Optimizing First-Line Therapy for BRAF-Mutant Colorectal Cancer

Amanda Brink, DNP, APRN, FNP-BC, AOCNP

Oncology providers continually seek ways to improve cancer treatment. While developing new drugs is one approach, another critical strategy is optimizing existing therapies. One way to enhance treatment outcomes is by exploring novel drug combinations to determine whether they offer greater efficacy than previously used single agents or established regimens.

Understanding BRAF-Mutated Colorectal Cancer

BRAF-mutated colorectal cancer (CRC) is a distinct molecular subtype characterized by mutations in the BRAF gene, most commonly the V600E variant. These mutations occur in approximately 8-12% of metastatic CRC cases and are more frequently observed in patients with right-sided tumors. Compared to BRAF wild-type CRC, BRAF-mutated disease is associated with a poorer prognosis and resistance to standard chemotherapy regimens such as FOLFOX and FOLFIRI.¹

Targeted therapies that inhibit BRAF and MEK, often combined with EGFR inhibitors, have shown promise in improving outcomes for patients with BRAF-mutated CRC. When only BRAF is inhibited, cancer cells can bypass the blockade by reactivating the MAPK signaling pathway, leading to resistance. Adding a MEK inhibitor helps shut down this pathway more effectively, reducing the likelihood of resistance and improving treatment efficacy.²

EGFR inhibitors are also frequently included in treatment regimens for BRAF-mutated CRC. Even with a BRAF mutation, colorectal cancer can continue to rely on EGFR signaling for growth. By blocking EGFR as well, the combination therapy is more effective at slowing or stopping tumor progression.³

BREAKWATER: A New Approach in First-Line Therapy

Kopetz et al. recently published findings from the phase 3 BREAKWATER study, which explored whether BRAF-targeted monotherapy or combination therapy with chemotherapy could improve outcomes when used in the first-line setting.⁴

BREAKWATER was designed as an open-label, global study enrolling patients with untreated BRAF V600E-mutant metastatic CRC. Participants were randomized to receive either encorafenib (Braftovi) plus cetuximab (Erbitrux) with or without mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin; mFOLFOX6) or standard-of-care (SOC) chemotherapy alone. The primary goal was to evaluate objective response rate (ORR) and progression-free survival (PFS), while secondary measures included overall survival (OS), duration of response, and time to response.

The results were encouraging. Patients treated with encorafenib/cetuximab plus mFOLFOX6 had a significantly higher ORR compared to those who received SOC (60.9% vs. 40.0%; odds ratio, 2.443; 95% CI, 1.403-4.253; one-sided P = 0.0008). The responses were not only more frequent but also longer-lasting: 68.7% of patients in the encorafenib/cetuximab plus mFOLFOX6 group had responses lasting at least 6 months, compared to 34.1% in the SOC group, and the proportions of patients with a duration of response of 12 months or more were 22.4% and 11.4%, respectively. While PFS and OS data were still maturing at the time of analysis, early findings suggested a meaningful survival advantage for encorafenib/cetuximab plus mFOLFOX6, with a median OS not yet reached (95% CI, 19.8-not evaluable) compared to 14.6 months (95% CI, 13.4-not evaluable) in the SOC group (HR, 0.47; 95% CI, 0.318-0.691).

The safety profile of encorafenib/cetuximab plus mFOLFOX6 remained manageable, with no unexpected toxicities. Serious adverse events (SAE) were more common in the encorafenib/cetuximab plus mFOLFOX6 group (37.7%) compared to SOC (34.6%), but the overall tolerability of the regimen was consistent with what is known for each individual agent. Treatment-related SAEs were similar in both arms (18.2% vs 19.3%, respectively).

Results of the BREAKWATER trial supported the FDA’s accelerated approval of encorafenib/cetuximab plus mFOLFOX6.

Nursing Considerations

For oncology nurses and advanced practice providers (APP), these findings highlight a promising new first-line treatment option for BRAF V600E-mutant metastatic CRC. With higher response rates and the potential for improved survival, encorafenib/cetuximab plus mFOLFOX6 marks a significant advancement in managing this challenging disease. Nurses and APPs play a crucial role in educating patients and their families about the benefits of combination therapy, setting expectations for treatment, and providing guidance on potential toxicities. By ensuring patients understand possible side effects and encouraging early symptom reporting, nurses and APPs can help optimize treatment tolerance and overall care.

References

1. Martinelli E, Cremolini C, Mazard T, et al. Real-world first-line treatment of patients with BRAFV600E-mutant metastatic colorectal cancer: the CAPSTAN CRC study. ESMO Open. 2022;7(6):100603. doi:10.1016/j.esmoop.2022.100603
2. Subbiah V, Baik C, Kirkwood JM. Clinical Development of BRAF plus MEK Inhibitor Combinations. Trends Cancer. 2020;6(9):797-810. doi:10.1016/j.trecan.2020.05.009
3. Barras D. BRAF Mutation in Colorectal Cancer: An Update. Biomark Cancer. 2015;7(Suppl 1):9-12. Published 2015 Sep 6. doi:10.4137/BIC.S25248
4. Kopetz S, Yoshino T, Van Cutsem E, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. Published online January 25, 2025. doi:10.1038/s41591-024-03443-3