Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk pt population with correlative biomarkers. Here we report the primary and available secondary endpoints (EPs). Methods: Stage II/III LARC pts (with ONE or more of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy +/- pembrolizumab 200mg IV Q3 wks x 6 doses) → surgery 8-12 wks following last dose of radiotherapy. Primary EP: Improvement in Neoadjuvant Rectal Cancer (NAR) score for EA v control potentially representing a 3-4% absolute OS improvement. Secondary EPs: Comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter sparing surgery (SSS), and exploratory assessments of molecular and radiographic predictors of response and distant failure. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 8/2018-5/2019, 185 pts were randomized to control (n=95) or pembrolizumab (n= 90). Baseline characteristics were relatively well balanced. 137 pts were evaluable for NAR (68 control, 69 pembrolizumab). Mean NAR was 14.08 for control (95% CI: 10.7-17.4) v 11.53 for pembrolizumab (CI: 8.5-14.6) (p=0.26). pCR=29.4% v 31.9% (p=0.75); cCR=13.6% v 13.9% (p=0.95); and SSS=71.0% v 59.4% (p=0.15). The side effects on Arm 3 were consistent with both CRT and pembrolizumab safety profile. Grade 3/4 AEs were slightly increased on the pembrolizumab arm during and after CRT (48.2 v 37.3%). There were 2 deaths during FOLFOX, one on the control arm due to sepsis; the other on the EA due to pneumonia. There were no statistically significant differences in RT (fractions, dose, boost fractions, or boost dose), FOLFOX or capecitabine doses. Conclusions: Pembrolizumab added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. The secondary endpoints including PFS and OS have not been reached. Correlative analysis for both T-cell and myeloid cell populations in the tissue and blood in addition to comprehensive cytokine analysis is ongoing. NCT02921256. Support: U10CA180868, -180822; UG1-189867; U24-196067. Clinical trial information: NCT02921256