Dr Parikh on the Rationale for Adding ERAS-007 to the BEACON Regimen in BRAF V600E–Mutant mCRC

Aparna Parikh, MD, associate professor, medicine, Harvard Medical School; assistant in medicine, Hematology, Oncology, Massachusetts General Hospital; attending oncologist, Tucker Gosnell Center for Gastrointestinal Cancers, the Henri and Belinda Termeer Center for Targeted Therapies, discusses the rationale for evaluating the addition of ERAS-007 to cetuximab (Erbitux) and encorafenib (Braftovi), also known as the BEACON regimen,in BRAF V600E–mutated metastatic colorectal cancer (mCRC).

BRAF V600E–mutated CRC accounts for approximately 10% to 15% of patients with stage IV CRC and is associated with a poor prognosis, Parikh begins. Historically, treatment options for this subgroup were limited, but the BEACON regimen has emerged as a targeted therapy for these patients in the second line, she says. Despite its benefits, this regimen has limitations, including modest improvements in progression-free survival (PFS), overall survival (OS), and response rates. Additionally, the regimen is associated with short response durability, highlighting the need for more effective therapies, Parikh notes.

To address these limitations, the phase 1/2 HERKULES-3 trial (NCT05039177) was designed to evaluate the addition of ERAS-007, an oral ERK inhibitor, to the BEACON regimen, Parikh says. The rationale for this combination is based on the role of ERK in the MAPK pathway, she details. Since ERK is downstream of the targets of encorafenib and cetuximab, the hypothesis was that concurrent inhibition of ERK might enhance the efficacy of the BEACON regimen by blocking additional signaling pathways involved in tumor growth, Parikh explains.

At the 2024 ASCO Annual Meeting updated results from the HERKULES-3 trial were presented. Although the combination of ERAS-007 with encorafenib and cetuximab was reportedly well tolerated, the efficacy results did not show a significant improvement compared with the BEACON regimen alone. Instead, the response rates and overall outcomes were comparable to those observed with the BEACON regimen without ERAS-007. Consequently, the addition of ERAS-007 did not meet the required efficacy threshold to justify further development, suggesting that while the combination is tolerable, it does not offer substantial clinical benefit over existing therapies.