FDA Approves Encorafenib/Cetuximab Combo for BRAF+ mCRC

The FDA has approved the combination of encorafenib (Braftovi) and cetuximab (Erbitux) for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.¹

Findings from the study published in 2019 in the New England Journal of Medicine showed that, 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).² The median OS in the doublet arm was 8.4 months (HR vs control, 0.60; 95% CI, 0.45-0.79; P = .0003).

Both the triplet (HR, 0.38; 95% CI, 0.29-0.49; P <.001) and the doublet (HR, 0.40; 95% CI, 0.31-0.52; P <.001) significantly improved progression-free survival (PFS) over the control arm. The median PFS was 4.3 months in the triplet arm, 4.2 months with the doublet, and 1.5 months in the control arm.

Updated OS results reported at the 2020 Gastrointestinal (GI) Cancers Symposium showed a median OS of 9.3 months with either the triplet or doublet compared with 5.9 months in the control arm.³ The ORRs were 26% with the triplet, 20% with the doublet, and 2% in the control arm.

"BRAF mutations are estimated to occur in up to 15% of people with metastatic colorectal cancer and represent a poor prognosis for these patients,” lead study investigator Scott Kopetz, MD, PhD, FACP, associate professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a press release. “As the first-and-only targeted regimen for people with BRAF V600E-mutant metastatic CRC who have received prior therapy, Braftovi in combination with cetuximab is a much-needed new treatment option for these patients.”

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 most common adverse events (AEs; ≥ 25%) seen in patients treated with encorafenib in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia and rash.¹ The rates of grade 3/4 AEs, and serious AEs were comparable across the 3 arms.

An analysis presented at the GI Cancers Symposium also showed that 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.³

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.

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. Additionally, the triplet regimen has been included as a category 2A treatment for patients with BRAF V600E—mutant metastatic CRC, following failure of 1 or 2 prior lines of therapy in National Comprehensive Cancer Network guidelines for colon and rectal cancers in the United States.

The ongoing phase II ANCHOR-CRC study (NCT03693170) is investigating the triplet as frontline treatment for patients with metastatic BRAF V600E—mutant CRC.

References

1. U.S. FDA APPROVES BRAFTOVI® (ENCORAFENIB) IN COMBINATION WITH CETUXIMAB FOR THE TREATMENT OF BRAFV600E-MUTANT METASTATIC COLORECTAL CANCER (CRC) AFTER PRIOR THERAPY. Published April 8, 2020. https://bit.ly/34opTAr. Accessed April 8, 2020.
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.
3. 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.

The approval is based on findings from the phase III BEACON CRC study, which evaluated encorafenib plus cetuximab with or without binimetinib (Mektovi) in this patient population. Results showed that both the doublet and triplet approaches demonstrated an improvement in overall survival (OS) as well as objective response rates (ORRs) versus cetuximab plus irinotecan-containing regimens.