Background: Preclinical models suggest that WT KRAS mCRC may retain EGFR dependency despite resistance developed to anti-EGFR mAb treatment (eg, cetuximab or panitumumab). Sym004 is the first-in-class drug mixture of two mAbs targeting non-overlapping epitopes of EGFR causing augmented receptor degradation. Cohorts of weekly 9 and 12 mg/kg from the multicenter phase 1 trial exploring multiple doses and schedules of Sym004 have recently reported antitumor activity and a tolerable safety profile. Methods: We here report safety (primary endpoint) and efficacy (exploratory endpoint) from the two Sym004 Q2W cohorts of this trial. Eligible pts had WT KRAS mCRC with prior clinical benefit to anti-EGFR mAbs and subsequent progression during or within 6 months after treatment cessation. Sym004 was administered until disease progression or unacceptable toxicity. Results: A total of 29 pts (median age was 64 years; 62% had liver metastasis [non-]target lesions; 86% had >2 prior lines of therapy) were treated at 12 (N=12) and 18 mg/kg (N=17) Sym004 Q2W. Drug-related AEs were manageable with dose reduction and supportive medication. Grade ≥3 toxicities in 12 and 18 mg/kg cohorts were skin rash (3/12 [25%]; 6/17 [35%]; no grade 4) and hypomagnesemia (3/12 [25%]; 6/17 [35%]). Grade 3 diarrhea was seen in one pt of each cohort (8%; 6%). Infusion-related reactions were observed in 2/29 (7%) pts (grade 1 and 2, each). Efficacy assessments are shown in the Table. Conclusions: Single-drug Sym004 was well tolerated and antitumor responses seen at 18 mg/kg Q2W in the first assessment at week 4-8 suggest clinical activity of Sym004 in anti-EGFR mAb resistant WT KRAS mCRC pts. The early benefit:risk profile remained favorable; no new toxicities were found. Clinical trial information: NCT01117428.