SUMMARY: The FDA on December 20, 2024, granted accelerated approval to Encorafenib (BRAFTOVI®) in combination with Cetuximab (ERBITUX®) and modified Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) for patients with metastatic colorectal cancer with a BRAF V600E mutation, as detected by an FDA-approved test (Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit). ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 152,810 new cases of CRC were diagnosed in the United States in 2024 and about 53,010 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.
Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations, and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.
The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.
BRAFTOVI® (Encorafenib) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. The FDA in 2020, approved Encorafenib in combination with Cetuximab (ERBITUX®) for the treatment of adult patients with metastatic ColoRectal Cancer (mCRC) with a BRAF V600E mutation, detected by an FDA-approved test, after prior therapy, based on the BEACON CRC trial. However, first line treatment options for this group of patients remains an unmet need.
BREAKWATER is an ongoing, active-controlled, open-label, multicenter, randomized, Phase 3 study in which first line Encorafenib plus Cetuximab plus or minus chemotherapy was compared with Standard of Care chemotherapy alone, in patients with BRAF V600E-mutant mCRC. In this trial, patients were initially randomly assigned 1:1:1 to receive either Encorafenib orally once daily with Cetuximab IV infusion every 2 weeks (Encorafenib plus Cetuximab arm), Encorafenib orally once daily with Cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (Encorafenib plus Cetuximab plus mFOLFOX6 arm), or control group patients who received mFOLFOX6 (Leucovorin, Fluorouracil and Oxaliplatin) or FOLFOXIRI (Leucovorin, Fluorouracil, Oxaliplatin, and Irinotecan), both every 2 weeks, or Capecitabine plus Oxaliplatin (every 3 weeks), each with or without Bevacizumab . The trial was subsequently amended to limit randomization and compare the Encorafenib plus Cetuximab plus mFOLFOX6 group and the control group. Treatment in both groups continued until disease progression, unacceptable toxicity. The Primary endpoint was Progression Free Survival (PFS) and Objective Response Rate (ORR) and Secondary endpoints included Duration of Response, Overall survival, Time to Response and patient Reported Outcomes.
The present FDA accelerated approval was based on the results of the Encorafenib plus Cetuximab plus mFOLFOX6 group, compared to the control group. The major efficacy outcome measure was confirmed ORR assessed by Blinded Independent Central Review and evaluated in the first 110 patients randomly assigned in each treatment group. The ORR was 61% in the Encorafenib plus Cetuximab plus mFOLFOX6 group compared to 40% in the control group. Median Duration of Response was 13.9 months and 11.1 months in the two groups respectively. PFS and OS data in this ongoing trial are immature. The most common grade 3 or 4 laboratory abnormalities were increased lipase and decreased neutrophil count.
In conclusion, a combination of Encorafenib and Cetuximab plus mFOLFOX6 resulted in a statistically significant and clinically meaningful improvement in Response Rate and Durability of Response in treatment-naïve metastatic CRC patients with a BRAF V600E mutation. Continued approval for this indication is contingent upon verification of clinical benefit.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
