Regulatory Decision Summary for Braftovi

The primary efficacy and safety data for the proposed indication for Braftovi were provided by one pivotal Phase 3 study performed in the target population. The BEACON study was a randomized, active-controlled, open-label, 3-arm, international multicentre trial comparing treatment with Braftovi (encorafenib) in combination with cetuximab and binimetinib (Triplet regimen) and Braftovi in combination with cetuximab (Doublet regimen) to the Investigator’s choice of cetuximab in combination with irinotecan or cetuximab in combination with Folfiri (Control regimen). Eligible patients were required to have BRAF V600E mutation-positive metastatic colorectal cancer. Patients were randomized 1:1:1 to receive the Triplet regimen (encorafenib 300 mg QD + binimetinib 45 mg BID + standard cetuximab [400 mg/m² followed by 250 mg/m² IV QW]), the Doublet regimen (encorafenib 300 mg QD + standard cetuximab), or the Control regimen (standard cetuximab + irinotecan [180 mg/m² Q2W] or cetuximab + Folfiri [irinotecan 180 mg/m² Q2W + Folinic acid 400 mg/m² Q2W + 5-fluorouracil 400 mg/m² bolus then 1,200 mg/m²/day continuously for 2 days, Q2W]). Treatment continued until disease progression or unacceptable toxicity.

The Sponsor’s evaluation of the totality of efficacy and safety data concluded that the addition of binimetinib to the Braftovi and cetuximab (Doublet) combination did not provide meaningful clinical benefit to patients and that the safety profile was less favourable. Thus, the Sponsor proposed an indication for only the Doublet regimen (Braftovi in combination with cetuximab).

The primary efficacy endpoints were overall response rate (ORR) as assessed by blinded independent central review (BICR) and overall survival (OS), comparing the Triplet regimen to the Control regimen. The key secondary efficacy endpoint was OS, comparing the Doublet regimen to the Control regimen.

Patients treated with the Triplet regimen demonstrated a statistically and clinically significant improvement in ORR (BICR) with a confirmed ORR of 26.1% compared with 1.9% in the Control arm (p <0.0001). The primary analysis of OS demonstrated a clinically and statistically significant improvement in OS for the Triplet arm with a hazard ratio (HR) of 0.52 (95% CI: 0.39, 0.70; p <0.0001). This corresponded to an increase in OS of 9.03 months (95% CI: 8.02, 11.43) in the Triplet arm and 5.42 months (95% CI: 4.76, 6.57) in the Control arm. For the key secondary endpoint of OS, Doublet arm compared with the Control arm, patients in the Doublet arm demonstrated a clinically and statistically significant improvement in OS with a HR of 0.60 (95% CI: 0.45, 0.79; p = 0.0002). This corresponded to an increase in OS of 8.41 months (95% CI: 7.46, 11.04) in the Doublet arm compared with 5.42 months (95% CI: 4.76, 6.57) in the Control arm. As the primary and key secondary endpoints were statistically significant, three additional secondary endpoints were formally tested in the pre-specified hierarchical testing strategy and were found to be statistically significant. These included ORR by BICR, Doublet versus Control arm; progression-free survival (PFS) by BICR, Triplet versus Control arm; and PFS by BICR, Doublet vs. Control arm. All prespecified sensitivity, supportive, and subgroup analyses demonstrated differentiation between the Triplet and Doublet arms and the Control arm, consistent with the primary analyses.

The study was not designed or powered to directly compare the efficacy of the Triplet and Doublet regimens. The majority of analyses slightly favoured the Triplet regimen; however, descriptive statistics demonstrated no significant differences between the Triplet and Doublet regimens.

Overall, the reported safety data from the BEACON trial, based on a median duration of treatment of 15.9, 14.0, and 6.3 weeks in the Triplet, Doublet, and Control arms, respectively, was generally consistent with the known safety profiles of marketed BRAF and MEK inhibitors. The Doublet regimen demonstrated an overall superior safety and tolerability profile compared with the Triplet and Control regimens. The overall exposure-adjusted incidence rate (EAIR) for any preferred term per 100 patient-months of exposure was 359.69 for patients receiving the Doublet regimen compared with 485.66 for patients receiving the Triplet regimen and 526.91 for patients receiving the Control regimen.

Fewer patients receiving the Doublet regimen experienced adverse reactions that led to dose interruptions and reductions of Braftovi, and adverse reactions that led to discontinuation of Braftovi were similar between the Triplet and Doublet regimens. On-treatments deaths were slightly higher in the Doublet arm compared with the Triplet and Control arms.

The most common adverse reactions in patients receiving the Doublet regimen were nausea, diarrhea, dermatitis acneiform, vomiting, decreased appetite, abdominal pain, and asthenia. A lower percentage of patients receiving the Doublet regimen experienced Grade ≥3 adverse events (AEs), serious AEs, and AE of special interest (AEoSI) compared with the Triplet and Control (not containing encorafenib) arms. The most clinically significant adverse drug reactions identified in this patient population were new primary cutaneous malignancies, major hemorrhagic events, venous thromboembolism, and QT prolongation.

The clinical pharmacological and non-clinical data support the intended use of Braftovi in the target population. Key findings, relevant risks, and uncertainties were addressed in the final Product Monograph.

The Risk Management Plan was considered acceptable.

Overall, the safety profile of Braftovi in combination with cetuximab is considered acceptable in the target population of patients with this life-threatening disease, with adverse events generally manageable by dose reduction, temporary interruption, or additional therapy. Appropriate labelling in the final Braftovi Product Monograph, including recommendations for AE monitoring and dose modifications, has been completed for adequate management of risks associated with Braftovi therapy.

Overall, the benefit-risk profile of Braftovi in combination with cetuximab is favourable, and this regimen provides a new treatment option for patients with BRAF V600E mutation-positive metastatic colorectal cancer whose disease has progressed after one or two prior regimens in the metastatic setting.