Background: We previously presented safety data for the combination of D with carboplatin/paclitaxel (C/P) and RT for locally advanced esophageal cancer (J Clin Oncol 2018;36:172 [abstr]). Based on the positive results of the CALGB 80803 study (J Clin Oncol 2017;35:1 [abstr]), we amended the study to administer induction FOLFOX prior to PET assessment. Here, we present updated results. Methods: Patients (Pts) had T_anyN+ or T3-4N_anyM0 esophageal and Siewert Type I-III GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received mFOLFOX6 ×2 prior to repeat PET/CT. PET responders (PETr) received 5-FU or capecitabine and oxaliplatin with RT to 50.4Gy, while PET non-responders (PETnr) received C/P with RT. All Pts received D 1,500 mg q4W ×2 starting 2 wks prior to and during CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg q4W ×6. Results: 20 Pts have been enrolled: 16 GEJ, 4 esophageal; 3 T1-2N+, 8 T3-4N0, 1 T3Nx, 8 T3-4N+. 13 of 20 Pts (65%) are PETr. Of 13 Pts who have had surgery (8 PETr, all R0), pathologic complete response (pCR) was seen in 3 (23%; 2 PETr); 3 Pts (23%; all PETr) had ypT1bN0 tumors with 99% response and 1 Pt (8%; PETnr) had ypT0N1 (1/30 LN) with profound response in LN. 2 Pts had MSI tumors (1 PETr; 1 pCR, 1 ypT2N0 with 90% response). Notable gd 3/4 adverse events (AEs) observed were lymphopenia in 16 Pts (80%), neutropenia in 4 Pts (20%) and diarrhea and dysphagia in 1 Pt each (5%). Notable gd 1/2 AEs in ≥20%: thrombocytopenia (18 Pts), fatigue (13 Pts), anemia (12 Pts), increased AST (12 Pts), constipation (11 Pts), nausea (11 Pts), diarrhea (7 Pts) and odynophagia (7 Pts). Immune-related AEs noted were gd 3 hepatitis and gd 2 dermatitis in 1 Pt and gd 1 hypothyroidism in 1 Pt. Median length of post-op stay is 8 days, with 18% anastomotic complication rate. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT is safe and feasible. pCR and near-pCR in ½ of Pts is encouraging and compares favorably to our historical pCR rate of 15% in PETr (Cancer 2016:122:2083) and pCR rate of 31% in CALGB 80803 Pts who received induction FOLFOX. Accrual to 36 Pts continues and updated outcomes and immune correlative data will be presented. Clinical trial information: NCT02962063