The combination of encorafenib plus cetuximab, with or without binimetinib, improved the quality of life based on patient-reported assessments better than current standard of care in the treatment of patients with metastatic colorectal cancer (CRC) and BRAF V600E mutation, according to the BEACON CRC study, which was presented at the 2020 Gastrointestinal Cancers Symposium.
In the BEACON CRC study, the triplet and the doublet regimens reduced the risk for quality-of-life deterioration by more than 40% by multiple assessment instruments compared with the control regimen, according to Scott Kopetz, MD, PhD, FACP, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, M.D. Anderson Cancer Center, Houston, TX. The median overall survival (OS) of the doublet was equal to that of the triplet with additional follow-up; therefore, the 2-drug combination of encorafenib plus cetuximab will be submitted to the FDA for review, said Dr Kopetz.
“On the basis of these results, the decision has been made not to submit the binimetinib [triplet] to the FDA, and the doublet of encorafenib plus cetuximab is now under review,” Dr Kopetz said.
The BEACON CRC study was an international open-label phase 3 clinical trial of 665 patients with metastatic CRC and BRAF V600E mutation whose disease had progressed after 1 or 2 previous regimens. After a safety lead-in, patients were randomized to 3 groups: the triplet targeted therapy of encorafenib, binimetinib, and cetuximab; the doublet targeted therapy of encorafenib and cetuximab; or the control group of the investigators’ choice of current standard of care with either cetuximab plus irinotecan or cetuximab plus FOLFIRI (folinic acid, fluorouracil, and irinotecan).
As was published in late 2019 (Kopetz S, et al. N Engl J Med. 2019;381:1632-1643), 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 (hazard ratio [HR], 0.52; P <.001). The median OS in the doublet arm was 8.4 months (HR, 0.60; P <.001).
Dr Kopetz reported updated OS results showing additional improvement in OS of 1 month—to 9.3 months—in the doublet arm, with a median OS follow-up of nearly 13 months.
“There’s no discernible difference in the survival curves,” Dr Kopetz said. “So in my practice right now, I’m using the doublet.”
The rates of adverse events, including grade 3 to 4 events and serious adverse events, were comparable across the 3 arms. The overall adverse events were 50% with the doublet, 58% with the triplet, and 61% in the control group. The most common grade 3 to 4 adverse events in the triplet arm were diarrhea (10% vs 2% in the doublet arm and 10% in the control arm), abdominal pain (6% vs 2% and 5%, respectively), and nausea (5%, <1%, and 1%).
“We recognized that safety doesn’t always capture the patient experience, and that is the rationale for incorporating quality-of-life metrics into the study. This is an important component that really helps to understand the patient experience and complements the clinical efficacy end point,” Dr Kopetz said.
Four quality-of-life measures were used, including EORTC QLQ-C30, FACT-C, EQ-5D-5L, and PGIC. The results were evaluated at baseline, then at day 1 of every treatment cycle, at end of treatment, and again at a 30-day follow-up safety evaluation.
The median time to deterioration in the EORTC QLQ-C30 was delayed by 45% with the triplet arm versus the control arm (4.96 months vs 2.2 months). In the doublet arm, the median time to deterioration on this same scale was 4.6 months, translating to a 46% delay in deterioration compared with controls.
In the doublet arm, the median time to deterioration on the FACT-C was 5.36 months, corresponding to a 54% reduction versus the control arm.
The median time to deterioration on the EQ-5D-5L was delayed by 51% in the doublet arm versus the controls.
At least a minimal improvement in symptoms on the PGIC was reported by 53% of the patients randomized to the triplet, 58% randomized to the doublet, and only 36% of the controls.
Commenting on this study, Christopher M. Booth, MD, FRCPC, Canada Research Chair in Population Cancer Care, Queen’s University, Kingston, Canada, focused on the financial toxicity of the new regimens, noting that a 28-day supply of the doublet would cost approximately $23,000 compared with approximately $32,000 with the triplet regimen. The average treatment course would cost $109,000 and $168,000, respectively, with annual costs reaching $280,000 and $305,000.
“We have to be pragmatic about the resources we have for cancer care and think very carefully about the magnitude of benefit relative to the price, so I think I would leave the answer to a formal cost-effectiveness analysis,” said Dr Booth.