FDA Greenlights Companion Diagnostic for Encorafenib Plus Cetuximab in BRAF V600E+ mCRC

The FDA has approved FoundationOne CDx for use as a companion diagnostic to determine patients with BRAF V600E–mutated metastatic colorectal cancer (mCRC) who may be candidates to receive encorafenib (Braftovi) in combination with cetuximab (Erbitux).¹

The qualitative next-generation sequencing–based, in vitro test examines 324 genes by utilizing circulating cell-free DNA.¹ The assay utilizes technology that allows it to identify substitutions, insertions, and deletions in a total of 311 genes; this includes rearrangements in 8 genes and copy number alterations in 3 genes.²

In April 2020, the FDA approved the encorafenib for use in combination with cetuximab in adult patients with mCRC harboring a BRAF V600E mutation following prior therapy.³ The decision was supported by data from the phase 3 BEACON CRC trial (NCT02928224), in which encorafenib plus cetuximab resulted in a median overall survival (OS) of 8.4 months (95% CI, 7.5-11.0) vs 5.4 months (95% CI, 4.8-6.6) with the control regimen of irinotecan or FOLFIRI plus cetuximab (HR, 0.60; 95% CI, 0.45-0.79; P = .0003).

In September 2021, the regulatory agency approved a new indication for cetuximab for use in combination with encorafenib in adult patients with mCRC and a BRAF V600E mutation, following prior treatment.⁴ Again, the decision was based on BEACON CRC findings.4 Additional data showed that the doublet elicited an objective response rate (ORR) of 20% (95% CI, 13%-29%) vs 2% (95% CI, 0%-7%) with the control regimen (P < .0001). The median progression-free survival in the investigative and control arms was 4.2 months (95% CI, 3.7-5.4) and 1.5 months (95% CI, 1.4-1.7), respectively (HR, 0.40; 95% CI, 0.31-0.52; P < .0001).

“Companion diagnostics are high-quality, well-validated genomic tests that provide critical information to help oncologists make informed treatment decisions for our patients,” Mia Levy, MD, PhD, chief medical officer at Foundation Medicine, stated in a press release. “This new companion diagnostic indication for FoundationOne Liquid CDx provides oncologists with an important, non-invasive genomic testing option for metastatic patients with this difficult-to-treat condition.”

FoundationOne CDx is intended to be leveraged to determine which patients may derive benefit from approved targeted therapies such as alectinib (Alecensa); EGFR inhibitors like erlotinib (Tarceva), osimertinib (Tagrisso), gefitinib (Iressa), afatinib (Gilotrif), dacomitinib (Vizimpro); mobocertinib (Exkivity); capmatinib (Tabrecta); and entrectinib (Rozlytrek) in non–small cell lung cancer.⁵ It is also approved as a companion diagnostic for olaparib (Lynparza) and rucaparib (Rubraca) in prostate cancer, alpelisib (Piqray) in breast cancer, and entrectinib in solid tumors.²

The global, multicenter, open-label, phase 3 BEACON CRC trial enrolled patients with histologically or cytologically confirmed mCRC harboring a BRAF V600E mutation who progressed following 1 or 2 prior regimens.⁶

Study participants (n = 665) were randomly assigned 1:1:1 to receive encorafenib at a daily dose of 300 mg, binimetinib at a twice-daily dose of 45 mg, and cetuximab at an initial dose of 400 mg mg/m2 followed by a weekly dose of 250 mg/m2 (n = 224); encorafenib plus cetuximab at the same doses and schedule (n = 220); or investigator’s choice of cetuximab at the same dose and schedule plus irinotecan at 180 mg/m2 on days 1 and 15 or cetuximab at the same dose and schedule plus FOLFIRI, which was comprised of fluorouracil at an initial dose of 400 mg/m2 followed by 1200 mg/m2 for 2 days on days 1 and 15, and irinotecan at the same dose and schedule (n = 221).

Treatment continued until progressive disease, intolerable toxicity, withdrawn consent, initiation of subsequent treatment, or death.

Key stratification factors comprised ECOG performance status (0 vs 1), prior irinotecan (yes vs no), and cetuximab formulation (US licensed vs European approved).

OS served as a major efficacy measure of the study, with additional measures comprising PFS, ORR, and duration of response by blinded independent central review.4 OS and PFS was evaluated in all patients who underwent randomization. ORR and DOR were examined in the first 220 patients who were randomly assigned to the doublet and control arms of the study.

A total of 216 patients were evaluated for safety. These patients received cetuximab at an initial dose of 400 mg/m2, followed by a weekly dose of 250 mg/m2, plus encorafenib at a daily dose of 300 mg. The most common toxicities reported with the doublet included fatigue, diarrhea, nausea, dermatitis acneiform, abdominal pain, reduced appetite, arthralgia, and rash.

References

1. US Food and Drug Administration (FDA) approves FoundationOne LiquidCDx as a companion diagnostic for Pfizer’s Braftovi (encorafenib) in combination with cetuximab to identify patients with BRAF V600E alterations in metastatic colorectal cancer. News release. Foundation Medicine Inc. June 9, 2023. Accessed June 13, 2023. https://www.foundationmedicine.com/press-releases/f9b285eb-db6d-4f61-856c-3f1edb803937
2. FoundationOne Liquid CDx. Foundation Medicine Inc. Accessed June 13, 2023. https://info.foundationmedicine.com/hubfs/FMI%20Labels/FoundationOne_Liquid_CDx_Label_Technical_Info.pdf
3. FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. FDA. April 8, 2020. Accessed June 13, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-combination-cetuximab-metastatic-colorectal-cancer-braf-v600e-mutation
4. 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. News release. Eli Lilly and Company. September 28, 2021. Accessed June 13, 2023. https://investor.lilly.com/news-releases/news-release-details/fda-expands-lillys-erbituxr-cetuximab-label-combination
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