Background: Colitis-associated cancer (CAC) is a devastating complication of inflammatory bowel disease. CAC tumor biology differs from that of sporadic colorectal cancer (CRC). Patients (pts) with (w/) metastatic CAC (mCAC) treated w/ 1st line (1L) chemotherapy have worse outcomes than pts w/ sporadic metastatic CRC (mCRC). EGFR inhibitor (EGFRi) w/ chemotherapy is standard of care for mCRC that is left (L) sided, RAS wild type (WT), without BRAF V600E mutation (mut) or ERBB2 amplification (amp). There are no published data on efficacy of EGFRi in CAC. We report outcomes of mCAC pts treated w/ EGFRi. Methods: Cases were identified by querying a prospectively maintained database of CAC pts seen at Memorial Sloan Kettering Cancer Center from 1/2000-present. Among mCAC pts who received EGFRi (n = 16), outcomes of interest: best response, progression-free survival (PFS), and overall survival (OS). PFS was calculated from date of 1st treatment w/ EGFRi until progression or death. OS was calculated from date of 1st treatment w/ EGFRi until death or last follow-up. Survival analyses were performed using Kaplan-Meier method. Data were obtained through review of electronic medical records. Results: 84 pts w/ mCAC were identified (52 L sided, 24 right [R] sided, 8 small bowel). Genomics were consistent w/ our prior reports: 79% TP53 mut, 19% APC mut, 14% MYC amp/gain, 32% KRAS mut, 4% BRAF mut, 6% ERBB2 amp. Limiting to pts w/ tumors that were L sided, RAS WT, without BRAF V600E mut or ERBB2 amp, we identified 34 (40%) mCAC pts. 16 (47%) of these pts received EGFRi as 2L or 3L therapy. 3 pts (19%) received EGFRi alone, 13 pts (81%) received EGFRi w/ FOLFIRI or irinotecan. 8 pts (50%) had tumors that were high grade and/or w/ signet ring features. Metastatic sites at initiation of EGFRi: lymph node (69%), liver (50%), lung (50%), peritoneum (38%), bone (38%), soft tissue (38%). 2 pts (12.5%, 95% CI: 1.5-38.3%) had a response, 4 pts (25%) had stable disease (SD), and 10 pts (62.5%) had progressive disease (PD) as best response. Median PFS and OS: 3.0 months (95% CI: 1.8-8.7) and 11.5 months (95% CI: 8.8-17.4), respectively. 2 additional pts w/ R sided CAC received EGFRi w/ SD and PD as best responses. Conclusions: Pts w/ mCAC, who by established criteria are eligible for treatment w/ EGFRi, have rapid progression and low response rates to EGFRi. This suggests that unlike sporadic CRC, CAC may not be driven primarily by EGFR. Many had high grade histology and unusual sites of metastases (bone, soft tissue). Experiments are under way to elucidate mechanisms underlying resistance to EGFRi and will be reported. These include immunohistochemistry for EGFR and its ligands, transcriptomic analyses to classify consensus molecular subtypes, and assessment of EGF dependence and EGFRi sensitivity in CAC organoids.