Scott Kopetz, MD, PhD, FACP, sheds light on encorafenib triplet and doublet options for patients with BRAF V600E–mutant metastatic colorectal cancer and other novel regimens under investigation.
Scott Kopetz, MD, PhD, FACP
The triplet of BRAF, MEK, and EGFR inhibition, as well as BRAF plus EGFR inhibition, in patients with BRAF V600E—mutant metastatic colorectal cancer (mCRC) are regimens that derive clinical benefit in this poor-prognostic population, explained Scott Kopetz, MD, PhD, FACP. Moreover, he added, it also improves quality of life (QoL) over current standard therapy.
In the randomized portion of the phase III BEACON CRC study (NCT02928224), patients with BRAF V600—mutant mCRC were randomized 1:1:1 to receive encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux); encorafenib and cetuximab; or cetuximab and irinotecan-based treatment.
Previously, results showed that the triplet regimen elicited a median overall survival (OS) of 9.0 months compared with 5.4 months in the standard-of-care arm, leading to a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.39-0.70; 2-sided P <.0001).1
In findings presented at the 2020 Gastrointestinal Cancers Symposium, data demonstrated a substantial improvement in patient-reported QoL assessments with both the triplet and doublet regimens versus the control arm in this patient population.2
Previously, the FDA granted a priority review designation to a supplemental new drug application for the combination of encorafenib and cetuximab as a treatment for patients with advanced BRAF V600E—mutant mCRC following up to 2 prior lines of therapy. The FDA is expected to decide on the application in April 2020.
In an interview with OncLive during the 2020 Gastrointestinal Cancers Symposium, Kopetz, who is the lead BEACON CRC study author, and a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, closely examined the triplet and doublet option for patients with BRAF V600E—mutant mCRC and other novel regimens being explored.
OncLive: What options are available for patients with BRAF V600E—mutant mCRC?
Kopetz: Patients who have BRAF V600E—mutant mCRC have a very poor prognosis compared with other subtypes of patients with metastatic CRC. As a result, the standard-of-care options until recently were fairly limited. A key option was acknowledging that while BRAF inhibition was able to transiently inhibit the key pathways, it takes a combination of BRAF inhibition with EGFR inhibition to maximize the clinical benefit. That was the rationale for the phase III BEACON CRC study.
Could you discuss the BEACON CRC study design?
This was a large, phase III study that enrolled more than 600 patients and looked at BRAF V600E—mutated mCRC, in the second- or third-line setting. Patients were randomized to receive either a control arm of [cetuximab plus an irinotecan-containing regimen] versus the 2 intervention arms, which is the triplet arm of BRAF, MEK, and EGFR inhibition with encorafenib, binimetinib, and cetuximab, or the doublet of encorafenib and cetuximab.
What results were presented at the 2020 Gastrointestinal Cancer Symposium?
The study met its primary endpoint, both with a higher response rate of 26% and 20% in the 2 experimental arms, triplet and doublet, respectively versus 2% in the control arm. There was also an improvement in median overall survival with the triplet at 9.0 months for the patients versus 5.4 months.
A question [from this research] is, “How does this impact the quality of life for our patients?” This was the focus of updated data being presented here at the 2020 Gastrointestinal Cancers Symposium.
What is your strategy for determining an optimal strategy for patients with mCRC?
The data are looking at how to optimally treat these patients. We know that patients with a BRAF V600E mutation should be treated differently than others. This is showing that aggressive chemotherapy may be effective initially, but the duration of benefit from standard cytotoxic chemotherapy is less than we see in others. You have to think about how you address the targeting of the BRAF mutation itself.
We think about this population as a very distinct entity, as it is. At a biologically level, the precursor lesions, polyps, and the activated carcinogenic pathways are different. The clinical outcomes are different for these as well.
What is the current standard of genomic testing for patients with mCRC?
For the current standard of care, the guidelines are to incorporate testing, at a minimum for KRAS, BRAF, and NRAS, as well as for microsatellite instability status. We increasingly recognize that other subgroups may have therapies that are considered to be the standard of care, including HER2 amplification and NTRK fusions. These are subgroups that either have therapies [listed] on the guidelines or are FDA approved.
Traditionally, this testing is done with a next-generation sequencing panel combined with either immunohistochemistry for mismatch repair deficiency and HER2, although there are other methods to evaluate those [markers]. The key is to try to obtain the information quickly. This means not doing the testing later in treatment but when the patient walks in the door with metastatic disease. We have to get that molecular information back to the patients, so that we can understand what path they're going to follow over subsequent lines of therapy.
Some data suggest that there may be differences in a mutation that can occur over time. The most well-described data are on resistance mechanisms that can develop to EGFR inhibition. However, they can also regress over time. There's an idea, that with time, there may be opportunities to re-challenge with several EGFR inhibitors.
Similarly, we are finding acquired alterations to BRAF-targeted therapies, a better understanding of how that occurs, and what the patterns are of those mutations. This remains an area of continued research in many trials, including the BEACON CRC study.
What is an ongoing treatment challenge with this patient population?
For patients with BRAF V600E mutations, while we're encouraged by the response rate, survival, and maintenance of the quality of life that we see with targeted therapies; we are always wanting to do better and get longer duration of benefit. We also want to find therapies that intercept the mechanisms of resistance. We're building on the new standard of care that has been established for the population and asking, “How do we come up with better regimens to follow?”
What data with nivolumab (Opdivo) and regorafenib (Stivarga) are being presented at this meeting?
[The combination of] regorafenib and nivolumab has a lot of interest based on an early study out of Japan, which showed a high response rate above 30% in CRC, including microsatellite stable mCRC. There are many similar confirmatory single-institution and multi-institution phase II studies that are ongoing, and we're looking forward to seeing these data.
There is a lot of hope in the field that this may indeed provide some benefit, but also a recognition that this is something that we have to replicate in a larger population and better define the benefit, in order to understand how to move forward with this. If this signal is confirmed, the hope is that this could lead to more definitive randomized phase III studies, such as one that's planned to get this combination across the finish line and make more broadly available to patients.
Are there any other combination studies in mCRC that appear to be promising?
This an area where we're continuing to follow some interesting promising biology. However, the list of studies that have shown reproducible clinical benefit with these novel combinations remains low. The number of combinations that have that proof of component for clinical benefit remains a challenge.
The goal for the field is to continue to explore broadly and understand the refractory nature of any patients with mCRC. In general, the area of interest is, how do we target KRAS? There is some promise on KRAS G12C inhibitors. How do we improve on targeting HER2? Can we continue to improve the outcomes that we are seeing with the agents currently on the National Comprehensive Cancer Network guidelines for HER2? Whether that's using antibody-drug conjugates, or other combinations of tyrosine kinase inhibitors and monoclonal antibodies, remains to be seen.