Pembrolizumab + ATRA (MDSC-Targeting) Posts 55% 5-Year OS in Metastatic Melanoma

All-trans retinoic acid (ATRA), a differentiating agent that depletes immunosuppressive myeloid-derived suppressor cells, was pulsed at 150 mg/m² orally on days −1/0/+1 of the first four pembrolizumab 200 mg Q3W doses in a single-center Phase I/II study (NCT03200847) enrolling 24 anti-PD-1-naïve patients with unresectable/metastatic melanoma. After 48 months’ median follow-up, 5-year PFS and OS were 36% and 55%, with 33% of patients maintaining complete responses; grade 3/4 treatment-related AEs occurred in 21% (only one grade 4 event, stroke) and led to 25% discontinuations. For context, pembrolizumab alone delivers ~43% 5-year OS with 17% ≥grade 3 TRAEs (KEYNOTE-006), while the nivolumab + ipilimumab doublet achieves ~52% OS but incurs 59% high-grade toxicity (CheckMate-067).