Impact of sex on efficacy and safety of 1st-line treatment with FOLFIRI plus cetuximab or bevacizumab in RAS/BRAF wildtype metastatic colorectal cancer - A subgroup analysis of the FIRE-3 (AIO KRK-0306) trial.

[BACKGROUND] Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespectively of sex. However, differences relating to safety and efficacy in the treatment of mCRC between male and female patients are of growing interest.

[METHODS] The randomized FIRE-3 study compared first-line treatment with folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) plus cetuximab to FOLFIRI plus bevacizumab in patients with RAS wildtype (RAS WT) mCRC. The present analysis focusses on the impact of sex and primary tumor (PT) sidedness on outcome parameters.

[RESULTS] Of 352 patients with RAS WT tumors, 249 (71 %) were male and 103 (29 %) female. In male patients with left-sided RAS/BRAF WT tumors, a significant benefit from cetuximab was noted with regard to ORR (OR 1.15; P = 0.035) and OS (0.66; P = 0.010), while in right-sided patients cetuximab improved ORR (OR 2.92) and had no significant effect on PFS or OS. In female patients with left-sided, RAS/BRAF WT PT, a comparable effect of cetuximab versus bevacizumab was observed with regard to ORR (OR 1.05; P > 0.999), while a numerical OS benefit was noted in the cetuximab-arm (HR 0.78; P = 0.385). By contrast, in female patients with right-sided PT, a clearly detrimental effect of cetuximab-based therapy was observed for ORR (OR 0.44; P = 0.617), PFS (HR 4.95; P = 0.005), and OS (HR 2.58; P = 0.080). In the bevacizumab arm, neutropenia grade ≥ 3 was more frequent in female versus male patients (30.6 % versus 18.3 %; P = 0.063). Otherwise, there was no significant difference of grade ≥ 3 adverse events between male and female patients.

[CONCLUSIONS] The exploratory analysis of FIRE-3 suggests that the efficacy of cetuximab combined with FOLFIRI in RAS wild-type mCRC is related to sex and primary tumor sidedness. The results support the inclusion of patient sex into the design of future trials.