Background: FIRE-4 (AIO KRK-0114) is performed in RAS-wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1^st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab (FOLFIRI/Cet). In arm A, patients were randomized to continue FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with Fluoropyrimidin plus bevacizumab was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab every two weeks at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued every 2 weeks until progression or intolerable toxicity. De- and re-escalation was allowed according to the local standard of care. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with Fluoropyrimidin plus bevacizumab (5mg/kg) every two weeks until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Here, we report PFS in first-line (part 1) as a secondary study endpoint of the study. Other secondary endpoints included ORR, OS, safety, and tolerability. Results: From August 2015 to January 2021, 672 patients were randomized and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 arm A and 329 in arm B). PFS was comparable between both treatment arms (10.7 vs 11.3 months, HR 0.92 (95% CI: 0.76-1.10), p = 0.36). ORR in evaluable patients was not different and reached 75.7% and 72.3% with a DCR of 94.6% vs. 92.5% in the respective arms. Preliminary OS (≤40% of OS events recorded) was also similar between both arms (HR 1.030; p = 0.81). Updated results will be presented at the meeting. No new or unexpected toxicities were observed. Conclusion: Switch from FOLFIRI cetuximab to maintenance therapy with 5-FU plus bevacizumab did not induce superior efficacy (PFS, ORR, OS) compared to continued application of cetuximab. The results suggest that early switch maintenance from cetuximab to bevacizumab is not effective to postpone disease progression during targeted therapy. FIRE-4 confirms the efficacy of FOLFIRI plus cetuximab as first-line treatment of patients with RAS wild-type mCRC. Clinical trial information: NCT02934529.