Scott Kopetz, MD, PhD, FACP
-mutant colorectal cancer (CRC), a subtype that comprises approximately 6% to 7% of patients overall, is an area in need of more effective targeted therapies, said Scott Kopetz, MD, PhD, FACP.
Recent data, however, particularly from the phase III BEACON and phase II SWOG 1406 trials, 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 metastatic BRAF
V600E–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
The disease control rate was 67% versus 22% in favor of the combination with vemurafenib.
In an interview with OncLive®
, 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.
OncLive: How would you describe the current CRC treatment landscape?
: 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 of KRAS
mutations and NRAS
mutations 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 was BRAF
mutations. 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 in BRAF
. 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 with BRAF
What are other recent data within BRAF-positive CRC you are particularly excited about?
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’s an ongoing randomized phase III trial. Within BRAF
-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.
can 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.
What other subgroups have been recently addressed?
There have also been developments in HER2
amplification. 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.