Low-dose nivolumab in patients at high risk of immune-related adverse events: A retrospective cohort study.

2656 Background: Immune checkpoint inhibitors (ICIs) are relatively contraindicated in patients with prior severe immune-related adverse events (IRAEs) and/or have pre-existing serious auto-immune diseases (AID). Such patients are generally excluded from immunotherapy trials due to toxicity concerns, and data on ICI (re)exposure is limited. Our correlative data [Tachiki L 2024 SITC] suggest that low-dose (LD) nivolumab (Nivo; 40 mg) achieves PD-1 receptor occupancy comparable to standard-dose (SD) Nivo (240 or 480 mg), suggesting a potentially similar risk of developing IRAEs. However, faster serum clearance observed with LD Nivo may allow easier management of IRAEs when they occur. Based on this rationale, we have offered LD Nivo to high-risk patients after careful clinical discussion. In this study, we present the outcomes of our institutional experience. Methods: This single institution, retrospective cohort study included patients with advanced skin cancers who received LD Nivo (40 mg) due to a high-risk of IRAEs, including those with a previous history of IRAEs from SD ICIs or ICI-naïve patients with pre-existing AID. We analyzed efficacy and safety endpoints, including best objective response rates (BORR) per RECIST v1.1 and rates of IRAE with SD and LD ICIs. Outcomes were analyzed using descriptive statistics and stratified Cox models. Results: From 2015 – 2025, 23 patients with advanced skin cancers (22-Melanoma; 1-Merkel cell carcinoma) received LD Nivo due to an elevated IRAE risk. Sixteen patients had a history of treatment-limiting IRAEs on SD ICIs (“Prior-IRAE” cohort: 7 SD anti-PD-1 monotherapy; 9 SD combination ICI), and 7 patients were ICI-naïve with pre-existing AID (“AID” cohort). In the Prior-IRAE cohort, treatment hold/discontinuation due to IRAEs occurred in 100% with SD ICI versus 43.8% with LD Nivo (p = 0.032). Among the 7 patients previously treated with SD anti-PD-1 monotherapy, the incidence of grade ≥2 IRAEs was 100% (median duration 75 days; range, 12–217) on SD therapy versus 42.8% (median duration 43 days; range, 23–146) on LD Nivo. In the AID cohort, 100% patients experienced at least one grade 2 IRAE, but no grade 3 or 4 events were observed. In patients with evaluable disease (measurable and progressing at LD Nivo initiation), BORR was 57.1% (4/7; 1 complete response [CR], 3 partial responses) in the Prior-IRAE cohort and 33.3% (2/6; both CR) in the AID cohort. Conclusions: LD Nivo demonstrates biological activity, as evidenced by both anti-tumor responses and toxicities, in patients at high risk of IRAEs. Compared to SD ICI, LD Nivo may offer an advantage in toxicity management, potentially enabling more consistent treatment delivery with fewer interruptions and reduced need for immunosuppressive interventions. This strategy warrants further evaluation in prospective clinical trials.