FDA Approves Indication of Cetuximab in Combination With Encorafenib for Metastatic Colorectal Cancer

The FDA has approved cetuximab (Erbitux) in combination with encorafenib (Braftovi) for the treatment of adult patients with metastatic colorectal cancer harboring a BRAF V600E mutation, after prior therapy, according to a press release by Eli Lilly and Company.¹

Cetuximab is the only anti-EGFR antibody approved in combination with encorafenib in this patient population. In addition to colorectal cancer, cetuximab is also approved for use in head and neck cancer.

The label expansion is based on the results of the BEACON CRC study (NCT02928224).² The phase 3 interventional, parallel assignment study has an actual enrollment of 702 participants and an estimated completion date of May 2022. Primary end points include the number of participants with dose limiting toxicities, the number of participants with adverse events (AEs), incidence of dose interruptions, dose modifications, and discontinuations, overall survival (OS), and overall response rate (ORR). Secondary end points include duration of response (DOR), time to response, progression-free survival (PFS), and quality of life.

Patients were randomized 1:1:1 into 3 arms. In arm 1, patients received a triplet combination of encorafenib. binimetinib, and cetuximab. In arm 2, patients received encorafenib and cetuximab. In arm 3, the control arm, patients received investigators choice of therapy.

In total, 220 participants were randomized to receive cetuximab and encorafenib and 221 were randomized to receive investigators choice. The median OS for the cetuximab and encorafenib combination was 8.4 months (95% CI, 7.5-11.0), compared to 5.4 months (95% CI, 4.8-6.6) in the control arm. The ORR for the experimental combination was 20% (95% CI, 13%-29%) compared to 2% in the control arm. (95% CI, 0%-7%). The partial response rate for the combination arm was 15% compared to 2% in the control arm. The median DOR for the experimental group was 6.1 months (range, 4.1-8.3) and was not reached in the control group (2.6 to not reached [NR]).

The median PFS for the experimental arm was 4.2 months (95% CI, 3.7-5.4) and 1.5 months for the control arm (95% CI, 1.4-1.7). Progressive disease was seen in 50% of patients in the experimental arm versus 46% of patients in the control arm. Death was observed in 10% of patients in the control arm versus 12% of patients in the experimental arm. 

AEs occurring in 25% or of patients treated with cetuximab in combination with encorafenib included fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.

"The BEACON study showed that the combination of ERBITUX and encorafenib significantly improved overall survival in patients with metastatic colorectal cancer with a BRAF V600E mutation – a subtype that typically has worse outcomes compared to those without the mutation," said David Hyman, MD, chief medical officer, oncology at Lilly in a press release. "We are grateful to Pfizer for their collaboration as we've worked to bring this treatment regimen to patients."

In order to participate, patients must be 18 years of age or older, have confirmed metastatic colorectal cancer harboring a BRAF V600E mutation, progression after 1 or 2 prior lines of therapy in the metastatic setting, evidence of measurable disease, adequate bone marrow, cardiac, kidney, and liver function, and be able to take oral medication. Patients with prior treatment with any RAF or MEK inhibitors, systemic brain metastasis, known history of acute chronic pancreatitis, uncontrolled blood pressure, impaired gastrointestinal function, or known HIV infection were not eligible to participate. 

_REFERENCES:

_{1. FDA expands Lilly's ERBITUX® (cetuximab) label with combination of BRAFTOVI® (encorafenib) for the treatment of BRAF V600E mutation-positive metastatic colorectal cancer (CRC) after prior therapy. Eli Lilly. News release. September 28, 2021. Accessed September 29, 2021. https://bit.ly/3ohEl9j.}

_{2. Study of encorafenib + cetuximab plus or minus binimetinib vs. irinotecan/cetuximab or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI)/cetuximab with a safety lead-in of encorafenib + binimetinib + cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer (BEACON CRC). ClinicalTrials.gov. Accessed September 29, 2021. https://bit.ly/3kPDfiU.}