Encorafenib Plus Cetuximab Approved in Europe for BRAF V600E-Mutant mCRC

Josep Tabernero, MD, PHD, MSc

The European Commission has approved encorafenib (Braftovi) in combination with cetuximab (Erbitux) for the treatment of adult patients with BRAF V600E—mutant metastatic colorectal cancer (mCRC) who have received prior systemic therapy.¹

The approval is based on findings from the pivotal phase 3 BEACON CRC trial, in which encorafenib plus cetuximab with or without binimetinib (Mektovi) was found to improve overall survival (OS) as well as objective response rates (ORRs) in this patient population compared with cetuximab plus irinotecan-containing regimens.

“The approval is truly great new and much needed for patients with BRAF V600E—mutant mCRC and for physicians treating this devastating cancer, as until now, there has been no EC-approved therapies specifically indicated for this high-medical-need population," Josep Tabernero, MD, PhD, lead investigator of the trial and director of the Vall d’Hebron Institute of Oncology, commented in a press release. “The new encorafenib and cetuximab combination regimen will now change the way we treat these patients, with the possibility of delaying disease progression and prolonging their lives.”

This decision follows the recommendation issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use earlier this month, which was based on earlier findings from the trial published in the New England Journal of Medicine. At a median follow-up of 7.8 months, the median OS was 9.0 months with encorafenib plus cetuximab and binimetinib versus 5.4 months with the control (HR, 0. 52; 95% CI, 0.39-0.70; P <.001).² The median OS with the doublet was 8.4 months (HR vs control, 0.60; 95% CI, 0.45-0.79; P = .0003).

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) both led to significant improvements in progression-free survival (PFS), as well. Specifically, 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.

The ORR was found to be significantly higher with the triplet therapy compared with the control. The independently reviewed confirmed ORR, assessed in the first 331 patients who underwent randomization on the trial, was 26% (95% CI, 18-35) in the triplet arm versus just 2% (95% CI, 0-7) in the control arm (P <.001). In the doublet arm, the ORR was 20% (95% CI, 13-29), which was also determined to be significantly higher than what was observed in the control arm (P <.001).

Updated data presented at the 2020 ASCO Virtual Scientific Program showed continued OS benefit for encorafenib with or without binimetinib versus the control. Results from the posthoc updated analysis demonstrated at a median follow-up of 12.8 months, the median OS was 9.3 months in the doublet arm versus 5.9 months in the control arm (HR, 0.61; 95% CI, 0.48-0.77).³ The median OS with the triplet was also 9.3 months (HR vs control; 0.60; 95% CI, 0.47-0.75).

Notably, in both the triplet and doublet arms, the OS benefit was maintained in comparison with the control arm across all key subgroups, including those defined by the use of prior irinotecan, microsatellite instability status, and number of prior regimens.

Additionally, the ORR in the triplet, doublet, and control arms were 27%, 20%, and 2%, respectively. The ORR with the triplet was comprised of a complete response (CR) rate of 4% and a partial response (PR) rate of 23%. An additional 48% of patients achieved stable disease on the treatment, while 11% experienced disease progression and 14% were not evaluable for response. The ORR in the doublet arm was comprised of a CR rate of 3% and a PR rate of 16%. Another 56% of patients had stable disease with the doublet, while 10% experienced disease progression and 15% were determined to be unevaluable for response.

The updated data revealed a 3-month improvement in PFS with the triplet versus the control arm, at 4.5 months versus 1.5 months, respectively (HR, 0.42; 95% CI, 0.33-0.53). The median PFS with the doublet was 4.3 months (HR vs control, 0.44; 95% CI, 0.35-0.55).

An analysis presented at the 2020 Gastrointestinal Cancers Symposium also indicated that the triplet and the doublet regimens reduced the risk of quality of life (QoL) deterioration by more than 40% via multiple QoL assessment instruments versus the control regimen.⁴

The following 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 evaluated at screening/baseline, day 1 of every treatment cycle, at the end of treatment, and at the 30-day safety follow-up visit. Compliance with the tools were high across all arms.

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

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

The median TTD in the EQ 5D 5L was 5.59 months with the triplet versus 5.36 with the doublet, and 2.37 in the controls, translating to reductions in risk of 5.1% in the triplet arm versus the control (HR, 0.49; 95% CI, 0.38-0.63) and 51% in the doublet arm versus the control (HR, 0.49; 95% CI, 0.39-0.63).

Moreover, more than half of the patients who received the triplet, or 53%, and 58% of those who were given the doublet experienced at least a minimal improvement in symptoms on the PGIC versus only 36% of those who received the control regimen.

Based on data from this trial, the FDA approved the doublet in April 2020 for use in adult patients with mCRC whose tumors harbor a BRAF V600E mutation, as detected by an FDA-approved test, following prior therapy.

The ongoing phase 2 ANCHOR-CRC trial (NCT03693170) is evaluating the triplet as frontline treatment for patients with BRAF V600E—mutant mCRC.

References

1. Pierre Fabre receives European approval for Braftovi (encorafenib) in combination with cetuximab for the treatment of adult patients with BRAFV600E-mutant metastatic colorectal cancer. News release. June 3, 2020. Accessed June 3, 2020. bwnews.pr/30aUJwt.
2. Kopetz S, Grothey A, Yaegar R, Van Cutsem E, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi:10.1056/NEJMoa1908075
3. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020;38(suppl 15):4001. doi:10.1200/JCO.2020.38.15_suppl.4001
4. 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). J Clin Oncol. 2020;38(suppl 4):8. doi:10.1200/JCO.2020.38.4_suppl.8