Patients (pts) with metastatic (met) MSS CRC are treated with sequential lines of chemotherapy (chemo), but most experience progression and prolonged toxicities during their disease course. BOT is a 2 nd -gen Fc modified anti-CTLA-4 agent, exhibiting enhanced antibody dependent cell mediated cytotoxicity of Tregs and Fc-receptor mediated myeloid activation. A phase I/II study with BOT/BAL (an anti-PD-1 antibody) in pretreated patients with MSS CRC achieved a 73% disease control rate (DCR) in pts without liver mets. We tested the hypothesis that anatomically selected pts with met MSS CRC would benefit from BOT/BAL in the 1L, delaying or negating the need for chemo.We enrolled 15 untreated Stage IV MSS CRC pts who did not have liver, bone, or brain mets (NCT06268015). Pts received BOT (75 mg q6 weeks (w) up to 4 doses)/BAL (240 mg q2w) 1L, followed by staging CT scans and iRECIST measurements q6w. If iCPD was observed, standard-of-care chemo (SOC: FOLFOX + bevacizumab or panitumumab) was added to BAL. Tissue biopsies were taken prior to treatment and at the time of progression. Primary objectives included safety, feasibility, and DCR to BOT/BAL. Secondary objectives included best overall response to BOT/BAL alone and at chemo crossover (ORR1, iRECIST; ORR2/DCR2, RECIST), overall and progression-free survival (OS, PFS1; PFS2). Exploratory objectives include spatial studies on tumor tissue biopsies taken prior to treatment and at the time of progression to predict response and resistance. As of 1/5/2026, one pt withdrew from treatment (BRAF mut); 13 pts were evaluable for response and 14 pts for irAEs (6 Gr 1-2; 7 Gr 3; no Gr 4), with a median follow up of 4.3 mo (95% CI, 1.6-Not Estimable, NE). Pts were a median age of 50 (Q1:40, Q3:62) at time of consent, with 10 (66.7%) males. Distribution of sites of mets included lymph nodes (3; 20%), other (3; 20%), peritoneum (4; 26.7%), and lungs (5; 33.3%). A median of 3 cycles of BOT were given. Gr 3 toxicity was primarily colitis (5), which we managed with short course prednisone that patients were given to take home before starting therapy, followed by infliximab within 48 hours. Categories of all grades of irAEs experienced by >1 pt included diarrhea/colitis (7), fatigue (7), rash (5), AST/ALT (3), fever (3), hypothyroidism (2), and arthritis (2), which was effectively managed with naproxen or ibuprofen. Median freedom from crossover to chemo was 8.7 mo (95% CI, 6.2-NE). There was 1 confirmed iPR to BOT/BAL alone in a pt with lung mets and TMB of 1 mut/mb, and 4 iSD at 24w of follow-up, resulting in a 71% DCR. Five BOT/BAL only pts are too early to assess at cutoff. Of 4 pts crossing over to SOC at a median of 6.3 mo (95% CI, 3.7-NE) from BOT/BAL start, 3 were evaluable for response to chemo by RECIST with a 67% DCR. No deaths occurred. Initial analysis of multiplex IHC demonstrated an increase in cDC1s in responders to BOT/BAL compared to non-responders, who exhibited an increase in Spp1/CXCL9 macrophage ratios.Our study is the first to demonstrate the safety and feasibility of 1L BOT/BAL in MSS CRC pts without liver, bone, or brain mets. 1L BOT/BAL has durable activity in some pts and can delay the need for chemo, which was added safely in pts who do progress. Further studies including the development of biomarkers are warranted in PhII studies to establish this approach in 1L MSS CRC.