Background: Magrolimab (M, Hu5F9-G4) is an antibody targeting CD47, a macrophage “don’t eat me” signal that demonstrates preclinical synergy with cetuximab (C) in refractory KRAS wild type (KRASwt) and KRAS mutant (KRASm) colorectal (CRC) tumors. Methods: Phase (Ph) 1 doses of M+C were escalated in solid tumor patients (pts) and Ph 2 efficacy was explored in previously treated KRASwt and KRASm CRC patients. Day 1 priming with 1 mg/kg of M was used to mitigate on-target anemia followed by maintenance doses ranging from 10 to 45 mg/kg in combination with C. Ph 2 pts were treated with 30 or 45 mg/kg of M and 400/250 mg/m2 of C. Results: In 78 treated pts (32 Ph 1 and 46 Ph 2), the median age was 59 years (range 19-82), and median prior therapies was 5 (range 1-14). No maximum tolerated dose was reached. Treatment-related adverse events (TRAEs) of any Grade (G) included dermatitis acneiform 36%, dry skin 33%, fatigue 32%, infusion reactions 31%, headache 30%, diarrhea 23%, nausea 23%, chills 23%, and anemia 22%. There were no fatal TRAEs and 3/78 (4%) discontinued M treatment due to any adverse events. In the combined Ph 1+2 study, 2 of 30 evaluable KRASwt CRC pts had confirmed PRs for 7.0 and 12.5 months (mo), for a 6.7% objective response rate (ORR). Both had prior C treatment. The median progression-free survival (mPFS) and median overall survival (mOS) was 3.6 mo (95%CI 1.8-5.4) and 10.1 mo (95%CI: 6.9-14.4), respectively. In 40 evaluable KRASm pts, there were no responses but 45% had stable disease (SD) and the mPFS and mOS were 1.9 mo (95%CI: 1.8-3.5) and 10.4 mo (95%CI: 5.7-16.4), respectively. In 28 KRASm pts who were TAS102/regorafenib naïve, preliminary mOS was 12.4 mo (95%CI: 5.9-not reached) which is longer than that reported for historical controls. Tumor biopsies showed treatment-related increases in macrophage immune cell infiltrates in SD pts, and baseline T cell infiltration was associated with longer OS. Pharmacokinetic profiles will be presented. Conclusions: M+C is a novel, well-tolerated combination immunotherapeutic treatment regimen. Responses were observed in two previously treated CRC pts and survival is encouraging in KRASm pts. Funded by Forty Seven and California Institute for Regenerative Medicine. Clinical trial information: NCT02953782.