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BRAF Inhibitors in CRC
Combination Therapy With BRAF Inhibitors: A New Frontier in BRAF-Mutant CRC

Released: August 14, 2017

Expiration: August 13, 2018

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I’d like to share one of my cases with you that illustrates my thoughts about managing patients with BRAF V600E–mutated colorectal cancer (CRC). My patient was a 58-year-old woman with BRAF V600E–mutated CRC as well as extensive peritoneal disease and ovarian implants. Her disease had progressed on first-line standard-of-care chemotherapy within 4 months.

We enrolled her in the phase II SWOG S1406 study—which I will discuss in more detail below—and she received the BRAF inhibitor vemurafenib in combination with irinotecan and cetuximab (VIC). Although she developed treatment-associated arthralgia, it was managed with nonsteroidal antiinflammatory drugs. She responded well but did not quite meet the formal criteria for a partial response: There was a good reduction in the size of her peritoneal disease, and the cramping abdominal pain that she had been experiencing improved. She has been on therapy for more than 14 months, and I am happy to report that she is continuing treatment with good disease control.

BRAF -Mutated CRC: An Unmet Clinical Need
Approximately 8% of patients with metastatic CRC have a BRAF mutation that is associated with a poor prognosis and unique biology. BRAF-mutated tumors are commonly identified in the right side of the colon, and they arise out of the sessile serrated adenoma pathway. When these tumors metastasize, they spread more commonly via peritoneal disease and/or to distant lymph nodes than do BRAF wild-type tumors.

Presently, the median survival period among patients diagnosed with BRAF V600E–mutated CRC is approximately 11 months compared with approximately 43 months among patients with BRAF wild-type disease. There is limited activity with standard chemotherapy and EGFR inhibitors in BRAF-mutated CRC. Thus, although guidelines now encourage BRAF testing, CRC with a BRAF V600E mutation represents a substantial unmet need.

BRAF Inhibitors in Patients With CRC
Unlike in BRAF-mutated melanoma, single-agent BRAF inhibitors have not been effective for patients with CRC due to feedback activation of EGFR. However, preclinical and early-phase studies suggested that the combination of a BRAF inhibitor with an EGFR inhibitor could offer benefit. This combination was investigated in the phase II SWOG S1406 trial that my patient was enrolled in.

In the SWOG S1406 study, patients with BRAF V600E–mutated metastatic CRC who had been treated with 1-2 lines of chemotherapy were randomly assigned to receive IC or VIC, which is an inhibitor that is selective for mutated BRAF kinase. As we reported at ASCO 2017, the trial met its primary endpoint of PFS: The triple combination (VIC) was associated with a significantly longer median PFS of 4.3 months vs 2.0 months with IC (HR: 0.48; P = .001). The disease-control rate was 67% vs 22% with VIC vs IC, respectively. There was a trend toward improved OS, with approximately one half of IC-treated patients crossing over to VIC treatment at the time of progression. The disease-control rate on crossover was 72%.

The safety profile of VIC was acceptable. There were increased rates of anemia, nausea, and neutropenia, and 16% of patients discontinued treatment with VIC due to adverse events vs 6% with IC. The addition of vemurafenib was also associated with arthralgia in 7% of treated patients, including my patient.

Encouragingly, subgroup analyses indicated that responses occurred regardless of tumor location or microsatellite instability (MSI) status. Therefore, this regimen appears to be broadly active among patients with advanced CRC and BRAF V600E mutations.

BRAF Inhibitors: Clinical Applications and Future Directions
As a result of these promising results, the VIC regimen is increasingly being used in the clinic, and insurance companies have been reimbursing patients for it in the United States. However, it is not yet approved by the FDA or listed in guidelines, so its use requires a case-by-case discussion with the insurance companies. In my practice, I would consider VIC for a patient with BRAF V600E–mutated metastatic CRC whose disease had progressed on first-line therapy.

BRAF inhibitors are currently being investigated in other trials. For example, patients are currently being recruited for a phase III study to evaluate a BRAF inhibitor combined with EGFR and MEK inhibitors. Furthermore, because the BRAF-mutated population is enriched for MSI high—approximately 50% of patients with BRAF mutation also have MSI-high tumors—studies involving the combination of BRAF inhibitors with immune checkpoint inhibitors are also being developed.

Your Thoughts?
Do you test for BRAF V600E mutation in your patients with newly diagnosed CRC? Please share your feedback below.

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In your current practice, would you consider VIC for your patients with BRAF V600E–mutant metastatic CRC after progression on chemotherapy?
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