Phenotype-tailored prophylactic immunomodulation enables safe immune checkpoint inhibitor rechallenge after severe irAEs in high-risk patients

Background: Severe immune-related adverse events (irAEs) frequently lead to permanent discontinuation of immune checkpoint inhibitors (ICIs). Whether phenotype-tailored prophylactic immunomodulation (PTPI) can safely enable ICI rechallenge in such high-risk patients is unknown. Methods: We retrospectively studied patients with ICI interruption after at least one grade ≥2 irAE who were subsequently rechallenged under prophylactic biologic immunomodulation in a tertiary immuno-oncology toxicity program. Prophylaxis was selected according to the dominant inflammatory phenotype of the index irAE, with or without low-dose steroids. Primary endpoints were ICI discontinuation due to irAEs at 3 and 6 months and incidence of grade ≥3 irAEs during rechallenge. Secondary endpoints included timing and phenotype of recurrent irAEs, an “immune tolerance enabling strategy” (ITES; on ICI at 6 months without grade ≥3 irAEs), disease control rates (DCR) and exploratory comparisons by prophylaxis class Results: Thirty-eight patients were rechallenged under prophylaxis. irAEs were rheumatologic (39%), colitis (32%) and uveitis (8%); 66% were multi-organ. Twelve patients (32%) had received combination and 26 (68%) anti-PD-(L)1. The main tumour types were lung (39%), melanoma (32%), renal cell carcinoma (13%). Prophylaxis consisted of IL-6R blockade in 61% and TNF blockade in 26%. During rechallenge, 26% developed grade ≥3 irAEs. IrAE-related ICI discontinuation occurred in 16% and 24% at 3 and 6 months, respectively; among 15 patients who discontinued for irAEs, median time to discontinuation was 130 days. Median time to recurrent irAE was 108 days with 50% occurring >90 days. ITES was achieved in 55% of patients, with median ICI duration 201 days. In colitis, TNF-based prophylaxis was associated with rare colitis recurrences (11%) and fewer irAE-related discontinuations than non-TNF strategies. In rheumatologic phenotypes, IL-6R blockade showed lower recurrence (14%) and fewer irAE-related discontinuations than minimal/non-IL-6R prophylaxis. Only one patient (3%) discontinued ICI for an infectious complication, no grade 4 irAEs occurred. DCR at 3, 6, 9 and 12 months were 52%, 63%, 62% and 65%, respectively. Conclusions: In high-risk patients, PTPI enabled prolonged ICI exposure with acceptable high-grade toxicity, low irAE-driven discontinuation, preserved disease control, supporting organ-tailored prophylaxis as a strategy to be tested in prospective trials.