Independent Radiological Evaluation of Objective Response, Early Tumor Shrinkage, and Depth of Response in Fire-3 (Aio Krk-0306) in the Final Ras Evaluable Population

Aim: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type mCRC patients. An independent radiological review was carried out to evaluate tumor response according to RECIST 1.1 and to define early tumor shrinkage (ETS) and depth of response (DpR). Methods: Extended RAS analysis was carried out in KRAS and NRAS exon 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) using pyro-sequencing technique. Radiological data were evaluated independently. ETS was defined as a reduction in tumor diameter of more than 20% at first-tumor assessment after baseline (week 6). DpR was defined as the maximal tumor shrinkage observed in a patient. Reviewers were blinded to patient data. Calculations were done for both, the ITT- and the extended RAS wild-type population. Results: Within the ITT population, 475 patients (80.2%) were successfully tested for all RAS locations. Primary outcome data for the RAS wt population (n = 400) (table). FOLFIRI + Cetuximab (n= 199) FOLFIRI + Bevacizumab (n = 201) p HR ORR (%) 65.8 58.2 0.92* PFS (months) (95% CI) 10.3 (9.5 - 11.8) 10.2 (9.3 - 11.7) 0.77 0.97 OS (months) (95% CI) 33.1 (24.5 - 39.4) 25.0 (23.0 - 28.1) 0.0059 0.697 p = log-rank test; * = one-sided Fisher's exact test; HR = Hazard ratio 459 patients (77.5%) were evaluable according to RECIST. ORR significantly favored the FOLFIRI plus cetuximab arm (71.4% vs. 56.4%; two sided Fisher's exact test p = 0.015). The proportion of patients reaching ETS was significantly greater in the FOLFIRI plus cetuximab treated population (67.5% vs. 47.9% p = 0.0013), and was significantly associated with PFS in the cetuximab arm (logrank test p = 0.023) and OS (logrank test p = 0.0005 and p = 0.0043) in the respective treatment arms. Depth of response was significantly greater in FOLFIRI plus cetuximab treated patients (48.2% vs. 33.0%, Wilcoxon test p = 0.0005) and associated with post progression survival (Bravais Pearson test p Conclusions: Based on an independent radiological review, FOLFIRI plus cetuximab induced a significantly higher ORR, a greater rate of ETS, and an increased DpR compared to FOLFIRI plus bevacizumab. These response-related outcomes may in part explain the significant OS advantage of FOLFIRI plus cetuximab observed in FIRE-3. Disclosure: S. Stintzing: Honoraria: Amgen, Merck, Roche, Sanofi Travel expenses: Amgen, Merck, Roche, Sanofi; D.P. Modest: Honoraria and travel grants: Merck, Roche, Amgen; C. Giessen: Travel support: Roche; M. Moehler: Merck: Research grants and advisory board member Roche: congress speaker and advisory board member; V. Heinemann: Honoraria and travel expenses: Roche, Merck, Amgen, Sanofi, Bayer Research Fund: Merck, Roche. All other authors have declared no conflicts of interest.