Over the past decade, immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of cancer. Based on survival improvement, durable responses and favorable toxicity profiles, ICIs as monotherapy and in combinations have become the standard of care for many patients with advanced cancers. Furthermore, in some tumor types, these agents are now used or evaluated in early stage disease.

However, not all patients benefit from ICI-based therapy and some may develop immune-related adverse events (irAEs) that can affect any organ. Depending on severity, ICI discontinuation and treatment with immunosuppressive agents, such as steroids, may be necessary to resolve these irAEs. While permanent discontinuation of ICIs is recommended in patients with the most severe irAEs, ICI rechallenge is commonly considered in other patients, despite the lack of supporting data and questions regarding recurrence rate and safety of resuming the same ICI after intial irAEs.

In a recent retrospective, cross-sectional cohort study, investigators sought to answer these questions and identify factors associated with the recurrence of irAEs. The study analysed data from the World Health Organization VigiBase, which include case safety reports across a wide range of cancers and different immune-related regimens from more than 130 countries.

The analysis revealed 24,079 irAE cases associated with at least one ICI, and among them 6,123 (25.4%) were associated with an ICI rechallenge. Of these, 452 (7.4%) were informative rechallenges, defined as those with known irAE recurrence status. In these 452 cases, recurrence of the initial irAE was seen in 130 cases (28.8%) while different irAE occurred in 4.4% of cases. After rechallenge with anti-PD-1/anti-PD-L1 or anti-CTLA-4 monotherapy, the recurrence rates were 28.6% and 47.4% respectively, and 43.5% with combination therapy. The recurrence rates for colitis, hepatitis and pneumonitis were higher after rechallenge compared with other irAEs. Adrenal events were associated with lower recurrence rates, not unexpected since these are irreversible irAEs that require steroid replacement therapy. Pneumonitis recurred in 85.7% of cases, suggesting physicians should be cautious with rechallenging these patients.

The authors highlight that a key unanswered question is when to use immunotherapy rechallenge. Data from randomized trials indicate continued benefit of ICI after discontinuation of treatment due to irAEs, thus patients with ongoing stable or responding disease may not need ICI rechallenge as maintenance therapy. In contrast, patients who progress after ICI discontinuation due to irAE may benefit from ICI rechallenge. However, there are no specific recommendations.

While acknowledging the limitations of this observational study, the authors point out that this is the largest cohort study that has assessed the safety of ICI rechallenge after an initial irAE. Based on the results that indicate ICI rechallenge is associated with irAE recurrence in approximately one-third of cases, they conclude that immunotherapy rechallenge could be considered for select patients, with appropriate monitoring for treatment-related toxicity. They also noted the need for further investigation in a prospective clinical trial.

Reference

Dolladille C, et al. JAMA Oncol. 2020 Apr 16. [Epub ahead of print]