Clinical features of acquired resistance (AR) in stage IV melanoma patients (pts) treated with immune checkpoint inhibition (ICI)

Long-term benefit of ICI in stage IV melanoma pts achieving response is often observed, although progression after initial response (AR) unfortunately regularly occurs. Limited evidence exists regarding clinical features, outcome and treatment of pts with AR. Therefore, this monocenter study retrospectively analysed pts with AR. Stage IV melanoma pts treated at NKI between Jan 2013 and July 2021 and who developed AR after initial response upon ICI were included. AR is defined as progression after initial response (stable disease ≥6 months, partial response [PR] or complete response [CR]). Progression-free survival (PFS) from date of AR and from start date ICI (time to subsequent progression after treatment of AR [TTAR]) and overall survival (OS) from start date ICI were evaluated. 155 pts were identified with AR during ICI (n=50) and post ICI (n=105). Pts mostly developed AR after PR (67%) and CR (21%). Almost all CR pts belonged to the post ICI group, as opposed to the during ICI group (n=32 vs n=1). AR mostly occurred at isolated organ sites, but they were not specific for a site and were observed mainly in lymph nodes, lungs, brain and skin, with a median onset of 11mo after start of ICI. Pts received mostly local therapy alone (34%), switched systemic therapy (22%) or received combined local + systemic therapy (21%) as treatment of AR. Higher PFS, TTAR and OS rates were observed in pts developing AR post ICI, as compared to AR during ICI (median PFS 8mo vs 6mo, TTAR 26mo vs 22mo and OS 58mo vs 43mo). In the post ICI group PFS, TTAR and OS for CR were higher than for PR (median PFS 9mo vs 7mo, TTAR 35mo vs 22mo, OS not reached vs 55mo). For the various treatment strategies nearly all PFS rates were similar in both groups, except for continuation and restart of ICI. Restart of ICI resulted in the longest PFS, whereas continuation of ICI had the shortest PFS (12mo versus 6mo). This trend was also observed for TTAR and OS. In general pts with AR have a good outcome, due to sufficient clinical management options of often solitary progression. Inferior clinical outcomes in the during ICI group compared to the post ICI group were observed, which can partly be due to patient selection as illustrated by the lack of pts with CR in the during ICI group.