Patients (pts) with initially unresectable CRLM may qualify for curative-intent local therapy after downsizing by induction systemic therapy. CAIRO5 was designed to find the optimal induction regimen. We present results of pts with left-sided and RAS/BRAFV600E wild-type tumour. Pts were randomised between FOLFOX/FOLFIRI (patient preference) plus either bevacizumab (arm A) or panitumumab (arm B) up to 12 cycles. Prior systemic or local therapy for metastases was not allowed. (Un)resectability of CRLM was assessed by a liver expert panel of surgeons and radiologists, at baseline by predefined criteria and every 2 months thereafter by individual opinion. Primary endpoint was progression-free survival (PFS). Pts were stratified by potentially resectable vs permanently unresectable CRLM, serum LDH (normal/abnormal) and choice of irinotecan vs oxaliplatin. 256 events were required to detect a hazard ratio (HR) of 0.70 for PFS with 80% power and 2-sided log-rank test at 5% assuming a median PFS of 11.6 months in arm A. 236 pts (118 in each arm) were included in 43 Dutch sites from November 2014 until closure due to futility in March 2022. 6 ineligible pts were excluded. Median follow up was 44 months. Main characteristics were (arm A/B): median age 59/60, male 61/63%, synchronous CRLM 88/92%, prior adjuvant chemotherapy 4/3%, median number of CRLM 12/12. With 197 events, median PFS in arm A vs B was 10.6 vs 10.3 months (stratified HR 1.12, 95% CI 0.84-1.50, p=0.44). Response rate (RR) was 52% vs 76% (p<0.01). Median depth of response (DOR) was 33% vs 49% (p<0.01). R0/1 resection ± ablation rate was 58% vs 56% (p=0.79). Grade ≥3 toxicity occurred in 52% vs 69% (p=0.01), Clavien Dindo grade ≥3 surgical complications in 21% vs 14% (p=0.30). In first-line treatment of pts with initially unresectable CRLM and left-sided and RAS/BRAFV600E wild-type tumour there is no difference in median PFS between the addition of either bevacizumab or panitumumab to FOLFOX/FOLFIRI. The addition of panitumumab significantly increases RR and DOR but this does not translate in an increased local therapy rate of CRLM.