Encorafenib, Binimetinib, and Cetuximab Triplet Improves OS, ORR in BRAF+ CRC

Scott Kopetz, MD, PhD, FACP

The triplet regimen of encorafenib (Bratovi), binimetinib (Mektovi), and cetuximab (Erbitux) led to a 48% reduction in the risk of death compared with cetuximab and irinotecan-containing regimens in patients with BRAF V600E-mutant metastatic colorectal cancer (CRC) who previously received up to 2 lines of therapy, meeting both primary endpoints of the phase III BEACON CRC trial.¹

Results showed that the triplet therapy was associated with a median overall survival (OS) of 9.0 months compared with 5.4 months for those who received cetuximab/irinotecan-containing treatment (HR, 0.52; 95% CI, 0.39-0.70; P <.0001). The overall response rate (ORR), as assessed by blinded independent central review (BICR), was 26.1% and 1.9%, respectively (P <.0001).

Array BioPharma, Inc., the manufacturer of encorafenib and binimetinib, stated in a press release that it intends to submit these data for marketing approval in the second half of 2019.

"The BEACON CRC trial is the first phase III trial in patients with BRAF V600E-mutant mCRC and these results show a significant improvement compared to available standard of care options for this patient population," lead investigator Scott Kopetz, MD, PhD, FACP, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in a press release. "Given that there are no therapies currently FDA-approved for this patient population, I believe the results of the BEACON CRC trial will be practice-changing."

Patients with BRAF-mutant mCRC, who comprise 15% of all patients with CRC, generally have a worse prognosis; there are currently no FDA-approved therapies for this subgroup. V600E is the most common mutation.

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.

Also, in March 2019, the National Comprehensive Cancer Network updated their Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include encorafenib in combination with binimetinib and an anti-EGFR antibody as a category 2A treatment for patients with BRAF V600E-mutant mCRC, following failure of 1 or 2 prior lines of therapy for metastatic disease, also based on the safety lead-in BEACON CRC data.

In the open-label, international, BEACON CRC trial, 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. Regarding patient characteristics, 29 patients had a BRAF V600 mutation and 1% of patients had microsatellite instability¬—high status. Results had showed that the triplet regimen previously demonstrated good tolerability.²

In data presented at the 2019 Gastrointestinal Cancers Symposium, at a median follow-up of 18.2 months, results showed an estimated median progression-free survival (PFS) of 8.0 months and a median OS of 15.3 months. 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.

Regarding endpoints, the trial was amended to include an interim analysis of endpoints, which included ORR. The primary OS endpoint compared the of triplet regimen to 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 encorafenib/cetuximab.

The ORR analysis was first 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. Array stated that 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 BICR at 20.4% versus 1.9% (P <.0001). 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 positive trend across endpoints, including ORR and OS (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 therapy compared with 22.4% with encorafenib/cetuximab. Currently, the OS for both arms is consistent compared with the overall population.

Regarding safety, both the triplet and doublet regimens were well tolerated and there were no unexpected toxicities. Both safety profiles were also consistent with what has been seen with each regimen in prior studies.

Additional secondary endpoints include progression-free survival, duration of response, safety, tolerability, and health-related quality of life.

"We are pleased to announce positive results from the BEACON CRC trial, including that the Braftovi triplet reduced the risk of death by 48% versus control," said Ron Squarer, CEO, Array BioPharma. "We are deeply grateful to the patients and investigators whose participation has helped bring us one step closer to delivering a new standard of care for patients with BRAF-mutant mCRC. This has the potential to be the first chemotherapy-free, targeted regimen for mCRC patients, a population with a very high unmet need for effective treatments."

References

1. 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.
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.