Table 2 Critical issues in combination immunotherapy drug development

• Combination regimens should be based on scientific evidence of underlying tumor cell and immune system biology whenever possible. There is evidence that combinations within drug classes (e.g., T cell checkpoint inhibitors) and across classes may be clinically beneficial.

• Murine models have limitations but may be useful for early proof-of-principle for specific combination strategies and can be useful for understanding the biology and mechanisms of action for certain combinations. These models have generally not been useful for toxicity assessment.

• While combination therapy may be anticipated to improved therapeutic effectiveness, the approach may also increase the potential for adverse events. This possibility should be carefully considered in developing clinical study designs for combination immunotherapy.

• Innovative clinical study designs may be useful for early phase combination immunotherapy development. These may include dose escalation, dose de-escalation, zig-zag, run-in and sequential administration designs. A better understanding of the adverse event profile, as may be obtained from small monotherapy phase I studies, is helpful in optimizing the design of combination trials.

• The unique mechanism of action for immunotherapy agents suggests that new clinical endpoints may be needed for early phase drug development. The use of progressionfree survival may be misleading given the delayed kinetics of response that can occur with some agents and regimens. New endpoints, such as immune-related response criteria or durable response rate, may be better for predicting clinical benefit in late stage studies.

• Early and frequent discussion with regulatory agencies should be considered for combination immunotherapy regimens.

• Other issues, such as intellectual property, conflict of interest, quality of life, patientreported outcomes, and the financial costs vs. overall health benefits as defined in the value proposition of combination immunotherapy, will be important issues for further discussion.