Triplet and Doublet Regimens Outperform Standard of Care on Survival, QoL in BRAF+ CRC

Scott Kopetz, MD, PhD, FACP

Encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) demonstrated longer maintenance of quality of life (QoL) on patient-reported assessments over current standard of care in the treatment of patients with BRAF V600E-mutant metastatic colorectal cancer.

In the phase III BEACON CRC study, both the triplet and doublet regimens reduced the risk of QoL deterioration by more than 40% by multiple QoL assessment instruments compared with the control regimen, said Scott Kopetz, MD, PhD, at the 2020 Gastrointestinal (GI) Cancers Symposium.

In addition, updated overall survival (OS) results from the study showed additional improvement in median OS of 1 month, to 9.3 months, in the doublet arm (encorafenib plus cetuximab), with a median OS follow-up of almost 13 months.¹

As reported previously and published in the New England Journal of Medicine, 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 (HR, 0.52; 95% CI, 0.39-0.70; P <.001). The median OS in the doublet arm was 8.4 months (HR vs control, 0.60; 95% CI, 0.45-0.79; P <.001).²

Updated OS results showed median OS of 9.3 months with either the triplet or doublet compared with 5.9 months in the control arm, said Kopetz , professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston. The overall response rates at the updated analysis were 26% with the triplet, 20% with the doublet, and 2% in the control arm. No new safety signals were identified in the updated analysis.

BEACON CRC was an international open-label phase III trial that enrolled 665 patients with BRAF V600E—mutated metastatic colorectal cancer whose disease had progressed after 1 or 2 prior regimens. After a safety lead-in, patients were randomly assigned in a 1:1:1 ratio to the targeted therapy triplet of encorafenib, binimetinib, and cetuximab; the targeted therapy doublet of encorafenib and cetuximab; or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan).

Relative dose intensity was high in each arm. Dose intensity in the triplet arm was 91% for encorafenib, 87% for binimetinib, and 91% for cetuximab. In the doublet arm, it was 98% for encorafenib and 93% for cetuximab. For the control arm, it was 74% to 85%. The rates of adverse events (AEs), grade 3/4 AEs, and serious AEs were comparable across the 3 arms.

“We recognized that safety doesn’t always capture the patient experience and that is the rational for incorporating QoL metrics into the study. This is an important component that really helps to understand the patient experience and complements the clinical efficacy endpoint,” said Kopetz.

The QoL assessments, a secondary endpoint from BEACON CRC, were reported at the GI Symposium. Four QoL instruments were used: EORTC QLQ 30 (EORTC QOL Questionnaire), FACT C (Functional Assessment of Cancer Therapy Colon Cancer), EQ 5D 5L (EuroQoL 5D 5L), and PGIC (Patient Global Impression of Change). These instruments were assessed at screening/baseline, at day 1 of every treatment cycle, at end of treatment, and the 30-day safety follow-up visit.

Compliance with each of the tools was high across all arms: 85% to 97% with the EORTC QLQ 30, FACT C, and EQ 5D 5L instruments, and 67% to 89% with the PGIC. The primary assessment in the EORTC QLQ 30, FACT C, and EQ 5D 5L instruments scales was the time to definitive 10% deterioration in scores.

The median time to deterioration (TTD) in the EORTC QLQ 30 was 4.96 months in the triplet arm vs. 2.2 months in the control arm, corresponding to a delay in deterioration by 45% with the triplet (HR, 0.55; 95% CI, 0.43-0.70). In the doublet arm, median TTD on this same scale was 4.6 months, corresponding to a 46% delay in deterioration compared with controls (HR, 0.54; 95% CI, 0.43-0.69).

The median TTD in the FACT C scale was 5.65 months in the triplet arm versus 2.0 months in the control arm, for a reduction in risk of 52% (HR, 0.48; 95% CI, 0.38-0.62). In the doublet arm, the median TTD on the FACT C was 5.36 months, translating to a 54% reduction versus control (HR, 0.46; 95% CI, 0.36-0.59).

On the EQ 5D 5L, the median TTD was 5.59 months in the triple arm, 5.36 months in the doublet arm, and 2.37 months in the controls, corresponding to reductions in risk of 51% in the triplet arm versus controls (HR, 0.49; 95% CI, 0.38-0.63) and 51% in the doublet arm compared with the control arm (HR, 0.49; 95% CI, 0.39-0.63).

Some 53% of patients randomized to the triplet and 58% randomized to the doublet had at least a minimal improvement in symptoms on the PGIC compared with only 36% of the controls.

Published data showed that discontinuation of therapy due to AEs occurred in 7%, 8%, and 11% of patients in the triplet, doublet, and controls arms, respectively. The most common grade 3/4 AEs observed in the triplet arm were diarrhea (11% vs 3% in the doublet arm and 10% in the control arm), abdominal pain (6% vs 3% in the doublet arm and 5% in the control), and nausea (5%, <1%, and 2%, in the 3 arms, respectively).

“On the basis of these results, the decision was made not to submit binimetinib to the FDA, and the doublet of encorafenib and cetuximab is under review,” Kopetz said.

References

1. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Presented at GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 8.
2. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381:1632-1643.

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