FIRE-4 (AIO KRK-0114): Randomized study evaluating the efficacy of cetuximab re-challenge in patients with metastatic RAS wild-type colorectal cancer responding to first-line treatment with FOLFIRI plus cetuximab.

3513 Background: Several smaller studies performed in later lines of treatment have suggested a potential benefit from anti-EGFR re-challenge on survival of RAS wild-type (RAS WT) metastatic colorectal cancer (mCRC). FIRE-4 is a randomized phase-III study that prospectively evaluates re-challenge with chemotherapy plus cetuximab as compared to physician’s choice. Methods: The FIRE-4 study was performed with two steps of randomisation. Within the first randomisation, pts were either attributed to induction therapy with FOLFIRI plus cetuximab continued until disease progression (PD) or intolerable toxicity (arm A) or to a switch maintenance using 5-FU plus bevacizumab (arm B). After first PD, an anti-EGFR-free “window therapy” was recommended. After diagnosis of second PD, RAS WT pts (again selected by liquid- or tumor-biopsy), who had responded to cetuximab-based induction therapy within FIRE-4 (entry 1) or outside of the study (entry 2), could then proceed to 2 nd randomization attributing pts either to re-challenge with cetuximab or to physician’s choice. Overall survival (OS) after 2 nd randomization was evaluated as primary endpoint. Results: From August 2015 to February 2021, 672 pts were randomized and 657 pts were assigned to treatment in 120 German and 10 Austrian centers. Within the 2 nd randomization, 87 pts (entry 1: N = 62; entry 2: N = 25) were attributed either to physician’s choice (A2: N = 42) or (FOLF)IRI plus cetuximab (Arm B2: n = 45). Baseline characteristics were comparable between groups without significant differences regarding parameters such as age, sex, ECOG performance status, or primary tumor sidedness. All pts were RAS WT at the time of randomization. No statistically significant difference between arm A2 and B2 was observed regarding OS (15.1 months vs. 17.6 months; HR 0.84; P = 0.48) or PFS (4.6 months vs. 5.8 months; HR 0.91; P = 0.64). ORR was greater in the experimental arm (11.9% vs. 28.9%; OR 0.33; P = 0.07), while disease control rate was nearly identical (59.5% vs. 60.0%; OR 0.98; P > 0.99). Conclusions: FIRE-4 did not meet its primary endpoint. While the control arm using physician’s choice exceeded expectations, re-challenge with anti-EGFR therapy in RAS WT pts obtained comparable results in terms of OS. Clinical trial information: NCT02934529 .