BRAF Inhibition Offers New Standard of Care in for Colorectal Cancer

Colorectal cancer is the fourth most common cancer diagnosis in the United States and is associated with significant morbidity and mortality.¹ Although incidence appears to be declining overall, there is a concerning trend of increasing prevalence among patients under age 50 years for reasons not entirely understood. Hypotheses include factors such as generational changes in diet, lifestyle, and environmental exposures. Most patients present with localized disease.

However, approximately 50% to 60% of patients will progress to metastatic colorectal cancer (mCRC) after locoregional therapy is unsuccessful.²
As such, much recent research has aimed to improve disease response and overall survival (OS) in patients with metastatic disease, particularly after traditional chemotherapy is unsuccessful and for patients with targetable mutations.

BRAF mutations are present in approx- imately 5% to 15% of mCRC cases and represent an important therapeutic target.³ National Comprehensive Cancer Network (NCCN) guidelines recommend screening all patients upon diagnosis of mCRC for the presence of a BRAF mutation.⁴ Unfortunately, BRAF mutations are associated with poor prognostic factors, such as more invasive tumors, poor cellular differentiation, and right-sided heart failure. Patients with BRAF-mutated colorectal cancers have demonstrated poorer OS and diminished responses to treatment, particularly the antivascular EGFR inhibitors cetuximab and panitumumab when given as monotherapy. BRAF V600E is an activating mutation that perpetuates cellular growth and downstream signaling via MEK activation in the mitogen-activated protein kinase (MAPK) pathway.³ When BRAF inhibitors are used alone, EGFR signaling is upregulated, resulting in continued cell proliferation and survival. This led investigators to study the combination of BRAF inhibition, MEK inhibition, and an anti-EGFR monoclonal antibody (mAb) to synergistically block feedback signaling and cancer cell proliferation.

The BEACON trial (NCT02928224) was an open-label, phase 3 trial of patients
with mCRC after not achieving success with at least 1 prior line of therapy and randomized patients 1:1:1 to receive triplet therapy (encorafenib, binimetinib, and cetuximab), doublet therapy (encorafenib and cetuximab), or control (cetuximab, with either FOLFIRI [folinic acid, fluorouracil, and irinotecan] or irinotecan).⁵ At the time of the prespecified interim analysis, the results showed improved OS of 9 months with triplet therapy vs 5.4 months with the control (HR, 0.52; 95% CI, 0.39-0.70; P < .001). Grade 3 or greater adverse effects (AEs) were more common in patients receiving control compared with doublet or triplet therapy (61%, 50%, and 58%, respectively). The most common AEs in the triplet-therapy group included acneiform rash, diarrhea, and nausea.

In 2021, updated analyses of the BEACON trial were published and included 6 additional months of survival and objective response rates (ORRs) for all patients.⁶ With a median of 12.8 months of follow-up at the time of data cutoff, both doublet and triplet therapy were associated with 9.3 months’ OS compared with 5.9 months in the control group, representing an approximately 40% reduction in risk of death (HR for triplet, 0.60; 95% CI, 0.47-0.75). Although the trial was not adequately powered to compare the doublet and triplet therapy arms, this study demonstrated similar outcomes with respect to OS and response rates. As anticipated, the rates of grade 3 or greater toxicities were still higher in the triplet-therapy arm compared with doublet therapy in the final analysis. Quality of life also improved for patients receiving doublet or triplet therapy vs the control.⁷ Based on these findings, the investigators concluded that the OS benefit could be maintained with the doublet therapy of encorafenib and cetuximab, and the regimen received FDA approval in April 2020 for patients with mCRC and a BRAF V600E mutation after not achieving success with at least 1 prior line of therapy.

Encorafenib is given as a once-daily dose of 300 mg in four 75-mg capsules and can be administered with or without food.⁸ There are important AEs associated with BRAF inhibitors that warrant careful monitoring and patient education, including an increased risk of new primary malignancies, such as basal cell and cutaneous squamous carcinomas. Of note, significant dermatologic toxicities are more likely when encorafenib is used without concomitant MEK inhibition. Patients should have comprehensive dermatologic evaluations every 2 months during treatment and for up to 6 months
after completion. Prolongation of QTc is also possible. Baseline and periodic monitoring may be warranted in high-risk patients.

As demonstrated in the BEACON trial, BRAF inhibition in combination with an anti-EGFR mAb yielded clinically significant improvements in OS and ORR over standard therapy. The BEACON trial included binimetinib, a MEK inhibitor, along with encorafenib and cetuximab. However, there was no additional benefit in terms of OS and higher rates of toxicity. Although the BEACON trial used cetuximab for EGFR inhibition, panitumumab is considered therapeutically equivalent and may be substituted based on institutional or provider preferences. Given these findings, NCCN guidelines recommend doublet therapy with encorafenib and either cetuximab or panitumumab for patients with BRAF V600E–mutant mCRC who have progressed after at least 1 prior line of therapy.

Michelle Phillips, PharmD, BCOP, is a clinical pharmacist oncology specialist of gastrointestinal and neuro oncology at the University of Rochester Specialty Pharmacy/Wilmot Cancer Center in New York.

References

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3. Molina-Cerrillo J, San Roman M, Pozas J, et al. BRAF mutated colorectal cancer: new treatment approaches. Cancers (Basel). 2020;12(6):1571. doi:10.3390/cancers12061571

4. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 3.2021. Accessed February 1, 2022. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf

5. 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

6. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39(4):273-284. doi:10.1200/JCO.20.02088

7. Kopetz S, Grothey A, Van Cutsem E, at al. Encorafenib plus cetuximab with or without binime- tinib 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). J Clin Oncol. 2020;38(suppl 4):8. doi:10.1200/JCO.2020.38.4_suppl.8

8. Braftovi. Prescribing information. Array Biopharma; 2018. Accessed February 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf