Abstract 7787: Phenotype-tailored prophylactic immunomodulation enables safe immune checkpoint inhibitor rechallenge after severe irAEs in high-risk patients

Abstract 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. Citation Format: Lucrezia Mencarelli, Pierre Van Mol, Douglas Daoudlarian, Sofiya Latifyan, Nuria Alfonso Mederos, Hasna Bouchaab, Matteo Torsello, Antonia Stamatiou, Nicolas Etienne, Karim Abdelhamid, Nabila Ferahta, Athina Stravodimou, Keyvan Shabafrouz, Solange Peters, Michel Obeid. Phenotype-tailored prophylactic immunomodulation enables safe immune checkpoint inhibitor rechallenge after severe irAEs in high-risk patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7787.