Encorafenib Combination Approval Paves the Way Forward in BRAF V600E–Mutated CRC

The FDA approval of encorafenib (Braftovi) plus cetuximab (Erbitux) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) changes the BRAF V600E–mutated metastatic colorectal cancer (CRC) treatment paradigm, opening the door for frontline therapy with a targeted therapy/chemotherapy combination, according to E. Gabriela Chiorean, MD, FASCO.1

“Until now, patients with BRAF V600E–mutated CRC have [only] had access to targeted therapy with the encorafenib plus cetuximab doublet in the second-line setting, after progression on standard chemotherapy,” Chiorean said. “Nevertheless, BRAF V600E-mutated CRC tends to be quite aggressive, and overall survival [OS] with first-line chemotherapy, even with FOLFIRINOX plus bevacizumab, is less than 18 months. The fact that we now have an effective first-line FDA approved regimen for patients with BRAF V600E mutations with encorafenib plus cetuximab and mFOLFOX6 emphasizes the need for very rapid genomic profiling of patients’ tumors or blood at the time of diagnosis such that we are aware of their BRAF status and are able to implement this regimen in the frontline.”

Findings from the phase 3 BREAKWATER trial (NCT04607421), which supported the regulatory decision, showed that patients with treatment-naive BRAF V600E mutation-positive metastatic CRC experienced an objective response rate (ORR) of 61% (95% CI, 52%-70%) when treated with encorafenib plus cetuximab and mFOLFOX6 (n = 110) vs 40% (95% CI, 31%-49%) when treated with physician’s choice chemotherapy with or without bevacizumab (Avastin; n = 110).2 The median duration of response (DOR) was 13.9 months (95% CI, 8.5-not estimable) vs 11.1 months (95% CI, 6.7-12.7), respectively.

In an interview with OncLive®, Chiorean detailed the significance of the FDA approval and data to look forward to in the future. Chiorean is clinical director of the GI Medical Oncology Program, professor in the Clinical Research Division, and affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutch. She is also a professor of medicine at the University of Washington and director of the Clinical Research GI Oncology Program at the University of Washington/Fred Hutch in Seattle.

OncLive: What efficacy and safety data are important to note from BREAKWATER?

Chiorean: Patients with BRAF V600E mutations have a very poor prognosis and generally with standard chemotherapies, including with triplet chemotherapy such as FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin], the outcomes are not great; OS rates range from 14 to 17 months. Moreover, in the second-line setting with encorafenib plus cetuximab targeted therapies, the progression-free survival [PFS] is only approximately 4 months and the second line OS averages 9 months. Therefore, having a first-line treatment option for which the response rates are promising at 61% [is exciting]. We are very much anticipating the OS and PFS data, but the response rate of 61% and DOR of approximately 14 months looks extremely favorable knowing that the response rate with chemotherapy alone was only 40%. Our patients need any help we can provide as fast as possible for better outcomes starting with [the] first-line [setting] because chemotherapy alone is simply not good enough. We also witness many patients deteriorate after first-line therapy and do not have the opportunity to access second-line treatment.

mFOLFOX6 plus encorafenib and cetuximab is a very safe regimen [as well]. The main toxicities were the expected ones of neuropathy related to oxaliplatin and rash and diarrhea [resulting from treatment] with encorafenib and cetuximab. Overall, it is a well-tolerated, safe regimen that is readily applicable in real life community practices.

We must implement prompt testing for genomic alterations from the outset, from blood or tumor samples.

How could this approval fill an unmet need for patients with CRC?

We have no other approvals that are incorporating targeted therapies in the first-line setting for patients with [metastatic CRC and a] BRAF V600E mutation. Chemotherapy plus BRAF [targeting] plus EGFR targeting is tolerable, and clearly superior to chemotherapy alone; it is the new standard. The question is what are we going to do after patients progress? What is going to be our go to regimen in the second-line setting and beyond? Currently, we have encorafenib [plus] cetuximab with response rates of approximately 20% and a PFS of only 4 months approved for the second-line treatment of patients treated with chemotherapy with or without bevacizumab in the first line. We will likely go to FOLFIRI chemotherapy next.

Novel research will need to address whether we should continue chemotherapy plus BRAF targeted therapy after progression on encorafenib plus cetuximab for patients with cancers that maintain BRAF V600E–mutated status. My other question is whether BRAF-targeted therapy plus chemotherapy in the first line offers a longer PFS2 (progression from the start of first line to the end of second line therapy) and longer OS than if we sequence chemotherapy in the first line with BRAF targeted therapies in [the] second line. This is an important question that we hope to see results of soon.

What other aspects of this regimen’s approval are notable?

It was a surprise to see an FDA approval based solely on response rates without long-term efficacy outcomes [reported]. [However], we do sometimes see accelerated approvals especially in tumor types of huge medical need and we do have a huge unmet need in BRAF-mutated CRC. We expect to see the longer-term survival data imminently and we hope that those are positive data. It was also very encouraging to see that BRAF-targeted therapies in combination with FOLFIRI [leucovorin, fluorouracil, and irinotecan] had incredible response rates of approximately 80% when used in first line treatment, and these data were presented [from BREAKWATER] at the 2024 ESMO Congress, but they are preliminary.

In all, the addition of BRAF-targeted therapy to chemotherapy in the first-line treatment of BRAF V600E–mutated CRC is tolerable and induces rapid and durable responses. Albeit we eagerly await PFS and OS data, these results are practice changing and emphasize the need for testing our patients’ genomic status (BRAF V600E mutation status in addition to KRAS, NRAS, microsatellite instability) with blood and/or tumor molecular profiling as soon as possible after diagnosis.

References

1. U.S. FDA approves Pfizer’s Braftovi combination regimen as first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. News release. Pfizer. December 20, 2024. Accessed January 15, 2025. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-combination-regimen-first
2. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed January 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf