FOLFOXIRI versus FOLFOX or FOLFIRI with targeted therapy in patients with mutant BRAF metastatic colorectal cancer: A systematic review and meta-analysis

Introduction. Based on the subgroup analysis of the TRIBE study FOLFOXIRI with bevacizumab is the recommended option for patients (pts) with mBRAF metastatic colorectal cancer (mCRC) in the 1st line. However, subgroup analysis of other studies showed conflicting results. Therefore, we performed systemic review and meta-analysis to compare efficacy FOLFOXIRI and doublets with targeted therapy in pts with mBRAF mCRC in terms of progression free survival (PFS), objective response rate (ORR) and overall survival (OS).

Methods. We performed a search of all prospective randomizes studies in PubMed, ASCO and ESMO congresses for all years before May, 2020, compared FOLFOXIRI plus bevacizumab or anti-EGFR antibodies and FOLFOX or FOLFIRI with targeted agents at the 1st line with information of the BRAF status. Primary outcome was hazard ratio (HR) for PFS and 95% confidence interval (CI); secondary – HR for OS and odds ratio (OD) for ORR. Fixed effects were used for analysis. Meta-analysis was conducted by Review Manager Ver. 5.3.

Results. We identified 6 trials (CHARTA, STEAM, TRIBE, TRIBE2, VISNU, METHEP2), which included 158 pts with mBRAF (FOLFOXIRI – 82 (52%) and doublets – 76 (48%). According to results of the meta-analysis there was a tendency for higher ORR in pts with FOLFOXIRI (OR 2.07, 95% CI 0.61–7.06; p = 0.24; I² = 27%, p for heterogeneity 0.26; 3 trials). However we didn’t find any significant improvement in PFS (HR 0.89, 95% CI 0.64–1.23; p = 0.48; I² = 0%, p for heterogeneity 0.63; 5 trials) or OS (HR 0.9, 95% CI 0.37–1.19; p = 0.048; I² = 71%, p for heterogeneity 0.06; 2 trials) in the group of triplet.

Conclusions. FOLFOXIRI with targeted therapy did not show significant improvement in the PFS and OS in pts with mBRAF compared with FOLFOX or FOLFIRI with targeted antibodies. A prospective randomized trial is needed to determine the optimal chemotherapy regimen at the 1^st line for pts with mBRAF mCRC.

1. Li H.T., Lu Y.Y., An Y.X., Wang X., Zhao Q.C. KRAS, BRAF and PIK3CA mutations in human colorectal cancer: relationship with metastatic colorectal cancer. Oncol Rep. 2011;25(6):1691–1697. doi: 10.3892/or.2011.1217.

2. Nakanishi R., Harada J., Tuul M., Zhao Y., Ando K., Saeki H. et al. Prognostic relevance of KRAS and BRAF mutations in Japanese patients with colorectal cancer. Int J Clin Oncol. 2013;18(6):1042–1048. doi: 10.1007/s10147-012-0501-x.

3. Bae J.M., Kim J.H., Cho N.-Y., Kim T.Y., Kang G.H. Prognostic implication of the CpG island methylator phenotype in colorectal cancers depends on tumour location. Br J Cancer. 2013;109(4):1004–1012. doi: 10.1038/bjc.2013.430.

4. Cheng H.H., Lin J.K., Chen W.S., Jiang J.K., Yang S.H., Chang S.C. Clinical significance of the BRAFV600E mutation in Asian patients with colorectal cancer. Int J Colorectal Dis. 2018;33(9):1173–1181. doi: 10.1007/s00384-018-3095-6.

5. Yuan Z.X., Wang X.Y., Qin Q.Y., Chen D.F., Zhong Q.H., Wang L., Wang J.P. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis. PLoS ONE. 2013;8(6):e65995. doi: 10.1371/journal.pone.0065995.

6. Modest D.P., Ricard I., Heinemann V., Hegewisch-Becker S., Schmiegel W., Porschen R. et al. Outcome according to KRAS-, NRASand BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol. 2016;27(9):1746–1753. doi: 10.1093/annonc/mdw261.

7. Chu J.E., Johnson B., Morris V.K., Raghav K.P.S., Swanson L., Lim H.J. et al. Population-based screening for BRAF V600E in metastatic colorectal cancer (mCRC) to reveal true prognosis. J Clin Oncol. 2019;37(15 Suppl.): 3579–3579. doi: 10.1200/JCO.2019.37.15_suppl.3579.

8. Mao C., Liao R.Y., Qiu L.X., Wang X.W., Ding H., Chen Q. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep. 2011;38(4):2219–2223. doi: 10.1007/s11033-010-0351-4.

9. Xu Q., Xu A.T., Zhu M.M., Tong J.L., Xu X.T., Ran Z.H. Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a metaanalysis. J Dig Dis. 2013;14(8):409–416. doi: 10.1111/1751-2980.12063.

10. Loupakis F., Cremolini C., Salvatore L., Masi G., Sensi E., Schirripa M. et al. FOLFOXIRI plus bevacizumab as firstline treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer. 2014;50(1):57–63. doi: 10.1016/j. ejca.2013.08.024.

11. Cremolini C., Loupakis F., Antoniotti C., Lupi C., Sensi E., Lonardi S. et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as firstline treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16(13):1306–1315. doi: 10.1016/ S1470-2045(15)00122-9.

12. Van Cutsem E., Cervantes A., Nordlinger B., Arnold D. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3 Suppl.):iii1-iii9. doi: 10.1093/annonc/mdu260.

13. Fedyanin M., Achkacov S., Bolotina L., Gladkov O., Glebovskaya V., Gordeev S. et al. Practice guidelines for the treatment of colon and rectosigmoid junction cancer. Malignant tumors: Practical Guidelines RUSSCO. 2019;3s2(9):324–364. (In Russ) Available at: https://rosoncoweb.ru/standarts/RUSSCO/2019/2019-21.pdf.

14. Hurwitz H.I., Tan B.R., Reeves J.A., Xiong H., Somer B., Lenz H.J. et al. Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM). Oncologist. 2019;24(7):921–932. doi: 10.1634/theoncologist.2018-0344.

15. Cremolini C., Antoniotti C., Rossini D., Lonardi S., Loupakis F., Pietrantonio F. et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(4):497–507. doi: 10.1016/S1470-2045(19)30862-9.

16. Schmoll H.-J., Meinert F.M., Cygon F., Garlipp B., Junghanss C., Leithäuser M. et al. “CHARTA”: FOLFOX/bevacizumab vs FOLFOXIRI/bevacizumab in advanced colorectal cancer – Final results, prognostic and potentially predictive factors from the randomized phase II trial of the AIO. J Clin Oncol. 2017;35(15 Suppl.):3533–3533. doi: 10.1200/JCO.2017.35.15_suppl.3533.

17. Sastre J., Vieitez J.M., Gomez-España M.A., Calle S.G., Salvia A.S., Suárez B.G. et al. Randomized phase III study comparing FOLFOX + bevacizumab versus folfoxiri + bevacizumab (BEV) as 1st line treatment in patients with metastatic colorectal cancer (mCRC) with ≥ 3 baseline circulating tumor cells (bCTCs). J Clin Oncol. 2019;37(15 Suppl.):3507–3507. doi: 10.1200/JCO.2019.37.15_suppl.3507.

18. Lopez-Crapez E., Adenis A., Thezenas S., Assenat E., Francois E., Guimbaud R. et al. FOLFIRINOX plus cetuximab (CET) or bevacizumab (BEV) in patients (pts) with initially unresectable colorectal liver metastases (CRLM) with BRAF mutated (mut) tumors: A subgroup analysis of the UNICANCER PRODIGE 14-ACCORD 21 (METHEP2) trial. J Clin Oncol. 2018;36(15 Suppl.): 3548–3548. doi: 10.1200/JCO.2018.36.15_suppl.3548.

19. Lopez-Crapez E., Adenis A., Thezenas S., Guimbaud R., Ghiringhelli F., Blas A.M. et al. Induction chemotherapy (CT) with FOLFIRINOX or FOLFOX/FOLFIRI, plus cetuximab (CET) or bevacizumab (BEV) (by RAS status), in patients (pts) with primarily unresectable colorectal liver metastases (CRLM): Results of the randomized UNICANCER PRODIGE 14-ACCORD 21 (METHEP-2) trial. Clin Oncol. 2018;36(15 Suppl.):3535. doi: 10.1200/JCO.2018.36.15_suppl.3535.

20. Lagakos S.W. The challenge of subgroup analyses – reporting without distorting. N Engl J Med. 2006;354(16):1667–1669. doi: 10.1056/NEJMp068070.

21. Bokemeyer C., Van Cutsem E., Rougier P., Ciardiello F., Heeger S., Schlichting M. et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48(10):1466–1475. doi: 10.1016/j.ejca.2012.02.057.

22. Hu H., Wang K., Wang W., Qiu M., Lin R., Zhang H. et al. mFOLFOXIRI with or without cetuximab as conversion therapy in patients with RAS/BRAF wildtype unresectable liver metastases colorectal cancer: The FOCULM study. J Clin Oncol. 2020;38(4 Suppl.):99–99. doi: 10.1200/JCO.2020.38.4_suppl.99.

23. Modest D.P., Martens U.M., Riera-Knorrenschild J., Greeve J., Florschütz A., Wessendorf S. et al. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019;37(35):3401–3411. doi: 10.1200/JCO.19.01340.

24. Cremolini C., Antoniotti C., Stein A., Bendell J., Gruenberger T., Rossini D. et al. Individual patient data meta-analysis of FOLFOXIRI plus bevacizumab versus doublets plus bevacizumab as initial therapy of unresectable metastatic colorectal cancer. J Clin Oncol. 2020;38(28):3314–3324. doi: 10.1200/JCO.20.01225.