Encorafenib, Binimetinib, and Cetuximab Regimen Improves Survival in BRAF+ CRC

Scott Kopetz, MD, PhD, FACP

Encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) demonstrated a significant improvement in overall survival (OS) compared with cetuximab and an irinotecan-containing regimen in patients with BRAF-mutant colorectal cancer (CRC), according to results of the phase III BEACON CRC study that were presented at the 2019 World Congress on Gastrointestinal Cancers.¹

In the study, the triplet regimen elicited a median OS of 9.0 months compared with 5.4 months in the standard-of-care arm, leading to a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.39-0.70; 2 sided P <.0001). Moreover, the overall response rates (ORRs) were 26% and 2% for encorafenib/binimetinib/cetuximab and standard therapy, respectively.

"This study builds on a decade of research into the tumor biology of BRAF-mutated colorectal cancer, and reflects a rationale combination to address the vulnerabilities unique to this tumor," Scott Kopetz, MD, lead BEACON CRC study author, stated in a press release ahead of the meeting. "We are encouraged to see a meaningful improvement in outcomes with this new regimen for our patients."

BRAF mutations are identified in up to 15% of all patients with metastatic CRC; V600E is the most common BRAF mutation and represents a poor prognosis for this patient population.

The FDA previously granted the triplet regimen a breakthrough therapy designation for the treatment of patients with BRAF V600E-mutant mCRC as detected by an FDA-approved test, following failure of 1 or 2 prior lines of treatment. This decision was based on findings from the safety lead-in phase of the BEACON CRC trial.

In the open-label, international, BEACON CRC study, researchers evaluated the efficacy and safety of encorafenib, binimetinib, and cetuximab in patients with BRAF V600E-mutant mCRC who had disease progression on 1 or 2 prior therapies. In the safety lead-in phase, 30 patients were treated with the triplet regimen at 300 mg daily of encorafenib, 45 mg twice daily of binimetinib, and standard cetuximab. Twenty-nine patients had a BRAF V600 mutation and 1% of patients had microsatellite instability—high status. Data demonstrated that the 3-drug regimen had showed good tolerability.

The safety lead-in results were previously presented at the 2019 Gastrointestinal Cancers Symposium. At a median follow-up of 18.2 months, the estimated median progression-free survival (PFS) was 8.0 months and the median OS was 15.3 months.² The ORR by local assessment was 48% and 3 patients achieved a complete response.

In the randomized portion of the trial, 665 patients with BRAF V600-mutant mCRC were randomized 1:1:1 to receive encorafenib, binimetinib, and cetuximab; encorafenib and cetuximab; or cetuximab and irinotecan-based treatment.

The trial was then amended to include an interim analysis of endpoints, which included ORR. The primary OS endpoint compared the triplet regimen with the control arm, and key secondary endpoints looked at the efficacy of encorafenib/cetuximab compared with the control arm, as well as encorafenib/binimetinib/cetuximab compared with the encorafenib doublet.

Initially, the ORR analysis was based on the first 331 randomized patients; the interim analysis for OS included all 665 randomized patients with a data cutoff date of February 2019. Future analyses will assess ORR on the overall population and OS with longer follow-up.

Results from the secondary endpoint analysis showed that patients treated with the combination of encorafenib and cetuximab demonstrated a statistically significant improvement in ORR per blinded independent central review (BICR) at 20.4% versus 1.9% (P <.0001).³ The median OS was also improved with the doublet compared with the control arm at 8.4 months and 5.4 months, respectively (HR, 0.60; 95% CI, 0.45-0.79; P = .0003).

In findings from a descriptive comparison of the triplet regimen of encorafenib, binimetinib, and cetuximab to encorafenib/cetuximab, there was a trend toward improved OS and ORR with the triplet (HR, 0.79; 95% CI, 0.59-1.06; nominal P = .1164).

Moreover, in patients who had 1 prior treatment, the ORR by BICR was 34.3% with the triplet versus 22.4% with encorafenib/cetuximab. Currently, the OS for both arms is consistent compared with the overall population.

Regarding safety, encorafenib/binimetinib/cetuximab was found to be well tolerated with no unexpected toxicities. Grade ≥3 adverse events were reported in 58% of patients on the triplet arm, 50% of those on encorafenib/cetuximab, and 61% of those in the standard group.

"This targeted therapy combination should be a new standard of care for this patient group," Kopetz concluded in the press release. "Further investigation is needed to determine if this combination may also benefit those with less advanced disease or as a first-line treatment."

Additionally, the triplet regimen has been included as a category 2A treatment for patients with BRAF V600E-mutant metastatic CRC, following failure of 1 or 2 prior lines of therapy in National Comprehensive Cancer Network guidelines for colon and rectal cancers in the United States.

The ongoing, phase II ANCHOR-CRC study (NCT03693170) is investigating the effects of triplet therapy as frontline treatment for patients with metastatic BRAF V600E-mutant CRC.

References

1. Kopetz S, Grothey A, van Cutsem E, et al. BEACON CRC: a randomized, 3-arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E. Presented at: 2019 World Congress on Gastrointestinal Cancers; July 3-6, 2019; Barcelona, Spain. Abstract LBA-006.
2. Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). J Clin Oncol. 2019;37 (suppl; abstr 688). doi: 10.1200/JCO.2019.37.4_suppl.688.
3. Array Biopharma Announces Braftovi + Mektovi + Cetuximab Meet Primary Endpoints Of ORR And OS In Phase 3 Beacon Crc Trial Interim Analysis For The Treatment Of Braf(V600e)-Mutant Metastatic Colorectal Cancer. Array BioPharma. Published May 21, 2019. https://bit.ly/2YFrjCw. Accessed May 21, 2019.