Minimal Efficacy of Single-Agent Anti-PD-(L)1 Re-Exposure in Anti-PD-(L)1-Refractory Merkel Cell Carcinoma: A Retrospective Cohort Study of 16 Patients

Background/Objectives: Anti-PD-(L)1 immune checkpoint inhibitors (ICIs) provide durable responses in nearly 50% of patients with advanced Merkel cell carcinoma (MCC). However, for those progressing on first-line ICI therapy, optimal subsequent therapy remains unclear. Although presumed to have limited benefit, the efficacy of re-exposure with anti-PD-(L)1 alone has not been formally reported. We assessed real-world outcomes of patients within a Seattle-based MCC repository who received this salvage approach. Methods: Among 106 patients who received salvage therapy after first-line ICI progression, 16 underwent single-agent anti-PD-(L)1 monotherapy re-exposure during salvage. Patients progressing >3 months after their last immunotherapy dose were excluded. Outcomes included progression-free survival (PFS), disease-specific survival (DSS), and objective response rate (ORR). Results: The median time from end of first-line ICI therapy to anti-PD-(L)1 re-exposure was 51 days (IQR 22–92). Most patients switched between PD-1 and PD-L1 inhibitors (n = 9), while others were re-exposed with the same agent (n = 5) or a different PD-1 inhibitor (n = 2). One of 16 patients experienced a partial response with the same PD-1 inhibitor (ORR 6%; 95% CI: 0.2–30%) at 3 months after re-exposure, followed by progression 10 months after re-exposure. Median PFS was 2.2 months (95% CI: 1.3–5.1 months), and median DSS was 14.7 months (95% CI: 10.4–NR). Conclusions: These data suggest that re-exposure with anti-PD-(L)1 monotherapy confers minimal and short-lived benefit in ICI-refractory MCC, reinforcing the need to develop alternative salvage strategies. Future trials for ICI-refractory MCC mandating an ICI monotherapy arm are unlikely to be appealing to patients or physicians based on a low chance of clinical benefit for this approach.