There have been great strides made in developing new and innovative treatment regimens for patients with metastatic colorectal cancer (mCRC) over the past decade. New treatment regimens are needed as it is not uncommon for patients with colorectal cancer to initially present with metastases; up to 30% of patients will have metastases at time of diagnosis.1 Older regimens relied more on 5-fluorouracil (5FU), where the overall survival (OS) would typically not exceed 12 months.2,3 Advances in drug development have improved chemotherapy regimens and combinations to become more targeted compared with the overall cytotoxic effects of solely 5FU-based regimens. This has resulted in improved outcomes, including 5-year survival rates.2   

In addition, the combination of cytotoxic regimens using irinotecan/oxaliplatin with 5FU/capecitabine have increased the overall survival to 18 months.1 More therapies targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFR) antibodies have further increased OS to between 22 months to 29 months.

Unfortunately, many patients with mCRC can eventually lose response to these targeted therapies based on the ability to undergo mutations. As future research focuses on improving targeted therapies in clinical trials, more investigators are attempting to find additional targets within mCRC in order to help combat the frequently encountered mutations. One such mutation undergoing increasing evaluation is the BRAF V600E mutation.  

Related Articles

BRAF V600E mutations are found in up to 15% of patients with mCRC.4 Patients with this mutation have a relatively poor prognosis with objective response rates (ORRs) to typical treatment regimens less than 10% with median progression-free survival (PFS) of 2 months and OS of 4 to 6 months.4,5

The study conducted by Kopetz and colleagues aimed to evaluate the tolerability, safety, and efficacy of a new regimen targeting those patients with the BRAF V600E mutation.4 This multicenter, randomized, open-label phase 3 study evaluated 665 patients with mCRC with the BRAF V600E mutation who had failed at least 1 or 2 previous regimens. These patients were given encorafenib (ENCO) and cetuximab (CETUX) with or without binimetinib (BINI) compared with the investigator’s choice of irinotecan (IRI) or FOLFIRI plus CETUX, which represented the control group or the “standard-of-care” arm.  

The triplet combination of ENCO plus CETUX plus BINI produced a median OS of 9.0 months (95% CI, 8-11.4) compared with 5.4 months (95% CI, 4.8-6.6) in the control group. The hazard ratio (HR) was 0.52 (95% CI, 0.39-0.70, P <.0001). The doublet combination of CETUX plus ENCO produced a median OS of 8.4 months (95% CI, 7.5-11) with a HR of 0.60 (95% CI, 0.45-0.79) when compared with the control group (P <.0003). 

Similarly, the triplet group had higher ORR (26%; 95% CI, 18-35%) compared with the control group (2%; 95% <1%-7%, P <.0001). Grade 3 or higher adverse events (AEs) were similar between all groups:  control arm (61%), triplet arm (58%), and doublet arm (50%). The authors concluded that triplet therapy consisting of ENCO plus BINI plus CETUX should be considered the new standard of care for patients with mCRC with the BRAF V600E mutation. 

These results are encouraging for patients with mCRC, especially considering those with BRAF mutations are known to have worse prognoses and outcomes.5 CETUX has extensive data as an anti-EGFR monoclonal antibody (mAb) for use in colorectal cancer; however, ENCO and BINI are agents that some health care professionals may not be as familiar with. ENCO targets the BRAF V600E mutation, and is also approved for use in patients with melanoma who have the same mutation. The combination of ENCO and BINI has greater antitumor activity against mCRC cells with the BRAF V600E mutation.

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108.  
  2. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trialLancet Oncol. 2014;15(10):1065-1075.
  3. Martini G, Troiana T, Cardone C, et al. Present and future of metastatic colorectal cancer treatment: a review of new candidate targetsWorld J Gastroenterol. 2017;23(26):4675-4688.
  4. Kopetz S, Grothey A, Van Cutsem E, et al.  BEACON CRC: a randomized, 3-arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E-mutant metastatic colorectal cancer. Presented at: ESMO World Congress on Gastrointestinal Cancer 2019; July 3-6, 2019; Barcelona, Spain. Abstract LBA-006.  
  5. Modest DP, Ricard I, Heinemann V, et al. Outcome according to KRAS-, NRAS- and 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.
  6. Encorafenib® [package insert]. Boulder, CO: Array BioPharma, Inc; 2018.
  7. Binimetinib®. Boulder, CO: Array BioPharma, Inc; 2018.