The neurotoxic effects of immune checkpoint inhibitor therapy for melanoma.

The advent of immune checkpoint inhibitors (ICIs), CTLA-4, PD-1 and PD-L1 inhibitors, have dramatically changed outcomes for patients with melanoma and other malignancies [1–3]. With this new class of antineoplastic agents comes a new range of adverse effects. These immune-related adverse events (irAEs) mediated by Tlymphocytes and other mechanisms including enhanced cytokine levels and antibodies [4] are often unpredictable, in contrast to adverse effects seen commonly with cytotoxic chemotherapy. Few of the initial Phase III trials evaluating the role of ICIs in the treatment of melanoma specifically reported immune-related neurotoxicity. When reported, the incidence of grade 3/4 neurotoxicity was low (<2%) [5]. Increasingly, immune-mediated neurological irAEs are being recognized and reported. Clinical presentation is varied and, while usually occurs early on in the course of therapy, in some cases neurological irAEs may occur many months after cessation of ICI therapy [6,7]. Importantly, the morbidity and mortality associated with this toxicity is relatively high. In a series of 613 fatal ICI-associated toxic events reported by Wang et al., 11% of these were attributed to neurological irAEs [8]. A review by Cuzzubbo et al. of neurological irAEs suggests that their incidence is higher with combination CTLA-4/PD-1 inhibition than for either class of agent when used as monotherapy. Interestingly, for monotherapy regimens, the reported rates of any grade neurotoxicity were higher for PD-1 inhibitors compared with CTLA4 inhibitors (anti-CTLA-4 3.8%, anti-PD-1 6.1%, combination therapy 13%). Severe (Grade 3 or 4) irAEs were infrequent, but more common with anti-CTLA-4 (0.7%) than anti-PD1 agents (0.4%). The majority of cases presented early with a median time to onset of 6 weeks [9]. These data are supported by other ‘real-world’ single-center retrospective series of patients treated with anti-CTLA-4 and/or anti-PD1 inhibitors [6] or anti-PD-1 inhibitors alone [10], reporting rates of neurological irAEs of 2.8 and 2.9%, respectively. In the former series, 14% of patients receiving combination therapy had neurological irAEs. In all three series, the clinical presentations were varied, highlighting the need for clinical vigilance when assessing patients for suspected irAEs.