Basic research in the 1990’s showed that antibodies aimed at a cell surface marker called cytotoxic T-lymphocyte antigen 4 (CTLA-4) stimulated an immune response that resulted in the killing of the tumor cells. Another cell marker, programmed death-1 (PD-1), was found to have the ability to prevent the immune system from killing cancer cells. These discoveries led to the development of cancer therapy using inhibition of negative immune regulation. Drs. James Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine in 2018 for their work on human cancer therapies aimed at these cell targets.

The first of the targeted antibodies to receive regulatory approval was ipilimumab, an anti-CTLA-4 antibody, approved on March 25, 2011 for the treatment of unresectable or metastatic melanoma. At that time, there were few approved treatments for melanoma, and the available therapies were characterized by low objective tumor response rates, and no evidence of improved survival. The study that led to the approval of ipilimumab also provided a few regulatory challenges. It was a randomized study comparing ipilimumab and ipilimumab plus an investigational cancer vaccine, gp100, to gp100 alone. While there was a statistically significant effect on survival in the ipilimumab treatment arms, there was no robust effect on tumor response or progression-free survival (PFS), parameters that are generally used as further supportive evidence in a study that is used as the primary basis for approval. In addition, immune-mediated adverse events raised concern. This resulted in the inclusion of a black box warning on the Prescribing Information, and the institution of a Risk Evaluation and Mitigation Strategy (REMS) focused on immune‑related adverse events. Of great interest was the survival curve and what came to be known as the “tail of the curve.” Unlike what we had seen with other agents used to treat melanoma, there was a small percentage of patients (approximately 20%) who did not progress. Many lived much longer than expected and became a pool of long-term survivors – something not seen before in melanoma patients.

Fast forward to 2021. FDA has approved 6 antibodies against PD-1 or PD ligand 1 (PD-L1), which also inhibits PD-1, for more than 75 indications. Ipilimumab remains the only FDA approved anti-CTLA-4 antibody, and in addition to its melanoma indications, it is also approved, in combination with nivolumab (an anti-PD‑1 antibody), in a number of other indications.

We have learned how to better manage the immune‑related side-effects of immunotherapy with delays in treatment and the use of steroids and other immunosuppressants. But, as always, there is a benefit/risk assessment when treating patients with immunotherapy. This was very evident to those of us who followed the recent February 9, 2021 Oncologic Drugs Advisory Committee (ODAC) discussion of pembrolizumab, an anti-PD-1 antibody, in combination with chemotherapy in the neoadjuvant setting followed by pembrolizumab alone in the adjuvant setting after surgery in high-risk, early-stage triple-negative breast cancer patients. The committee voted (10-0) that a regulatory decision on this indication should be deferred until further data are available. This recommendation to FDA was based on the magnitude of the treatment effect seen and because both the event-free survival (EFS) and overall survival (OS) data were not mature. One of the issues raised by FDA reviewers was the higher incidence of immune-related adverse events in the pembrolizumab arms; patient deaths due to immune-related reactions raised safety concerns. From FDA’s perspective, these findings shifted the benefit/risk balance in this potentially curative disease setting. The question may be, is one immune‑related death too many?

Was FDA’s hesitation justified? Had the benefit/risk ratio shifted as a result of an increase in the immune-related adverse events and deaths that were evident in the latest approved immunotherapy drugs? In the next installment of this series, we’ll look at how immunotherapies have been reviewed and approved in recent years and consider future steps to careful approval of these beneficial treatments.

But, as always, there is a benefit/risk assessment when treating patients with immunotherapy.

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