics effects of each agent, and ideally evidence of single agent activity. Evaluation of pharmacodynamic biomarkers is critical in early phase combination trials, and should be incorporated into trial objectives and go/no-go decisions. The Task Force also identified the need to develop assessment tools and end-points that capture the unique patterns of tumour responses to immunotherapy, including pseudoprogression and hyperprogression. At least one additional tumour measurement before baseline, and an early CT scan (at 4 weeks for example) would help define the incidence of hyperprogression, although a common definition is needed. Finally, the Task Force highlighted substantial redundancy and inefficiency in the combination immunotherapy space, and recommended the adoption of innovative trial designs.

Immunotherapy of Melanoma: Facts and Hopes

“…Activity signals are possibly more reliable for combinations studied in acquired or primary resistance to anti-PD-1 or to anti-PD-1/anti-CTLA-4, but even in this setting low rates of late response or pseudoprogression from prior therapy, or the potential for reresponse when disease progresses after an interval off-treatment, can lead to an overestimation of the combination partner's activity (82,83). Attention to pharmacodynamic or mechanistic activity of the combinatorial partner can be very informative, even if additional clinical activity is not observed (84). It is important to consider this point before abandoning a novel combination approach, which may be enhanced with additional agents or alterations in dosing.…”

Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies

“…With the rapid pace of immunotherapy drug development and the burgeoning number and often duplicate combination studies, 146 to increase the chances of success, rationally designed clinical trials of combination agents becomes imperative and should be based on robust pre-clinical data, together with the use of pharmacodynamic biomarkers and novel innovative endpoints. 147 It should be noted that much of our current knowledge on resistance mechanisms and its biomarkers is derived from melanoma studies, and the ability to apply this in the NSCLC setting is uncertain with further studies specific to lung cancer required. Such studies will ideally incorporate a standardized definition of primary and secondary ICI resistance as suggested in this review to allow accurate categorization of response and they will need to overcome the problem of sample accessibility to allow longitudinal tumor assessments in order to accurately depict on treatment changes underlying resistance.…”

“…With the rapid pace of immunotherapy drug development and the burgeoning number and often duplicate combination studies, 146 to increase the chances of success, rationally designed clinical trials of combination agents becomes imperative and should be based on robust pre-clinical data, together with the use of pharmacodynamic biomarkers and novel innovative endpoints. 147 …”

Lights and Shadows in Immuno-Oncology Drug Development

“…Another meta-analysis of 12 randomized clinical trials did not find a significant positive correlation between the OS and PFS hazard estimates, suggesting that PFS assessment is not sufficient to capture the benefit of PD-1-inhibitors in patients with solid tumors [42]. This is not surprising as the unique mechanism of immunotherapy's impact on tumors shows different patterns of response and progression from other conventional agents [45]. Emerging biological endpoints such as changes in Ki67 level are mainly driven by the antiproliferative effect of certain drugs; however, its use in trials evaluating the combination of IO agents with cytotoxic and targeted drugs should be further explored.…”