BEACON Lights Way for Chemo-Free Therapy in Colorectal Cancer

Liam Davenport

July 08, 2019

BARCELONA, Spain — New results from the BEACON clinical trial offer hope for a chemotherapy-free treatment option for certain patients with colorectal cancer (CRC).

Combinations of targeted therapies yielded significantly improved response rates and overall survival rates compared with traditional chemotherapy regimens among patients with previously treated BRAF V600E–mutated metastatic CRC.

This BRAF V600E mutation is found in 10% to 15% of metastatic CRC patients and is usually associated with a poor prognosis

The BEACON trial had three treatment arms. One group of patients received triplet therapy with three targeted agents — the BRAF inhibitor encorafenib (Braftovi, Array BioPharma), the MEK inhibitor binimetinib (Mektovi, Array BioPharma), and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).

Another group received doublet targeted therapy with encorafenib and cetuximab. A third (control) group received standard chemotherapy.

The new results, presented here at the World Conference on Gastrointestinal Cancer (WCGC) 2019, were from an initially unplanned interim analysis.

Presenter Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, showed that the triplet therapy was associated with a remarkable 48% improvement in overall survival vs standard chemotherapy.

Furthermore, progression-free survival (PFS) was improved by 62%, at 4.3 months with the triplet regimen vs 1.5 months with standard therapy.

This improvement was reflected in a highly significant increase in the objective response rate (ORR) with triplet therapy, at 26%. ORR increased to 34% among patients who had previously received just one therapy. It was only 2% with chemotherapy.

Importantly, these improvements were achieved without increasing toxicity, Kopetz added.

We think it really defines a new standard of care. Dr Scott Kopetz

At a press conference, Kopetz commented that he was "pleased to report that really this is the first evidence of a survival benefit with a chemotherapy-free targeted therapy regimen in a prospective biomarker-defined subgroup, in this case BRAF V600E mutations in colorectal cancer.

"On the basis of this, we think it really defines a new standard of care."

He said that the triplet therapy has already been added to the National Comprehensive Cancer Network guidelines for the treatment of metastatic CRC, "so this is now available to our patients for treatment of this difficult disease."

However, study coauthor Eric van Cutsem, MD, PhD, from the University Hospital Gasthuisberg, Leuven, Belgium, who is co-chair of the congress, said that European patients are not yet able to benefit from this triple therapy.

He told Medscape Medical News that the European Medicines Agency "is usually more conservative" than its US counterpart and that "the regimen is not yet approved for colorectal cancer."

Moreover, cetuximab is not available in Europe. Thus, any off-label use would have to be the doublet combination of encorafenib and binimetinib.

"But off-label use is of course not so easy in Europe," van Cutsem said, "so today it's not yet available for our patients."

Doublet Not Triplet?

However, another expert who commented on the results noted that the doublet of encorafenib and cetixumab performed almost as well as the triplet therapy. He questioned whether the doublet could in fact be preferable, because it would be less toxic.

The discussant for the study, Sharlene Gill, MD, professor of medicine at the BC Cancer Agency, University of British Columbia, Vancouver, Canada, said that the investigators deserve "much respect" for enrolling so many patients in a "highly selected population."

She noted, however, that "it is important to remind ourselves that when we heard the data from the safety lead-in a year ago, at that point the confirmed response rates exceeded 40%, which led to an understandable enthusiasm for the triplet regimen.

"But it reminds us to be mindful of the fact that sometimes with further analysis these very promising early data can regress towards the mean, as was seen here."

Gill added that with the doublet arm performing so well, the question becomes: "What is the value-add of an MEK inhibitor?"

She explained that although the rationale of the triplet therapy is "compelling," the evidence that it has superior clinical efficacy when compared to the doublet "is less compelling at this time."

The greater toxicity profile, coupled with the increased risk for retinal toxicity with MEK inhibitors, should also be borne in mind, along with the increased cost of giving three rather than two drugs, she said.

Nevertheless, Gill said that the results underline that the BRAF mutation status of tumors should be assessed not only for prognostic purposes but also for predictive assessment.

She believes that on the basis of current evidence, for patients with metastatic CRC with both a BRAF V600E mutation and microsatellite instability, the preferred approach would be the use of a checkpoint inhibitor prior to BRAF-targeted therapies.

For those with microsatellite-stable disease, the preferred first-line treatment is FOLFOXIRI plus bevacizumab, followed by BRAF-targeted combination therapy. The jury is still out on whether that should be a triplet or doublet combination.

Gill pointed out that the mature survival analysis of BEACON is awaited.

The phase 2 ANCHOR-CRC trial, which will examine the efficacy of the triplet combination in the first-line setting, has begun recruitment.

"Very Important" Data

Mario Dicato, MD, Hematology-Oncology Service, Luxembourg Medical Center, Luxembourg, and congress co-chair, who was not involved in the study, commented that the study is "very interesting."

He said that for the one in six metastatic CRC patients who with the BRAF mutation, the study "opens up the perspective of giving treatment without chemotherapy and with a different profile of side effects."

Dicato added that this "very important" because "it's the first time we see targeted treatment practically replacing chemotherapy, and with a profile which is not worse than the standard."

Need for Routine Testing of All CRC Patients

Andrés Cervantes, MD, PhD, professor of medicine, University of Valencia, Spain, commented in a press release that the findings mean that it is "essential" that patients be routinely tested for BRAF mutations.

Echoing Dicato's comments, he said: "The fact that we can give this targeted combination without the need for chemotherapy is very good news for patients, not least because of the side effects that they typically experience with chemotherapy."

Patients Facing Poor Prognosis

Kopetz noted that patients with metastatic CRC with the BRAF V600E mutation usually have a poor prognosis and that traditional chemotherapy regimens have not made much of an impact. For example, irinotecan-based chemotherapy has yielded poor outcomes, with median overall survival of 5.9 months, a median PFS of 4 months, and an objective response rate (ORR) of just 4%.

Despite the presence of a BRAF mutation, patients have not benefited from treatment with single-agent BRAF inhibitors, he noted, owing to the feedback activation of epidermal growth factor receptor (EGFR), which continues cell proliferation.

Combinations of targeted therapies have consequently been the subject of a great deal of interest.

With that in mind, the researchers undertook the BEACON study. It enrolled patients with BRAF V600E–mutated metastatic CRC who had experienced disease progression after one or two prior regimens but had not had any prior treatment with a RAF, MEK, or EGFR inhibitor.

The trial began with a safety lead-in that involved 30 patients who were treated with the targeted-therapy triplet of encorafenib, binimetinib, and cetixumab.

After this, patients were randomly assigned in a 1:1:1 ratio to one of three regimens:

  • Triplet therapy with encorafenib, binimetinib, and cetixumab

  • Doublet therapy with encorafenib and cetixumab

  • Standard chemotherapy with either FOLFOXIRI plus cetixumab or irinotecan plus cetixumab

Kopetz noted in the press conference that there is a "wealth of clinical and preclinical data" in support the triplet regimen as the ideal approach.

It is thought that tumors are able to develop resistance to the doublet regimen, "so the basis of the triplet is to improve the depth of response and the durability," he said.

It was originally intended that the primary endpoint would be overall survival in the triplet vs control arms, but the positive results seen in the safety lead-in led the researchers to add ORR and an interim overall survival analysis.

Kopetz said that the database cutoff for the interim analysis was February 11, just 10 days after the last patient entered the study.

This means that although the overall survival analysis included all patients currently enrolled in the study, the ORR focused solely on the first 330 patients.

Details of the Results

In all, of 665 patients, 224 were randomly assigned to the triplet arm, 222 to the doublet arm, and 221 to the control arms.

From 48% to 57% of the patients were women. The median age was approximately 61 years.

In a little more than half of cases, the primary tumor was located in the right colon, and 58% to 64% of patients had liver metastases.

Kopetz noted that, contrary to what would be expected in such a patient population, there was a low rate of microsatellite instability, at 5% in the control arm, 9% in doublet arm, and 10% in the triplet arm.

The primary endpoint of the study was met. Patients who received the triplet therapy experienced a significant improvement in median survival in comparison with those given standard chemotherapy, at 9.0 months vs 5.4 months (hazard ratio [HR], 0.52; P < .0001).

Importantly, those who had received only one prior regimen derived a similar benefit from triplet therapy as those given two or more regimens (HRs, 0.54 and 0.53, respectively).

The doublet regimen showed a similar benefit to that of the triplet therapy, at a median overall survival of 8.4 months (HR vs the control arm, 0.60; P = .0003).

Although the study was not powered to perform this analysis, the data also suggested that there was no significant difference in survival benefit between the triplet and doublet arms, Koptz commented.

In terms of ORR, both the triplet and doublet arms performed significantly better than control chemotherapy, at 26% and 20%, respectively, vs just 2% for patients treated with the current standard of care (P < .0001).

Interestingly, for those patients who had been treated with just one prior line of therapy, ORR was better if they were given triplet therapy, at 34%, vs 22% in the doublet arm and 2% in the control arm.

Among patients who had received more than one prior line of therapy, the ORR was 14% with triplet therapy, 16% with doublet therapy, and, once again, 2% in the control arm.

PFS was significantly better with both the triplet and doublet regimens vs control treatment.

Compared with a median PFS of just 1.5 months with control chemotherapy, triplet therapy was associated with a median of 4.3 months (HR, 0.38; P < .0001); for doublet therapy, median PFS was 4.2 months (HR, 0.40; P < .0001).

Details Regarding Toxicity

Safety outcomes were assessed after a median duration of exposure of 7 weeks for control therapy, 21 weeks for the triplet regimen, and 19 weeks for the doublet regimen.

The risk of grade 3/4 adverse events was similar across the patient groups, at 58% in the triplet arm, 50% in the doublet arm, and 61% in those treated with standard chemotherapy.

Events leading to discontinuation of all drugs were recorded in 7% of patients who received the triplet regimen, 8% of those given doublet therapy, and 11% of those given chemotherapy.

It was notable that, in terms of individual adverse events, patients given doublet therapy were less likely than those in both the triplet and chemotherapy arms to experience diarrhea, abdominal pain, vomiting, and pulmonary embolism.

The study is sponsored by Array BioPharma in collaboration with Merck KGaA, Darmstadt, Germany, Pierre Fabre Medicament and Ono Pharmaceutical Co Ltd. Kopetz has stock and other ownership interests in MolecularMatch and Navire and consulting or advisory roles with Roche, Genentech, EMD Serono, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amal Therapeutics, Amgen, Novartis, Eli Lilly, and Boehringer Ingelheim. He has received institutional research funding from Amgen, Sanofi, Biocartis, Guardant Health, Array Biopharma, Genetech, EMD Serono, MedImmune, and Novartis.

World Conference on Gastrointestinal Cancer (WCGC) 2019: Abstract LBA-006. Presented July 6, 2019.

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