FIRE-4 (AIO KRK-0114): Efficacy of third-line rechallenge with cetuximab versus investigator’s choice in relation to the interval between initial and third-line anti-EGFR therapy.

3575 Background: The randomized FIRE-4 study evaluated the effect of cetuximab rechallenge versus investigator’s choice in the 3 rd -line treatment of patients (pts) with RAS-wildtype (RAS-wt) metastatic colorectal cancer (mCRC). The present analysis focuses on the time between the end of initial anti-EGFR-based treatment and start of 3 rd -line therapy (TIS-3) as a potential predictor of response. Methods: In FIRE-4, all pts received induction therapy with FOLFIRI plus cetuximab. After 1 st PD, an anti-EGFR-free “window therapy” was recommended. At diagnosis of 2 nd PD, pts who had responded to induction therapy were re-evaluated for RAS status and, after exclusion of RAS mutations, were offered randomization to either rechallenge with cetuximab plus chemotherapy or investigator’s choice. Overall survival in 3 rd -line (OS-3) was evaluated as a primary endpoint. Results: Of the 87 pts entering 3 rd -line treatment in FIRE-4, 45 received (FOLF)IRI plus cetuximab (rechallenge arm), and 42 received investigator’s choice (standard arm). Numerically superior outcome parameters regarding ORR-3 (OR 2.70), PFS-3 (HR 0.87) and OS-3 (HR 0.86) were observed in the rechallenge arm, without, however, reaching the level of statistical significance. To evaluate the relevance of TIS-3, we focused on the median (13.8 months) and the first quartile (9.0 months). Based on these cut-off values, treatment effects were evaluated in pts with longer and shorter TIS-3 intervals (see Table). Conclusions: Longer TIS-3 intervals were associated with longer survival times in 3 rd -line treatment. This observation was particularly true for pts receiving cetuximab rechallenge, but also for those receiving investigator’s choice. Clinical trial information: NCT02934529 . Treatment arm N Interval PFS (mo) HR OS (mo) HR FOLF(IRI) + Cetuximab 21 > 13.8 mo 7.4 0.475P=0.019 20.0 0.639P=0.187 24 < 13.8 mo 4.1 12.6 34 > 9.0 mo 5.9 0.680P=0.274 19.6 0.601P=0.173 11 < 9.0 mo 4.0 10.8 Investigator’s choice 23 > 13.8 mo 5.6 0.772P=0.415 16.2 0.516P=0.055 19 < 13.8 mo 4.4 12.2 32 > 9.0 mo 5.5 0.690P=0.313 16.9 0.458P=0.042 10 < 9.0 mo 4.5 7.8