841 Background: Retifanlimab is a humanized anti–PD-1 monoclonal antibody, recently approved in May 2025, for advanced squamous cell carcinoma of the anal canal (SCAC) as monotherapy or in combination with carboplatin and paclitaxel. We conducted a systematic review to evaluate the available evidence on its efficacy and safety in gastrointestinal (GI) malignancies. This review summarizes published Phase I–III clinical trials focusing on objective response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), adverse events (AEs), and immune-related adverse events (irAEs). Methods: A comprehensive literature search of peer-reviewed publications was conducted on PubMed, Cochrane, Embase, Scopus and major conference proceedings through August 2025, to identify interventional trials of retifanlimab in GI cancers, including anal, gastric/gastroesophageal, colorectal, and pancreatic malignancies. Studies reporting efficacy and safety outcomes were included. Results: Three clinical trials evaluating retifanlimab in GI cancers met the inclusion criteria. Two trials in locally recurrent or metastatic SCAC demonstrated meaningful clinical activity. In the Phase II POD1UM-202 trial (n=94), retifanlimab monotherapy achieved an ORR of 13.8% with a median DOR of 9.5 months in platinum-refractory SCAC. Median PFS and OS were 2.3 and 10.1 months, respectively. In the Phase III POD1UM-303/InterAACT 2 trial (n=308), adding retifanlimab to carboplatin-paclitaxel significantly improved median PFS (9.3 vs 7.4 months, hazard ratio HR 0.63, P<0.001) and ORR (56% vs 44%) compared with chemotherapy alone. Interim OS favored the retifanlimab arm (29.2 vs 23.0 months, HR 0.70), but results were not statistically significant. Grade ≥3 AEs were higher in the retifanlimab group (83% vs 75%) and irAEs were also more frequent (49% vs 26%), however, toxicities were manageable with standard care. In HER2-positive, PD-L1-positive, advanced gastric/gastroesophageal adenocarcinoma (GEA), the Single-arm Phase II MAHOGANY Cohort A (n=43) reported ORR 53% and median DOR 10.3 months for first-line retifanlimab plus margetuximab, with 18.6% grade 3 treatment-related AEs and no grade 4–5 events. The regimen met its activity benchmark but was discontinued early due to evolving GEA treatment standards. No dedicated retifanlimab trials assessing efficacy and safety in colorectal or pancreatic cancer have yet been published. Conclusions: Retifanlimab demonstrates clinically meaningful efficacy in certain GI malignancies, especially SCAC. Its benefit in biomarker-selected gastric/GEA cancer is promising, whereas evidence in colorectal and pancreatic cancer remains limited. Retifanlimab’s efficacy and safety profile is comparable to other PD-1 inhibitors; however, further research is needed to define its role across GI cancers.
Siddiqi et al. (Sat,) studied this question.