Background: There is limited efficacy for immunotherapy (IO) in mismatch repair proficient CRC (pMMR-CRC) or PDAC. The mechanisms driving their intrinsic IO resistance are largely unknown. DAPPER (NCT03851614) is a phase 2 study randomizing patients (pts) with pMMR-CRC or PDAC to D+O or D+C. Methods: PDAC or pMMR-CRC pts with ECOG 0-1 were randomized to either D+O (arm A), or D+C (arm B). In a 28 day-cycle, D 1500mg every 4 weeks (w) IV was given with either O 300mg orally twice daily or C 20mg orally once daily 5d/week. Primary endpoint included pharmacodynamic immune changes in the TME. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples (baseline and cycle 2 (C2)) were analyzed by multiplexed immunohistochemistry (CD3, CD8, CD20, CD68 and FOXP3) and RNA-sequencing. A total of 48 publicly available gene expression signatures (GES) were associated with treatment outcomes and investigated with predictIO software (Bareche Y et al. Ann Oncol, 2022). Results: Thirty-one pMMR-CRC pts were randomized to arm A (n=16) or B (n=15). Median age was 59y (range 34-77y), M:F 19:12. In 28 evaluable pts, 3 pts had stable disease (SD) (2 pts on D+O and 1 pt on D+C) while 25 had progressive disease (PD). The median PFS of arm A and B were 2.6 (95% CI 2.5-2.6) and 2.4 (95% CI 1.5-2.7) months (m) respectively. Among 19 pts with PDAC, 9 and 10 pts were randomized to arm A and arm B respectively. Median age was 60y (range 48-76y), M:F 9:10.In 18 evaluable pts, 1 pt had an unconfirmed partial response with D+C, 1 pt had SD with D+O while 16 had PD. The median PFS of arm A and B were 1.3 (95% CI 0.8-NA) and 2.1 (95% CI 1.3-NA) m respectively. Increased CD8+ tumor-infiltrating lymphocytes (TILs) at baseline (p=0.04) and at C2 (p=0.023) and low baseline CD68+ cells (p=0.018) were associated with longer OS. Different GES at baseline were associated with OS and PFS (see table). None of these GES were associated with OS or PFS in CRC or PDAC pts in the TCGA database, suggesting specificity to IO. Conclusions: In pts with pMMR-CRC or PDAC, D+O and D+C showed limited anti-tumor activity. Although increased CD8+ TILs infiltration was observed in a subset of pMMR-CRC or PDAC pts and associated with longer OS, immune infiltration of the TME did not result in radiographic response or durable disease control. Clinical trial information: NCT03851614.