New FDA Approval for Colorectal Cancer Patients
- A new targeted approach, which combines a drug called encorafenib with cetuximab and chemotherapy regimen mFOLFOX6, has received accelerated FDA approval for metastatic colorectal cancer with a BRAF V600E mutation.
- This is the first time a BRAF-targeted therapy has been approved for use as a first treatment for this group of patients.
- Next-generation sequencing (NGS) — also called molecular testing — can help doctors find patients with certain mutations, like the BRAF V600E mutation. It helps doctors better determine if certain targeted treatments are likely to work.
- The new approval was based on results from the the BREAKWATER clinical trial, which found 61% of patients on the new combination saw their tumors shrink, compared to 40% on standard chemotherapy.
Thanks to next-generation sequencing (NGS) — a cutting-edge method of analyzing your tumor’s genetic makeup — doctors can determine whether this targeted approach is likely to work for you. This exciting development brings renewed hope and highlights the importance of molecular testing in personalizing cancer care.
The FDA’s Accelerated Approval of Encorafenib With Cetuximab and mFOLFOX6
Read More- Encorafenib (brand name Braftovi) – a BRAF kinase inhibitor designed to block abnormal signals caused by the mutated BRAF protein.
- Cetuximab (brand name Erbitux) – an EGFR (epidermal growth factor receptor) inhibitor that interrupts another key signal for cell growth and survival.
- mFOLFOX6 – a standard chemotherapy regimen that includes leucovorin (folinic acid), fluorouracil (5-FU), and oxaliplatin.
Why Accelerated Approval?
Accelerated approvals are granted to drugs that address serious or life-threatening diseases, offering promising benefits over existing treatments. The FDA bases these approvals on outcomes like tumor response rate, pending more definitive data on survival outcomes. In this case, the accelerated approval stemmed from clear evidence of better response rates and a longer duration of response in the new combination versus standard chemotherapy options.What is the BRAF Gene and the V600E Mutation?
Genes in our cells provide instructions for making proteins that keep our bodies functioning. Some genes, like BRAF, are specifically involved in cell growth and division. When the BRAF gene is mutated (abnormal), it can lead to the production of a protein that continuously signals cells to grow — even when they’re not supposed to. One particular type of BRAF mutation, called BRAF V600E, is present in around 5% to 10% of patients with metastatic colorectal cancer.
Historically, metastatic colorectal cancer driven by a BRAF V600E mutation has been more difficult to treat, and patients with this mutation have often had poorer outcomes than those without it.
Despite the significance of this mutation, many patients with advanced colorectal cancer are never tested for BRAF status. This can delay or prevent them from getting the most appropriate treatments.
Understanding whether you have a BRAF V600E mutation or any other gene changes in your tumor can make an enormous difference in your treatment plan. That’s where next-generation sequencing (NGS) or molecular testing becomes crucial.
Why Next-Generation Sequencing Matters
When you hear “molecular testing,” “genetic testing,” or “next-generation sequencing (NGS),” it refers to various techniques used to examine your cancer cells for specific gene mutations, including BRAF V600E. NGS can screen hundreds of genes at once, giving you and your oncologist a detailed profile of what’s driving your cancer.
The benefits of NGS include:
- Personalized Treatment: Instead of one-size-fits-all treatments, molecular testing lets doctors match targeted therapies to specific mutations.
- Access to Clinical Trials: If your tumor has certain biomarkers, you may qualify for clinical trials exploring the newest drugs.
- Informed Decision-Making: Understanding your cancer’s mutation profile can help weigh the risks and benefits of various treatments.
When should patients be offered next-generation sequencing?
Who benefits the most?
Molecular testing can be performed for all colon cancer patients.
“Molecular profiling is an important testing for all stages of cancer. In early stage colon cancer, it can have more predictive value where it can help predict utility of chemotherapy for cancer patients,” Dr. Aman Opneja, Medical Oncologist at Duke Cancer Center Gastrointestinal Clinic and Duke Cancer Center Raleigh, told SurvivorNet in a previous conversation
“It can also help us identify genetic syndromes, which is … more important in our younger patients with colon cancer. In advanced stages of colon cancer, it can help us understand tumor biology and also help us select the best treatment option and look for clinical trials.”
How is NGS performed?
Dr. Opneja explained that the test can be conducted via the cancer tissue that’s obtained during biopsy or surgery.
“Another way to do the testing, is it can be done via blood, where the test can pick up the cancer DNA in the blood and analyze it for the gene changes,” added Dr Opneja. This is known as liquid biopsy.
Low Rates of Testing
It might come as a surprise, but not every patient with advanced colorectal cancer receives BRAF mutation testing, even though guidelines suggest that advanced colorectal cancer patients should. Some studies indicate that only a fraction of eligible patients have their tumors genetically profiled.
This could be because of:
- Lack of awareness among patients about molecular testing
- Variation in clinical practice from one medical center to another
- Insurance or cost-related barriers
Encouraging Testing
If you or a loved one has been diagnosed with metastatic colorectal cancer, you can ask your physician, “Have I been tested for the BRAF V600E mutation?” or more generally, “Have we done comprehensive next-generation sequencing on my tumor?” By advocating for testing, you are empowering yourself with information that could directly impact your treatment path.
The New Approval: Key Takeaways
Cancer care is evolving rapidly. Each year brings new discoveries and refined treatments that can better target tumor pathways, improve quality of life, or both. This FDA approval of encorafenib, cetuximab, and mFOLFOX6 for BRAF V600E-mutant metastatic colorectal cancer is a testament to how far the field has come — even compared to just a few years ago.
Benefits of this approach include:
- Increased Response Rates: The 61% overall response rate in the BREAKWATER trial underscores the potential of blocking BRAF and EGFR simultaneously while using chemotherapy to further attack rapidly dividing tumor cells.
- Longer Disease Control: A median duration of response of nearly 14 months is significant; for many, it can mean more time to spend with loved ones, continue work, or accomplish personal milestones.
- Potential First-Line Use: This regimen doesn’t just come after other drugs have failed; it can be an up-front option for those newly diagnosed with BRAF V600E-mutant mCRC, granting patients a more tailored approach right from the start.
Of course, no one treatment is right for everyone. But if testing reveals your tumor harbors a BRAF V600E mutation, the path forward may include a therapy backed by robust data. And if you don’t have a BRAF V600E mutation, next-generation sequencing may reveal other mutations or genomic alterations that are also “druggable.”
The BREAKWATER Trial: A Closer Look
The FDA approved this new treatment (encorafenib + cetuximab + mFOLFOX6) mostly because of results from a research study called BREAKWATER.
People with metastatic (advanced) colorectal cancer who also had the BRAF V600E mutation took part in the study. They had good or fairly good health overall.
The following treatments were tested:
- Encorafenib + Cetuximab + mFOLFOX6 (the new combination)
- Encorafenib + Cetuximab (without chemotherapy)
- Chemotherapy alone (for example, mFOLFOX6, FOLFOXIRI, or CAPOX, sometimes with another drug called bevacizumab)
It was open-label, so everyone knew which treatment they got (no one got a “secret” treatment).
Researchers wanted to see how many patients’ tumors got smaller (Objective Response Rate, or ORR). They also checked how long those responses lasted, how long it took for cancer to worsen, overall survival, and how safe each treatment was.
The results showed:
- 61% of patients on encorafenib + cetuximab + mFOLFOX6 had their tumors shrink.
- 40% of patients on regular chemotherapy had their tumors shrink.
This difference was big enough that scientists said it was clearly better.
Patients on the new combination had a median of 13.9 months before their cancer started growing again. Those on regular chemotherapy had a median of 11.1 months.
Were there any side effects?
Common side effects (seen in at least a quarter of patients) included nausea, rashes, feeling tired, tingling in fingers or toes, diarrhea, having less of an appetite, vomiting, bleeding, belly pain, and fever.
Some serious side effects included very high levels of an enzyme called lipase, and low levels of neutrophils (a type of white blood cell). These happened in some patients at grade 3/4 severity.
In short, the BREAKWATER trial showed that adding encorafenib and cetuximab to mFOLFOX6 helps more patients shrink their tumors and keep that benefit longer than regular chemotherapy alone, though it can come with certain side effects that doctors carefully watch for.
Questions to Ask Your Doctor
Being an engaged participant in your own treatment can help you feel more in control. Here are a few points you may want to address with your oncology team:
- Have we done comprehensive next-generation sequencing on my tumor?
- Have I been tested for the BRAF V600E mutation?
- Am I eligible to receive targeted therapy? Am I more, or less, likely to respond to this treatment?
- Is there a clinical trial that would be relevant for me?
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