Metastatic Colorectal Cancer with BRAF V600E Mutation Gains New FDA Approval

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Aishat Motolani

Cetuximab, Panitumumab, Tucatinib, and Ipilimumab, just to name a few, are examples of drugs approved for metastatic colorectal cancer (mCRC) over the past two decades. However, due to the poor outcomes of some of these drugs in mCRC patients, researchers are exploring new treatment combinations to optimize efficacy. This situation highlights the heterogeneity and molecular complexity of the disease.

CRC is the third most diagnosed and leading cause of cancer-related death in the United States. Although the incidence of CRC has decreased within the past 40 years due to improved screening and early diagnosis, about 20% of patients will still present with mCRC in the clinic. For these patients, the first-line treatment includes oxaliplatin-based regimens such as FOLFIRI, FOLFOX, FOLFOXIRI, CAPIRI, or CAPOX. However, the median survival of patients following those treatments is between 17 to 23 months. So, there is a need to develop drugs with better patient outcomes.

Over the past twenty years, researchers have developed several targeted therapies, showing remarkable efficacy in suppressing tumors and improving survival. These therapies work on CRC cells by blocking the function of proteins or cells involved in cell growth and metastasis. Some examples of promising proteins that are piquing the interest of scientists for mCRC treatment include Epidermal Growth Factor Receptor (EGFR), RAS, BRAF, Vascular Endothelial Growth Factor (VEGF), and Human Epidermal Growth Factor Receptor 2 (HER2) pathways. 

Central to this article is a protein called BRAF. This protein functions downstream of the EFGR pathway and helps transmit signals through a cascade of other proteins to promote cellular growth and differentiation (Figure 1). When mutated, BRAF can lose its function and contribute to uncontrolled cell division, also known as cancer. Particularly, the point mutation of the 600th amino acid in BRAF from Valine (V) to Glutamate (E) occurs in about 15% of mCRC patients. Compared to the median survival time of 21–25 months in patients with Wild-type(WT) BRAF tumors, patients with BRAF V600E only survive half as long. The clinical success of BRAF inhibitors, like Encorafenib, combined with the MEK inhibitor binimetinib, in melanoma patients with V600E mutations has prompted researchers to explore the potential of applying a similar approach to mCRC treatment.

Thus, it is not surprising that in late December 20, 2024, the Food and Drug Administration (FDA) granted accelerated approval to encorafenib (Braftovi) with cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for mCRC patients with a BRAF V600E mutation. Cetuximab is a monoclonal antibody that blocks EGFR, while mFOLFOX6 disrupts cell division by crosslinking DNA. This FDA approval came after the ongoing Pfizer-sponsored phase 3 BREAKWATER clinical trial. This trial tested two drugs – Encorafenib plus Cetuximab taken alone or in combination with chemotherapy. The control group was administered standard oxaliplatin-based chemotherapy with or without bevacizumab, a VEGF inhibitor. The initial result showed that the Encorafenib+ Cetuximab+ mFOLFOX6 group had a 61% overall response rate (ORR) compared to 40% ORR in the control group. Also, the median response duration was longer in the treatment group (13.9 months) compared to the control group (11.1 months). Pfizer is continuing its testing of progression-free survival and overall survival. The results obtained from the BREAKWATER clinical trial will serve as supportive evidence for post-market surveillance of this treatment regimen.

The safety profile of the Encorafenib+ Cetuximab+ mFOLFOX6 combination treatment is consistent with the known toxicity of each single drug. Although no new safety concerns were identified, the most common adverse events in at least 25% of treated patients included fatigue, rash, hemorrhage, pyrexia, abdominal pain, decreased appetite, vomiting, nausea, peripheral neuropathy, and diarrhea. Increased lipase levels and decreased neutrophil counts also occurred in at least 20% of patients. The recommended dose of Encorafenib is 300 mg once per day in combination with Cetuximab and mFOLFOX6 until disease progression or unacceptable toxicity.

In a press release, Pfizer’s Chief Oncology Officer and Executive Vice President, Dr. Chris Boshoff, said, “With today’s accelerated approval of the BRAFTOVI (encorafenib) regimen, patients with metastatic colorectal cancer with a BRAF V600E mutation now have a first-line treatment option, which contains a targeted therapy specifically for a mutation that is driving their cancer.”  Therefore, this approval is a promising indication of continued disease management and a renewed hope for mCRC patients.

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Edited by Mercy Michelle Nweneary Ekanem

References

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Grothey, A., Fakih, M., Tabernero, J., Andrè, T., Yoshino, T., Garcia-Carbonero, R., … & Van Cutsem, E. (2021). BEACON CRC study safety lead-in: Updated efficacy and safety data with triplet therapy in BRAF V600E–mutant metastatic colorectal cancer. Therapeutic Advances in Medical Oncology, 13, 1758835921992974. https://doi.org/10.1177/1758835921992974 

Pfizer. (2024, December 20). U.S. FDA approves Pfizer’s BRAFTOVI® combination regimen as first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. Retrieved from https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-combination-regimen-first