Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma

Abstract

Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 AE anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. Patients and methods: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. Results: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were !grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). Conclusions: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Definition of a new blood cell count (BCT) score for early survival prediction for non-small cell lung cancer patients treated with atezolizumab: Integrated analysis of 4 multicenter clinical trials

“…Hence, prognostic biomarkers were ruled out using our approach. Furthermore, delays in immune response have been frequently observed during ICI therapy 29,30 . That is why later time points are hypothesized to have better indicative power as compared to earlier time points.…”

Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events

“…Acute irAEs have thus far attracted major attention owing to their dramatic clinical presentation and need for urgent treatment. However, increasing evidences indicate that chronic irAEs are more prevalent than originally recognized ( 46 , 47 ). Endocrinopathies (such as ICI-induced hypothyroidism and diabetes) and rheumatological toxicities (such as arthritis) are the most common chronic irAEs ( 48 , 49 ).…”

Stratified modestly-weighted log-rank tests in settings with an anticipated delayed separation of survival curves

“…One can see that there is a delay of several months before the separation of the survival curves. This feature is not unique to OAK and POPLAR as it has been observed in many trials involving immune-checkpoint inhibitors (see e.g., Owen et al [2021]), and arguably, therefore, is predictable at the design stage. A second feature of these figures is that patients with baseline ECOG=0 have, on average, longer survival times than patients with ECOG=1 at baseline.…”