Case Report: Durable remission in stage IV melanoma following strategic immune checkpoint inhibitor class rotation and rechallenge

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in patients with regional and distant melanoma metastases. Severe immune-related adverse events (irAEs) occur in 20% (single agent) to nearly 50% (dual agents) of patients and may necessitate treatment discontinuation. Upon disease progression, the safety and efficacy of ICI rechallenge remains uncertain. We report a 59-year-old male with an advanced nodular melanoma who initially received Nivolumab therapy but developed grade 4 irAEs requiring treatment cessation. Following appropriate treatment and resolution of the irAEs, rotation to an ICI agent targeting a different pathway, Ipilimumab, was trialed followed by rechallenge with Nivolumab. These sequential treatment strategies resulted in complete remission without recurrence of prior irAEs. Notably, the patient has remained off therapy and disease-free for nearly five years to date. This case highlights a strategic approach to ICI rechallenge in melanoma after severe irAEs. This approach leveraged the complementary mechanisms of CTLA-4 blockade, which mediates T-cell priming and expansion of the effector cells, and PD-1 blockade, which restores exhausted T-cell function. Rotation of ICI agents may have allowed reorganization of the immune repertoire before re-exposure to PD-1 blockade. Our findings provide further evidence that, in selected patients, ICI rechallenge after significant toxicity can provide meaningful antitumor activity without recurrence of prior irAEs.