Designing In and Around Tolerability Considerations for Immunotherapy Combinations

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With the recent clinical and commercial success of checkpoint inhibitors, especially those targeting CTLA4 and PD‐L1/PD‐1, has come a seemingly disproportionate increase in clinical investigations in immuno‐oncology (IO), now numbering over 1,000 trials.1 Immunotherapy combination trials comprise a substantial proportion of this unprecedented investment, suggesting that immunotherapies could become backbone therapies across a wide array of malignancies. The so‐called “cancer immunity cycle” partitions IO action into several conceptual steps and provides a concise rationale for IO combinations.2 The cancer immunity cycle commences first with release of cancer cell antigens and proceeds through a series of steps that are critical to generating immunity to cancer and ultimately killing cancer cells. These individual steps represent possible points of therapeutic intervention, and are affected not only by IO agents, but by a myriad of other classes of anticancer drugs, spanning cytotoxic chemotherapies to targeted agents. For example, cytotoxic agents act directly on cancer cell killing (the final step of the cancer immunity cycle), while anti‐vascular endothelial growth factor (VEGF) can affect T‐cell extravasation occurring in the middle of the cycle. Accordingly, IO–IO agent combinations represent only a small fraction of the possibilities. Exploration of this expansive IO combination landscape will continue to act as a driver for large numbers of clinical investigations well into the future.
The available clinical database across the possible combination partners for IO agents can prove to be inadequate to fully inform IO combination studies. On the one extreme, chemotherapy has a considerable history of use in oncology, now with an accompanying rich database to mine regarding the effect of dose and scheduling on tolerability. In contrast, the clinical database for IO agents is growing only just now for an increasing list of indications. The robustness of model‐based predictions for IO combinations can be limited by the lack of available data, although systems pharmacology approaches are beginning to show promise even with this limitation.3 Clinical investigation of an IO combination, often with one combination partner held at the approved dose and dose escalation for the investigational agent, can reveal information about the maximally tolerated dose (MTD) for that combination. However, especially in the early phase I setting, we explore only a fraction of the possible dosing and scheduling possibilities for a given combination, and are left with only a partial understanding of the underlying exposure–tolerability relationship for the combination (Figure1). A further complicating factor arises from the fact that immune‐related adverse events (irAE) can emerge following the first cycle of treatment with IO agents, and that management of these AEs may involve holding subsequent doses and, consequently, reduced overall dose intensity; especially given the unique kinetics of irAE onset and resolution, careful selection of safety endpoints is important to meaningfully inform the exposure–tolerability analysis for IO.4 In instances where the IO combination is poorly tolerated, we are faced with the prospect of designing a combination treatment regimen around the peaks and valleys of this underlying relationship with only a limited understanding of the topography, while maintaining sufficient levels required for efficacy.
Development of the ipilimumab (IPI) + nivolumab (NIVO) combination provides an important case example of enhancing tolerability through exploration of scheduling and dosing of drugs in the combination. In the phase III investigation CheckMate 067, melanoma patients received IPI 3 mg/kg and NIVO 1 mg/kg every 3 weeks for 4 doses (q3wx4) followed by NIVO alone 3 mg/kg q2w; patients were further randomized to receive NIVO alone 3 mg/kg q2w and IPI alone 3 mg/kg q3wx4.

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