NCCN 2025: Managing Immune Checkpoint Inhibitor-Related Toxicities in Cancer Care

The successful management of immune checkpoint inhibitor (ICI)-related toxicities in cancer care relies upon adequate risk assessment, early and effective intervention, and adherence to shifting guidelines as treatment paradigms evolve, according to a presentation at the National Comprehensive Cancer Network (NCCN) 2025 Annual Conference in Orlando, Florida.

Immune checkpoint inhibitors are effective in cancer care, but can cause related toxicites. | Image Credit: © netsay - stock.adobe.com

The presentation, titled “Management of Immune Checkpoint Inhibitor-Related Toxicities,” sought to provide a comprehensive review of current guidelines for treating serious adverse events (AEs) that may arise due to ICI-related toxicities in patients being treated with such therapies in oncology care. Current NCCN guidelines rely upon interventions with a high level of consensus, but few recommendations are based upon high-level, randomized trials or robust meta-analyses, according to Sunil A. Reddy, MD, Stanford Cancer Institute.

In addition, guidelines are consistently evolving as new research is conducted and investigations into proper interventions continue. Reddy cautioned treatment providers to keep in mind the frequent updating of NCCN guidelines, including any new recommendations issued by experts.

“While the guidelines have a lot of information, you have to think about what you think is going on and what the patients want to do,” Reddy explained. Ultimately, serious ICI-related AEs can occur and can be more common with double immunotherapy, according to Reddy, which should be kept in mind when counseling patients about the risk-to-benefit ratio of robust therapy. “There’s a litany of papers being published, but there’s really no recipe regarding risk-benefit analysis,” Reddy continued.

Common side effects of ICI therapy can include what Reddy calls the “4 + 1” of toxicities: myocarditis, encephalitis—which can overlap with serious neurological AEs—insulin-dependent diabetes mellitus (IDDM; also known as type 1 diabetes), presenting a hypoadrenal state, or Sjögren's disease (dry mouth). For encephalitis and myocarditis, NCCN guidelines recommend high-dose steroids, specifically intravenous methylprednisolone; however, there are no steroid recommendations in NCCN guidelines for IDDM. Instead, providers are recommended to hold immunotherapy and initiate insulin, followed by close glucose monitoring.

For hepatobiliary ICI-related toxicities, corticosteroids are again often utilized in treatment, according to Michael Li, MD, MPH, UCSF, assistant professor, division of gastroenterology and hepatology at the University of California, San Francisco. Multiple internationally recognized groups recommend 1 to 2 mg/kg/day of prednisone or methylprednisolone for ICI-related hepatotoxicity, but there are common dose-related AEs from corticosteroids, with a possible detrimental effect on cancer outcomes. However, Li explains that there is mixed data on the effects of steroids on overall and progression-free survival.

“This is probably because it is impossible to parse out,” Li explained regarding the mixed study results. In 1 retrospective trial that he conducted with a group of investigators and published in Hepatology aiming to see the effects of higher steroid doses on patient outcomes, results indicated that 1 versus 2 mg/kg/day of methylprednisolone led to no difference in the development of steroid-refractory hepatitis. Additionally, there was no difference in time to resolution of hepatitis; however, the higher-dosed group was indeed more likely to develop steroid-related complications, Li said. Current NCCN guidelines, reflecting these results, suggest that 1 mg/kg/day is sufficient for first-line treatment of ICI-related toxicities.

Having a hepatology specialist involved in a patient’s multidisciplinary care team will be critical for proper assessment of a patient’s liver injury and optimized treatment of toxicities with steroids. Li notes that steroid tapering is critical; in his practice, Li reduces the dose of prednisone weekly in one 20-mg and four 10-mg increments, taking the patient off their course of steroids after 5 weeks. Additionally, Pneumocystis pneumonia (PCP) prophylaxis will be critical to include once steroids are at a 20-mg dose, according to Li. If the patient does not improve after first-line treatment, second-line mycophenolate mofetil or another steroid-sparing immunosuppressive therapy can be implemented.

Liver specialists also contribute to generally improved patient outcomes when they experience an ICI-related toxicity. Li and his colleagues found in an investigation that early consultation with a liver specialist was associated with faster biochemical resolution of steroid-refractory hepatitis. Furthermore, in steroid-refractory patients, early consultation was associated with alanine aminotransferase normalization, and these patients received earlier additional immunosuppressive therapies, leading to better outcomes.

“Involving a liver specialist is a good idea if there is a concern that a patient isn’t responding appropriately to steroids,” Li explained.

Hematological toxicities are also a possibility following ICI treatment, according to Changchun Deng, MD, PhD, University Hospitals Cleveland Medical Center and associate professor at Case Western Reserve University School of Medicine. These can include hemolytic anemia, thrombocytopenia, and aplastic anemia. Although the mechanisms of ICI-associated hematologic toxicities remain unclear, meta-analyses of ICI trial participants have found a generally low risk of experiencing grade 3 or higher toxicities, according to Deng.

Though there is a low risk of severe hematological AEs, there remains a moderate risk of recurrence of toxicity, especially upon rechallenge of ICIs. First-line treatment of these toxicities, like other presenters explained, remains steroids. Overall, ICIs represent a major success story in oncology and present numerous benefits for patients with cancer, according to Deng. Understanding the incidence, recurrence risk, and management strategies of these toxicities will be critical for proper patient care, Deng explains.

“The relative risk of those hematologic toxicities is much lower with ICIs than chemotherapy drugs,” Deng said.

REFERENCE

Reddy S, Li M, Deng C. “Management of Immune Checkpoint Inhibitor-Related Toxicities.” National Comprehensive Cancer Network Annual Conference 2025. Presented March 28, 2025. Accessed March 31, 2025. https://custom.cvent.com/A534AF7FE15948CAB67ABDABC062DF76/files/d0aee06ab28d4de99a1830d0cb76aa2c.pdf