1. Hepp, Rebecca

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SAN FRANCISCO-The investigational triple combination therapy of encorafenib, binimetinib, and cetuximab has updated safety and efficacy data, including an extended median overall survival (OS) of 15.3 months for BRAFV600E-mutant metastatic colorectal cancer (mCRC) patients. The data from the safety lead-in of the phase III BEACON CRC trial was presented at the 2019 Gastrointestinal Cancers Symposium.

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The findings could open the door to a faster approval, according to the investigators, potentially changing the care paradigm for this subset of colorectal cancer patients. Welcome news, considering the current benchmark for median OS, based on today's standard of care, is 6 months at most.


Meeting a Need

Researchers estimate 140,250 patients in the U.S. will be diagnosed with colorectal cancer in 2018, and 15 percent of those with metastatic disease have the BRAF mutation, with V600 being the most common.


"BRAFV600E-mutant metastatic CRC is an area of high unmet need, as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC, and these patients derive limited benefit from available chemotherapy regimens," said Axel Grothey, MD, BEACON CRC trial lead investigator and Co-Chair of the NCI's Gastrointestinal Cancer Steering Committee.


Currently, the standard of care for patients with BRAFV600E consists of a chemotherapy triplet of 5-FU, irinotecan, and oxaliplatin with the addition of bevacizumab, Grothey noted, but the prognosis remains bleak. This regimen provides an overall response rate (ORR) of 4-8 percent and median progression-free survival (mPFS) of 2-3 months, in addition to the median OS of 4-6 months.


In August 2018, the triple combination therapy received the FDA's Breakthrough Therapy Designation for the treatment of patients with BRAFV600E-mutant mCRC who have failed one or two other therapy regimens. These patients are in desperate need of a better therapy avenue, given that the mortality risk for patients with BRAFV600E-mutant mCRC is more than double that of mCRC patients without the mutation.


Triple Threat

The therapy consists of encorafenib, an oral small molecule BRAF kinase inhibitor; binimetinib, an oral small molecule MEK inhibitor that targets key enzymes in the mitogen-activated protein kinase (MAPK) signaling pathway; and cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody.


"Mutations in BRAF can lead to increased cell proliferation and survival that can be abrogated through inhibition of BRAF and the downstream signaling protein, MEK," Grothey explained. "Research has shown that BRAF inhibitor monotherapy can actually increase signaling through EGFR and can restore MAPK signaling activity through RAS and an alternate RAF, CRAF. Therefore, inhibiting RAF, MEK, and the cell-surface signaling through EGFR with an EGFR antibody like cetuximab is thought to be critical to effectively ablating the MAPK signaling in BRAFV600E-mutant CRC."


While encorafenib plus binimetinib are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation (but not wild-type BRAF melanoma), the triplet has yet to receive approval.


The BEACON CRC trial, a randomized, open-label, global trial evaluating the triplet combination therapy, hopes to change that. The trial safety lead-in consisted of 30 patients, 29 with a BRAFV600 mutation and one with a defective DNA mismatch repair. Treatment with encorafenib 300 mg daily, binimetinib 45 mg twice daily, and cetuximab per label led to an 8-month mPFS and ORR of 48 percent. Among the 17 patients who received only one prior line of therapy, the ORR was 62 percent. These initial safety lead-in findings, announced June 28, 2018, included an OS of 62 percent at 12 months. The latest results are similar for mPFS and ORR, with the hopeful addition of significantly improved OS.


"The mature median OS of 15.3 months demonstrated in the safety lead-in of the BEACON CRC trial is unprecedented in this patient population," Grothey said.


The therapy was also well-tolerated, the safety lead-in found, with no unexpected toxicities. Still, the investigators report several grade 3 or 4 adverse events, including fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%), and urinary tract infections (10%).


The dual therapy of encorafenib plus binimetinib also comes with other risks, discovered in the 2018 COMPASS trial (LancetOncol 2018; doi:10.1016/S1470-2045(18)30142-6). The study found an increased risk of other primary malignancies such as cutaneous squamous cell carcinoma (2.6%) and basal cell carcinoma (1.6%), cardiomyopathy (7%), venous thromboembolism (6%), hemorrhage (19%), and ocular toxicities such as serous retinopathy (20%). The therapy's full prescribing information recommends clinicians screen patients regularly for any of these adverse effects.


Striving for Approval

With these safety and efficacy results under their belt, the investigators are forging ahead with the trial, which will randomize approximately 615 patients to receive the triplet combination, a doublet combination of encorafenib and cetuximab, or the control arm of irinotecan-based therapy and cetuximab. The team announced completed trial enrollment in December 2018.


The primary OS endpoint will be a comparison between the triplet combination and the control arm, while the secondary endpoints evaluate the efficacy of both the doublet combination compared with the control arm and the triplet combination compared with the doublet therapy. The study will include other outcomes such as PFS, duration of response, safety, tolerability, and health-related quality of life data.


The positive safety lead-in data led investigators to also amend the trial to add an interim analysis of endpoints, including ORR, "which the company believes could support an accelerated approval with positive results," according to Grothey.


"[Researchers] anticipate topline results from this interim analysis in the first half of this year. This timing allows for the subset of patients required for the interim analysis of ORR to achieve a response and for the durability of responses to be appropriately evaluated," he said.


Until trial results are available to move the therapy through the approval process, "clinicians should talk to their patients with BRAFV600E-mutant mCRC about what treatment is right for them," Grothey said.


Rebecca Hepp is a contributing writer.