Encorafenib With Cetuximab and mFOLFOX6 Receives Accelerated Approval for Patients With Metastatic Colorectal Cancer

The FDA granted encorafenib (Braftovi; Pfizer Inc) with cetuximab (Erbitux; Eli Lilly and Company) and mFOLFOX6 (5-Fluorouracil, leucovorin, and oxaliplatin) for treatment of patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA approved test. The decision is supported by clinically meaningful data demonstrating that capability of the combination therapy to improve response rates and durability of responses.¹

Colorectal cancer cells under microscope | Image Credit: © Navaporn - stock.adobe.com

“Historically, treatment options have been limited and outcomes poor for patients diagnosed with metastatic colorectal cancer with BRAF mutations,” Scott Kopetz, MD, PhD, FACP, professor and deputy chair of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial (NCT04607421), said in a news release. “As the first and only combination regimen featuring a BRAF-targeted therapy for this patient population, usable even in first-line treatment, the encorafenib regimen has demonstrated high response rates that are rapid and durable. This represents an encouraging sign of continued disease control and a source of renewed hope for patients.”^2,3

According to the Colorectal Cancer Alliance, CRC is the fourth most common cancer in the United States and is estimated to impact 152,810 individuals in 2024, of which 53,010 will die from the disease. Improved screening and awareness decreased rates of CRC; however, there appears to be a significant rise in cases amongst younger adults, which is attributed to diet and the potential consequences of microplastic exposure. CRC symptoms can be difficult to detect, meaning many patients have progressed to later stages of disease. Once metastatic, patients’ prognoses typically worsen, particularly those with BRAF mutations.^4,5

Encorafenib is an oral small molecule kinase inhibitor that targets BRAF V600E and is used for various types of cancer. In the open-label, multicenter, randomized phase 3 BREAKWATER trial, it demonstrated significant success when combined with cetuximab and mFOLFOX6. In the study, the investigators compared first-line encorafenib plus cetuximab with or without chemotherapy and standard of care therapy with a safety lead-in of encorafenib and cetuximab plus chemotherapy. They aimed to identify whether encorafenib plus cetuximab, alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy.^1,2

The trial randomized patients with treatment naïve BRAF V600E mutation-positive mCRC in a 1:1 ratio into 2 treatment arms: encorafenib orally once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks, or mFOLFOX6, FOLFOXIRI (both every 2 weeks) or CAPOX (every 3 weeks)-each with or without bevacizumab, the control arm.^1,2

According to the data, patients receiving the combination therapy achieved an overall response rate (ORR) of 61% (95% confidence interval [CI]: 52, 70), compared with a rate of 40% in the control arm (95% CI: 31, 49; P=.0008). The researchers also reported a median duration of response (DoR) of 13.9 months (95% CI: 8.5, not estimable) and 11.1 months (95% CI: 6.7, 12.7) in the combination and control arms, respectively.^1,2

The safety profile was consistent, and the researchers reported no new safety signals. Peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia were the most common adverse effects (AEs) (≥25%). Among patients who received encorafenib in combination with cetuximab and mFOLFOX6, 12% discontinued after experiencing an AE.^1,2

“Finding out that your cancer has spread can be a frightening time for those with colorectal cancer and their loved ones. The prognosis for those receiving a metastatic colorectal cancer diagnosis has improved slightly in recent years, but the same cannot be said for those with a BRAF mutation who unfortunately face an especially aggressive disease and worse outcomes,” Michael Sapienza, CEO of the Colorectal Cancer Alliance, said in a news release. “Today’s approval of the first combination regimen including a BRAF-targeted therapy for BRAF V600E-mutant metastatic colorectal cancer, which can be used for previously untreated patients, offers new promise for the community and marks an important step forward in our collective mission to end this disease.”²

REFERENCES

1. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. December 20, 2024. Accessed December 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf

2. 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 December 20, 2024. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-combination-regimen-first

3. A Study of Encorafenib plus cetuximab with or without chemotherapy in people with previously untreated metastatic colorectal cancer. Updated December 17, 2024. Accessed December 20, 2024. https://clinicaltrials.gov/study/NCT04607421

4. Colorectal Cancer Alliance. Colorectal cancer facts and statistics. Accessed December 20, 2024. https://colorectalcancer.org/basics/facts-and-statistics#:

5. Yale Medicine. Colorectal cancer: what millennials and gen zers need to know. January 17, 2024. Accessed December 20, 2024. https://www.yalemedicine.org/news/colorectal-cancer-in-young-people