This is the first randomized phase II, open-label, multicenter study to compared the efficacy and safety of SOX + bevacizumab with SOX + cetuximab in patients with previously untreated recurrent advanced colorectal cancer with wild-type KRAS. The ORR, the primary endpoint, was not significantly different between the two study groups (p = 0.29). However, the treatment effect tended to be better in the SOX + B-mab group than in the SOX + C-mab group. Although there was no significant difference between the two groups in PFS and OS, these outcomes tended to be better in the SOX + B-mab group than in the SOX + C-mab group; there were differences of about 10 months for OS and about 6 months for PFS in both groups. The SOFT study reported a PFS of 11.7 months and an ORR of 61.5% in the SOX + B-mab group10, which were similar to the results in the SOX + B-mab group of our study (PFS, 11.7 months; ORR, 59.1%). Additionally, in our study, there was no difference in the number of treatment courses, TTF, and rate of discontinuation due to side effects between the groups.
Because the SOX + B-mab and SOX + C-mab groups comprised about 80% of left-sided colon cancer in our study, we analyzed OS and PFS in only patients with left-sided colorectal cancer. Although OS was not different between the groups, PFS was significantly better in the SOX + B-mab group than in the SOX + C-mab group. In general, the significance of anti-epidermal growth factor receptor (EGFR) antibodies has been proven in wild-type RAS left-sided colorectal cancer12. The ESMO guidelines recommend the use of anti-EGFR antibodies as a treatment for wild-type RAS left-sided colon cancer13. In the FIRE-3 study, although there was no significant difference in PFS, there was a difference in OS with a benefit of 3.7 months in the C-mab-treated patients in the wild-type KRAS exon 2 population compared to B-mab-treated patients7. There are possibilities behind the differences in PFS in the SOX + C-mab and SOX + B-mab groups in patients with left-sided colorectal cancer. The first possibility is secondary or subsequent treatment after failure of this study regimen. In this study, we did not limit secondary or subsequent treatment. In fact, three patients (13.6%) in the SOX + B-mab group used a regimen that included cetuximab and nine patients (39.1%) of the SOX + C-mab group used a regimen that included bevacizumab in secondary or subsequent treatment. The second possibility is the number of treatment courses. In the SOFT study, the median number of treatment courses was eight. However, that of our study was five in both groups. This relatively shorter treatment course may affect the difference in PFS. The third possibility is dose intensity. Although AEs seemed to not be different in hematological events, non-hematological events of peripheral neuropathy and hypertension were high in the SOX + B-mab group. Allergic reactions and paronychia were distinctive, and skin and subcutaneous tissue disorders characterized AEs in the SOX + C-mab group. Notably, all grades of AEs in nausea, vomiting, and diarrhea were observed almost over double in the SOX + C-mab group. The combination of oral fluoropyrimidine with anti-EGFR agents is known to increase the risk of diarrhea14. The concomitant study of the MRC COIN trial showed that OxFU + cetuximab and OxCap + cetuximab were equivalent in terms of OS, ORR, and RRS(rate of radical surgeries). Nonetheless, PFS was longer with OxFU + cetuximab than with OxCap + cetuximab, and the authors described a possibility that the higher toxicity associated with ≥ grade 3 nausea, diarrhea, and palmar-plantar erythema in OxCap + cetuximab led to greater dose reductions and a lower total dose of oxaliplatin15. These AEs possibly decrease the dose intensity in the combination of SOX with cetuximab, and it is necessary to assess dose intensity in a large-scale study.
A limitation of this study is that KRAS status was assessed only on exon 2 (codons 12/13). Evidence from the PRIME study and CRYSTAL study has shown that tumors with additional RAS mutations (exons 3 and 4 of KRAS and exons 2, 3, and 4 of NRAS) other than those in KRAS exon 2 display a lack of response to EGFR-targeting monoclonal antibodies16,17. Furthermore, BRAF mutations are almost exclusively non-overlapping with RAS mutations and are reported to be negative predictive biomarkers for EGFR antibody therapy in patients with mCRC18–20. Final analysis of the randomized PEAK trial supports the importance of expanded RAS mutational analysis and showed longer median PFS and median OS for panitumumab versus bevacizumab in wild-type RAS and BRAF CRC21. In response to the results of these clinical trials, the ESMO consensus guideline recommends expanding RAS mutational analysis to at least KRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, 117, and 146) and NRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, and 117) alongside the assessment of tumor BRAF mutational status. The presence of these minor RAS and BRAF mutations may have affected the results of this study. Indeed, other RAS mutations were detected in 14.7% and 31% of evaluable tumors previously assessed to be wild-type KRAS exon 2 in the CRYSTAL study and in the OPUS study, respectively16,21.
Recently, ETS and DpR have been focused on as prognostic factors for RFS and OS after first-line treatment of mCRC6. In our study, OS and PFS did not significantly differ between ETS < 20 and ETS ≥ 20 in the SOX + B-mab group. However, OS and PFS were significantly better in the ETS ≥ 20 group than in the ETS < 20 group among patients in the SOX + C-mab group. Anti-EGFR antibody drugs are reported to have a shorter TTR, better DpR, and more ETS than B-mab21. Patients with ETS in both groups had an OS > 30 months and PFS > 11 months, but the benefits of ETS to OS and PFS were significantly higher in the SOX C-mab group than in the SOX + B-mab group. The assessment of ETS can be a powerful marker for prognosis even in patients receiving SOX with C-mab. When C-mab is used in combination with SOX, evaluation of ETS is indispensable, and if ETS is < 20 after 3 months, consideration of the treatment strategy including drug change may be useful for improving patient prognosis.