Kopetz Highlights Recent Advances in BRAF-Mutant CRC

Scott Kopetz, MD, PhD, FACP

Scott Kopetz, MD, PhD, FACP

While only about 5% of patients with metastatic colorectal cancer (CRC) haveBRAFmutations, patients in this subgroup have a poor prognosis, and more effective targeted therapies are needed, according to Scott Kopetz, MD, PhD, FACP.

However, data from recent clinical trials, such as the phase III BEACON trial and the phase II SWOG 1406 trial, indicate that this challenge is being addressed.

In August 2018, the FDA granted a breakthrough therapy designation to the combination of the BRAF inhibitor encorafenib (Braftovi), the MEK inhibitor binimetinib (Mektovi), and the EGFR inhibitor cetuximab (Erbitux), for the second- or third-line treatment of patients with metastaticBRAFV600E—mutant CRC, based on data from the BEACON trial. Results showed that the confirmed overall response rate (ORR) was 48% and the 1-year overall survival (OS) rate was 62% with the 3-drug regimen.¹

SWOG 1406 was a randomized study of irinotecan and cetuximab with or without vemurafenib (Zelboraf), showing that the addition of vemurafenib led to a prolonged progression-free survival (PFS) and a higher disease control rate. The median PFS was 4.4 months with vemurafenib versus 2.0 months with irinotecan and cetuximab alone (HR, 0.42; 95% CI, 0.26-0.66;P<.001).²The disease control rate was 67% versus 22% in favor of the combination with vemurafenib.

In an interview withTargeted Oncology, Kopetz, an associate professor in the Department of Gastrointestinal Medical Oncology and the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the current treatment landscape of CRC and the importance of molecular subtyping.

TARGETED ONCOLOGY:How would you describe the current CRC treatment landscape?

Kopetz:This is an area that has been actively developed over the past year. There are a number of molecularly defined subtypes for colon cancer. We're certainly well aware of the idea ofKRASmutations andNRASmutations as being part of [the molecular workup of this disease]. There are novel evolving biomarkers and therapies associated with them.

The first one we discussed wasBRAFmutations. This is a subgroup that represents about 5% of metastatic CRC, but it is a group with a very poor prognosis. The tumor is very aggressive. The therapies we have for this disease in terms of standard chemotherapy are just not very effective. This subgroup is predominately the V600E alteration inBRAF. There are a number of therapies that have been developed, but over the past year there was a recent addition to the standard of care. It was based on a randomized study, SWOG-1406, which looked at a population in either the second- or third-line setting, treated with cetuximab and irinotecan versus the combination with vemurafenib. This is the so-called VIC regimen.

The triplet demonstrated an improvement in PFS, with a hazard ratio of approximately 0.5. It met its primary endpoint and improved disease control rates. As a result of that study, it was added to the National Comprehensive Cancer Network (NCCN) guidelines. It's now considered a standard therapy for second- or third-line treatment for patients withBRAFV600E tumors.

TARGETED ONCOLOGY:What are other recent data withinBRAF-positive CRC you are particularly excited about?

Kopetz:We also tested encorafenib, binimetinib, and cetuximab. It had a very promising response rate of about 48% with a median PFS of about 8 months. It&rsquo;s an ongoing randomized phase III trial. WithinBRAF-positive disease, a lot of advances have been made this year. There has been a new addition into the NCCN guidelines, as well as this promising combination.

Remember,BRAFcan also be mutated in other areas besides V600E, and there are some interesting updates in understanding the biology of what we consider to be non-V600E mutations. They don't all behave the same. Again, there have been some interesting data and we hope to see more trials looking at this. These kinds of mutations only affect about 2% of patients with CRC. It's an area of interest.

TARGETED ONCOLOGY:What other subgroups have been recently addressed?

Kopetz:There have also been developments inHER2amplification. This is something we've been following in the field for several years. There is increasing evidence that perhaps this is a reason for resistance to EGFR inhibitors. A number of studies have also demonstrated that HER2-amplified tumors are sensitive to combination therapies. Trastuzumab (Herceptin) in combination with pertuzumab (Perjeta) is the one being highlighted the most. There are combinations being tested in Europe with different agents, as well.

Another area that was discussed included evidence of activity in fusions. A proportion of patients with CRC have fusions, such asRETandALK. Those are very promising. Patients who have these fusions have impressively high response rates to these particular inhibitors. The durability of these responses also remains very promising. For many of them, the OS has not been reached yet in these studies.

The difficulty here is that this a very uncommon patient population. These fusions are rare in CRC. The other hurdle is these fusions coexist with microsatellite instability (MSI). We know that MSI is associated with an excellent response to either PD-1 inhibition or PD-1/CTLA-4 combination regimens. This is a population with very durable control with immunotherapy.

The theme in all of this is that we're looking for smaller and smaller subsets. At the same time that we're thinking about doing DNA-based strategies, there is also interest in trying to evaluate convergent biology. Overall, there is a lot of interest in the field of CRC, and we're heading in the right direction. Where we are going next includes a number of immunotherapy studies.

TARGETED ONCOLOGY:What is the importance of genetic testing?

Kopetz:On the basis of this information, the key question I'm asked is, "OK, I have a patient in front of me in the clinic. What type of testing do I do?" The current guidelines strongly recommend MSI testing. You should do this in every patient with CRC, regardless of the stage. It has important implications for family, but also for availability of novel immunotherapy. Other testing that should be done is forKRAS,NRAS, andBRAF. Those should be considered standard at this point.

References:

1. Array Biopharma Receives FDA Breakthrough Therapy Designation for Braftovi&trade; in Combination With Mektovi&reg; and Cetuximab For BRAFV600E-Mutant Metastatic Colorectal Cancer. Array BioPharma Inc. Posted August 7, 2018. Accessed August 7, 2018. https://bit.ly/2vJUhEA.
2. Kopetz S, McDonough S, Van Karlyle M, et all. Randomized trial of irinotecan and cetuximab with or without vemurafenib inBRAF-mutant metastatic colorectal cancer (SWOG 1406). 2017;35(suppl 4; abstr 520). doi:10.1200/JCO.2017.35.4_suppl.520.