Encorafenib/Cetuximab Combos Sustain OS Benefit in BRAF+ Metastatic Colorectal Cancer

Scott Kopetz, MD, PhD, FACP

Encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) continued to show an overall survival benefit compared with cetuximab plus irinotecan-based regimens as treatment of patients with BRAF-mutated metastatic colorectal cancer (mCRC) in the updated findings from the phase 3 BEACON CRC clinical trial.¹

A posthoc updated analysis presented during the 2020 ASCO Virtual Scientific Program showed that at a median follow-up of 12.8 months, the median OS was 9.3 months with encorafenib/cetuximab compared with 5.9 months in the control arm (HR, 0.61; 95% CI, 0.48-0.77). The median OS with the triplet of encorafenib/cetuximab plus binimetinib was also 9.3 months (HR vs control, 0.60; 95% CI, 0.47-0.75). For both the doublet and triplet regimens, the OS benefit was maintained versus the control arm across all key subgroups, including those defined by use of prior irinotecan, microsatellite instability (MSI) status, and number of prior regimens.

The objective response rate (ORR) was 27% with the triplet, 20% with the doublet, and 2% in the control arm. The ORR with the triplet comprised a complete response (CR) rate of 4% and a partial response (PR) rate of 23%. An additional 48% of patients had stable disease, while 11% of patients had progressive disease and 14% were not evaluable for response. Among patients who received the doublet of encorafenib and cetuximab, the ORR comprised a CR rate of 3% and a PR rate of 16%. Another 56% of patients had stable disease, 10% had progressive disease, and 15% were not evaluable for response.

The updated data showed that the median progression-free survival (PFS) was 4.5 months with the triplet compared with 1.5 months for the control arm (HR, 0.42; 95% CI, 0.33-0.53). The median PFS with the doublet was 4.3 months (HR vs control, 0.44; 95% CI, 0.35-0.55).

“In the BEACON CRC study, encorafenib plus cetuximab significantly improved OS, ORR, and PFS relative to standard of care in patients with BRAF V600E–mutant mCRC, a population with historically dismal outcomes," said lead study author Scott Kopetz, MD, PhD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “With further follow-up after the primary analysis, the regimen of encorafenib plus cetuximab had similar overall efficacy as the encorafenib plus cetuximab with binimetinib regimen.”

Based on the BEACON CRC trial, the FDA approved the doublet regimen of encorafenib plus cetuximab in April 2020 for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

BEACON CRC was an international open-label phase 3 trial that enrolled 665 patients with BRAF V600E–mutated mCRC whose disease had progressed after 1 or 2 prior regimens. Patients had an ECOG performance status of 0 or 1 and no prior exposure to an EGFR inhibitor.

After a safety lead-in, patients were randomly assigned in a 1:1:1 ratio to the triplet of encorafenib, binimetinib, and cetuximab (n = 224); the doublet of encorafenib and cetuximab (n = 220); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan; n = 221). At the time of analysis, 13% of patients in the triplet arm and 14% in the doublet arm remained on treatment compared with 3% in the control arm.

Baseline characteristics were “overall reasonably balanced” among the 3 arms, according to Kopetz. “Importantly, MSI-high status accounted for between 5% and 10% of the patients. Two-thirds of the patients had 1 prior line of therapy, with one-third of patients having more than 1 line,” noted Kopetz.

Updated safety data showed that grade ≥3 adverse events and laboratory abnormalities were consistent with the previously reported safety profile for the treatments. “It’s notable that the encorafenib/cetuximab/binimetinib arm had slightly higher rates of GI toxicity, [as well as higher rates of anemia as indicated] by low hemoglobin in the triplet arm that was not seen in the [doublet arm]. [Low hemoglobin] is associated with the known safety profile of a MEK inhibitor,” said Kopetz.

Findings from the primary analysis of the BEACON CRC study were published in 2019 in the New England Journal of Medicine and showed that, after a median follow-up of 7.8 months, the median OS was 9.0 months in the triplet arm versus 5.4 months in the control group (HR, 0.52; 95% CI, 0.39-0.70; P <.001).² The median OS in the doublet arm was 8.4 months (HR vs control, 0.60; 95% CI, 0.45-0.79; P = .0003).

Both the triplet (HR, 0.38; 95% CI, 0.29-0.49; P <.001) and the doublet (HR, 0.40; 95% CI, 0.31-0.52; P <.001) significantly improved PFS over the control arm. The median PFS was 4.3 months in the triplet arm, 4.2 months with the doublet, and 1.5 months in the control arm. The ORRs were 26% with the triplet, 20% with the doublet, and 2% in the control arm.

_References

1. _{Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: Updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract 4001.}
2. _{Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381:1632-1643}