Identifying and Managing Toxicities From Pembrolizumab Combinations

Pembrolizumab (Keytruda) is currently approved in around 40 different indications covering a wide range of disease types. Omid Hamid, MD, was part of a team that assessed the safety profile of pembrolizumab, and he spoke with CancerNetwork® about how when it is combined with immunotherapies, the incidence of adverse effects (AEs) increases.1,2

More specifically, the incidence of grade 3 to 5 toxicities rises, particularly in anti–CTLA-4 combinations, as opposed to anti–LAG3 combinations that experience a significant rise.

Hamid, chief of Translational Research and Immunotherapy and director of the Melanoma Center and Phase I Immuno-Oncology Program at The Angeles Clinic and Research Institute, an affiliate of the Cedars Sinai Medical Center, also highlighted that when communicating with patients, it’s important to emphasize that the majority of these AEs will resolve, whether it’s through care, steroids, or tapering of treatment.

He also mentioned that it’s possible for the AEs to resolve themselves after treatment is discontinued.

Transcript:

[When combining pembrolizumab] with immunotherapies, the incidence [of AEs] increases, and not just the incidence of all toxicities, but the incidence of grade 3 to 5 toxicities. That’s been our experience with the anti–CTLA-4 combinations, specifically with higher doses in malignant, advanced melanoma. We now have anti-LAG3 combinations, and more interestingly, that rate is not as high, and the majority of grade 3 to 5 AEs that are increased have to do with the endocrinological pathways. We talked to patients about that. We talked to patients mostly about [how] when there’s an endocrinological toxicity, there’s risk for adrenal crisis with chemotherapy. What we have been seeing are changes in the incidence of toxicities, but also overlapping toxicities, where at some points, the risk of cytopenias, or long-duration cytopenias, can increase.

All of this is an important discussion to have. More importantly, when you look at the data presented here, it was based on trials, and there is no long-term post-discontinuation evaluation of the resolution of toxicities or late toxicities. These trials only looked [over] 30 days, so it’s important when someone has a toxicity to say, “Look, the majority [of toxicities] we take care of, and they resolve.” The majority can improve with steroids and tapering, so if you are on this type of therapy, and you do well when we discontinue [treatment], some of these AEs that you have [can] resolve on their own.

Reference

1. Selected indications for KEYTRUDA® (pembrolizumab). Keytruda. Accessed February 14, 2025. https://tinyurl.com/mtpnwhrr
2. Brahmer JR, Long GV, Hamid O, et al. Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients. Eur J Cancer. 2024;199:113530. doi:10.1016/j.ejca.2024.113530