A Treatment Evolution Is Underway in BRAF V600E–Mutated mCRC

According to the American Cancer Society (ACS), colorectal cancer (CRC) is the third most common form of cancer diagnosed in both men and women in the United States, with the ACS estimating 106,970 new cases of colon cancer and 46,050 new cases of rectal cancer in 2023.¹ Although improved cancer treatments and an increase in screening methods have resulted in identifying and managing many colorectal cancers at an earlier stage, a small subset of cases are diagnosed at an advanced stage and do not respond to conventional chemotherapy.

Nina Grenon, DNP, AGCNP-BC, AOCN

“Approximately 7% to 10% of patients with [a diagnosis of] metastatic CRC [mCRC] have a specific mutation in the BRAF gene called V600E,” Nina Grenon, DNP, AGCNP-BC, AOCN, said in an interview with Oncology Nursing News®. Grenon is a nurse practitioner in the Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. “It’s one of the rarest oncogenes, with only 1 in 10 patients [with] colorectal cancer having this mutation.”

Although median overall survival (OS) for patients with BRAF-mutated mCRC has been poor, Grenon said targeted therapies have resulted in longer progression-free survival (PFS). Patients who present with advanced CRC are therefore encouraged to undergo molecular tests to determine whether there are specific gene and protein changes that might respond well to targeted therapy drugs.

Grenon said that patients with metastatic and advanced CRC should have multipaned somatic tumor and germline testing done. Biomarker expression is driving treatment decision-making. “CRC with a BRAF mutation is a more aggressive form of cancer that doesn’t respond to standard chemotherapy. It is more common in women [older than] 70 [years]. The tumor is likely to be poorly differentiated and located on the proximal colon. Patients may present with pain on the right side of the abdomen,” Grenon said. “Their tumors tend to be larger at the time of diagnosis, typically with metastatic disease in the peritoneum vs the liver, leading to a larger burden of symptoms.” The current standard therapies for first-line management of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus or minus bevacizumab in patients with good performance status.²

In April 2020, pretreated patients with BRAF-mutated mCRC were offered a new treatment option when the FDA approved the BRAF inhibitor encorafenib (Braftovi) in combination with cetuximab (Erbitux), an EGFR inhibitor, for this patient population.³ “These drugs have been shown to help patients live longer without the risk of serious adverse events [AEs],” Grenon said. “Encorafenib inhibits BRAF and cetuximab targets EGFR.”

The FDA’s approval of the combination was supported by findings from the phase 3 BEACON CRC trial (NCT02928224), in which encorafenib plus cetuximab plus or minus binimetinib was administered to 113 patients, who achieved a median PFS of 4.3 months and an objective response rate (ORR) of 19.5%. In results from the later study ANCHOR-CRC (NCT03693170) of first-line encorafenib in combination with binimetinib in patients with BRAF V600E–mutated mCRC, patients achieved a longer median PFS of 5.8 months and an ORR of 48%.^4,5 The study results also found that the triple-drug therapy was generally well tolerated with few unexpected adverse effects, with fatigue being the most commonly reported event.

In an analysis from the BEACON trial presented at the 2020 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, the combination therapy maintained longer quality-of-life outcomes compared with standard of care, although the same analysis also showed that the doublet only prolonged OS by 1 month.⁵ Moreover, safety lead-in results ahead of the phase 3 BREAKWATER study (NCT04607421) presented at the 2023 ASCO Gastrointestinal Cancers Symposium in San Francisco, California, showed that encorafenib plus cetuximab and chemotherapy were associated with antitumor activity and a tolerable safety profile in patients with BRAF V600E– mutated mCRC.⁶ Among those who received frontline encorafenib/cetuximab and modified leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) (n = 19), the ORR was 68.4% (95% CI, 46.0%-84.6%). Of the 68.4% of patients who achieved a response in this group, 5.3% had a complete response, 63.2% had a partial response, 21.1% had stable disease, and 5.3% had progressive disease. The median PFS with frontline encorafenib/ cetuximab and mFOLFOX6 was 11.1 months (95% CI, 8.5-not evaluable).

According to Scott Kopetz, MD, PhD, FACP, professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, who presented the study findings, these data are encouraging and support further enrollment of the ongoing phase 3 BREAKWATER study. “We are encouraged that this combination shows a high degree of activity,” he said during the presentation.

Patient Education Is Crucial

Along with the emergence of new therapies to manage BRAF-mutated mCRC comes an increase in treatment-related toxicities that nurses need to be aware of, according to Grenon. “Depending on their severity, these toxicities can lead to dose reductions, delays, or in some cases, discontinuing therapy, which can also affect outcomes,” Grenon said. “Approximately 50% of patients being treated for BRAF-mutated mCRC experience diarrhea as an [adverse] effect, and 80% experience constipation and vomiting.”

Ambre White, BSN, RN, added that oncology nurses play a key role in educating patients and their caregivers about managing BRAF-mutated mCRC and teaching them how to identify and report early signs of neurotoxicity. White is a clinical nurse in the GI/Oncology unit at the University of Utah Huntsman Cancer Institute in Salt Lake City. “Some of the more common AEs are nausea, diarrhea, and fatigue,” she said. “[Because] nausea and diarrhea can both lead to dehydration, we want patients to report this to us as soon as possible so we can address the issue.”

Ambre White, BSN, RN

White and Grenon agreed that for oncology nurses to provide the best supportive care, it’s important to assess patients to determine whether AEs are being caused by the cancer treatment or progression of their disease. One method of assessment is using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, which grades severity based on the number of stools per day over baseline. It puts interference with activities of daily living at grade 3 and an indication for urgent intervention at grade 4.⁷

After being thoroughly assessed, patients with dehydration should receive hydration, electrolyte replacement, and dietary counseling. If a prescription medication is warranted, newer drugs such as opium tinctures, mesalamine, and cholestyramine have proven effective in helping patients on immune checkpoint inhibitors avoid or alleviate diarrhea.⁸

“Sometimes a patient will report an unusual AE such as vision problems, and it’s important to determine what could be causing the problem,” White said. “In the case of vision concerns, we’d request an ophthalmology [consultation] to help determine [whether] the AE was related to the medication.”

Another common AE with EGFR inhibitors is a skin rash, whereas with BRAF inhibitors, a painful nondermatitis reaction can occur, Grenon pointed out. Therefore, patients can get a rash from cetuximab or encorafenib. Dermatologic assessments before, during, and following treatment with cetuximab are advised with the combination (TABLE).⁹

White noted that molecular testing has dramatically changed how cancers such as BRAF-mutated mCRC are managed. Patients who have undergone molecular testing to determine whether they have mutations in KRAS, NRAS, and BRAF V600E can bypass traditional chemotherapy and begin targeted treatments.

However, despite the value of molecular testing, not all oncology patients are made aware of molecular profiling and its importance. In a study by Gutierrez et al, fewer than 60% of patients underwent testing for any of these biomarkers, a rate that had not increased since 2013.¹⁰

Research Explores New Treatment Options

Management of BRAF-mutated mCRC is continuing to evolve, with researchers studying additional therapies to improve patient outcomes. These clinical trials may also provide treatment options for patients with BRAF-mutated mCRC who have not responded to 1 or 2 prior lines of systemic therapy.

In January, Nature Medicine published findings from a clinical study assessing a combination of immunotherapy and targeted therapy in patients with BRAF V600E– mutated mCRC. Results showed that a combination of dabrafenib (Tafinlar), trametinib (Mekinist), and spartalizumab resulted in long-lasting responses for patients and suggested that targeted therapies combined with immunotherapies might improve survival times for BRAF-mutated mCRC patients.¹¹ An ongoing study (NCT05308446) sponsored by the SWOG Cancer Research Network is set to assess whether adding nivolumab (Opdivo) to an existing drug regimen of encorafenib and cetuximab will allow patients to remain on treatment longer before their cancer progresses.¹²

White, who has worked in oncology since 2006, told Oncology Nursing News that she is encouraged by the targeted therapies now being offered to help patients with rare mutations such as BRAF V600E. She hopes the new therapies being studied in clinical trials will offer longer disease-free and OS for patients and fewer AEs.

REFERENCES

1. Colorectal cancer facts & figures. American Cancer Society. Accessed March 7, 2023. https://bit.ly/3ZM009c

2. Grothey A, Fakih M, Tabernero J. Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines. Ann Oncol. 2021;32(8):959-967. doi:10.1016/j. annonc.2021.03.206

3. FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. FDA. April 9, 2020. Accessed March 7, 2023. https://bit.ly/3ZGnay3

4. 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

5. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Abstract presented at: ASCO Gastrointestinal Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 8.

6. Kopetz S, Yoshino T, Kim TW, et al. BREAKWATER safety lead-in (SLI): encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41(suppl 4):119. doi:10.1200/JCO.2023.41.4_suppl.119

7. NCCN. Clinical Practice Guidelines in Oncology. Management of immune-related toxicities, version 1.2022. Accessed November 9, 2022. http://bit.ly/3UK0VnZ

8. Hollander B, Khurana S, Jacob JS, et al. Mesalamine and cholestyramine for immune checkpoint inhibitor-mediated diarrhea and colitis. J Cancer Res Clin Oncol. Published online August 16, 2022. doi:10.1007/ s00432-022-04116-9

9. Fowler M, Tobback H, Karuri A, Fernández-Ortega P. Nursing care and management of adverse events for patients with BRAFV600E-mutant metastatic colorectal cancer receiving encorafenib in combination with cetuximab: a review. Support Care Cancer. 2023;31(4):204. doi:10.1007/s00520-023-07579-9

10. Gutierrez ME, Price KS, Lanman RB, et al. Genomic profiling for KRAS, NRAS, BRAF, microsatellite instability, and mismatch repair deficiency among patients with metastatic colon cancer. JCO Precis Oncol. 2019;3:PO.19.00274. doi:10.1200/PO.19.00274

11. Tian J, Chen JH, Chao SX, et al. Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial. Nat Med. 2023;29(2):458-466. doi:10.1038/s41591-022-02181-8

12. Adding the drug nivolumab to usual treatment for colorectal cancer that has a BRAF gene change. SWOG Cancer Research Network. Accessed March 7, 2023. https://bit.ly/3F7znU3