Continued OS Advantage With Encorafenib/Cetuximab Cements Role in BRAF+ mCRC

Scott Kopetz, MD, PhD, FACP

Updated data from the pivotal phase 3 BEACON CRC study continue to solidify the importance of identifying BRAF V600E mutations early in patients with metastatic colorectal cancer (mCRC), said Scott Kopetz, MD, PhD, FACP.

At the 2020 ASCO Virtual Scientific Program, updated findings from the BEACON CRC study continued to demonstrate improved overall survival (OS) and objective response rates (ORR) for encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) versus standard chemotherapy in patients with previously treated BRAF V600E—mutant mCRC.¹

The median OS was 9.3 months with the triplet regimen (95% CI, 8.2-10.8), 9.3 months with the doublet regimen (95% CI, 8.0-11.3), and 5.9 months with the control regimen (95% CI, 5.1-7.1). The confirmed ORRs were 27%, 20%, and 2%, respectively.

On April 8, 2020, the FDA approved the combination of encorafenib and cetuximab for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

The approval was based on earlier BEACON CRC findings, in which encorafenib plus cetuximab with or without binimetinib improved OS and ORRs versus cetuximab plus irinotecan-containing regimens in this patient population.²

"We hope that patients will now get broader access to the combination of encorafenib and cetuximab for the improved survival rates and response rates," said Kopetz. "We now have approved therapies that can improve survival for patients [with BRAF V600E—mutant mCRC], so we want to ensure we identify these patients as soon as possible. It is important to understand the molecular features of a patient's cancer very early in the disease course."

In an interview with OncLive, Kopetz, an associate professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, discussed the latest findings from the BEACON CRC study, the importance of testing for BRAF mutations in patients with CRC, and future directions with these agents.

OncLive: Could you provide a rationale for the triplet in this patient population?

Kopetz: The patients of interest are those with a BRAF V600E mutation in their tumor. [BRAF V600E—mutant CRC] is a subtype of CRC that is associated with poor prognosis. Until recently, there were no good, standard-of-care therapies.

The rationale for this study design was based on the recognition that BRAF inhibition alone is not associated with substantial regression in tumors due to a rapid tumor adaptation. The tumor utilizes feedback mechanisms through a number of growth factor receptors, most prominently EGFR.

The rationale for the BEACON CRC study was to try to understand how we can maximize the pathway inhibition while intercepting that resistance mechanism.

What prior data were seen with the triplet?

BEACON CRC is a 3-arm international study that included patients [who received] 1 or 2 prior lines of therapy. These patients were enrolled into 1 of 3 different arms: a control arm of FOLFIRI and cetuximab, a [triplet arm] of encorafenib, binimetinib, and cetuximab, and a [doublet arm] of encorafenib and cetuximab alone.

These results were previously published and showed an improvement in OS and higher ORR with the 3-drug regimen compared with the control regimen.

At the 2020 ASCO Virtual Scientific Program, we presented updated data with mature follow-up and response rates for the totality of the population. We looked at the differences between the 2-drug regimen and the 3-drug regimen.

What did the updated survival data presented at the meeting demonstrate?

The updated survival data that were presented at the 2020 ASCO Virtual Scientific Program is based on the response rate in all patients. Previously, we had reported only the first half of patients per the preplanned analysis. The updated data includes more mature follow-up.

The primary finding was that the OS in the 2 experimental arms both reached 9.3 months, which was superior to the control arm at 5.4 months. In addition, response rates were 27% and 20% with the [triplet and combination arms], respectively. The control arm had a 2% response rate.

How do the safety profiles of the triplet and doublet regimens compare with each other?

Overall, the safety data demonstrated that the regimens were well tolerated and consistent with their prior safety profiles. The treatment discontinuation rate was low; however, numerically, there was a slightly higher rate of discontinuation in the arm that included binimetinib.

Rates of notable, severe [treatment-related] adverse effects were very low, and the rate of patient compliance to the regimens was high.

What do we hope to see with longer follow-up?

While we have mature OS data now, we are hoping to further interrogate the potential subsets of patients that may benefit from 1 regimen versus the other.

Although this is certainly exploratory, we observed a trend suggesting patients with more aggressive disease, high inflammatory states, or poor performance status could derive more benefit with the addition of the MEK inhibitor.

Also, we want to understand the mechanisms of resistance using circulating tumor DNA and tumor profiling with RNA signatures to understand if there are subsets of patients who may derive additional benefit from this treatment compared with others.

What are your thoughts on the recent FDA approval of encorafenib/cetuximab in patients with BRAF V600E—mutant CRC?

We are pleased to see that this study has indeed resulted in an FDA approval of the combination of encorafenib and cetuximab. This provides more therapeutic options for patients with BRAF V600E—mutant tumors. Moreover, this is especially [significant] given the poor prognosis associated with this subgroup of patients.

The hope is that we will be able to build on this doublet regimen with additional therapies to improve patients' initial exposure to targeted therapies with BRAF [inhibitors], perhaps in combination with chemotherapy, additional targeted agents, or immunotherapy.

Finally, we hope to use this as a building block to better understand vulnerabilities at the time of progression to then target with subsequent therapies.

What is your take-home message to your colleagues?

One of the key messages we hope to leave people with is that testing for BRAF should be part of standard practice for every patient with mCRC, and it should be incorporated along with KRAS and NRAS testing.

References

1. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020;38(suppl 15; abstr 4001). doi:10/1200/JCO.2020.38.15_suppl.4001
2. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi:10.1056/NEJMoa1908075