EU Approval Sought for Encorafenib/Binimetinib in BRAF V600+ Advanced NSCLC

NSCLC

The European Medicines Agency had validated the submission of a marketing authorization application (MAA) seeking the approval of the combination of encorafenib (Braftovi) and binimetinib (Mektovi) for the treatment of adult patients with BRAF V600–mutant advanced non–small cell lung cancer (NSCLC) who are treatment naïve or have received prior therapy.¹

The MAA is supported by data from the phase 2 PHAROS trial (NCT03915951), which demonstrated that treatment-naïve patients who received the combination (n = 59) experienced an overall response rate (ORR) of 75% (95% CI, 62%-85%), including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates of 15%, 59%, 17%, and 3%, respectively.²

Previously treated patients (n = 39) achieved an ORR of 46% (95% CI, 30%-63%), including CR, PR, SD, and PD rates of 10%, 36%, 33%, and 8%, respectively.

"Lung cancer is the number one cause of cancer death worldwide, and there are currently limited effective targeted treatment options for patients with BRAF V600–mutant advanced NSCLC. With our strategic focus on lung cancer and oncology precision medicine, this submission is the next step in delivering clinically meaningful change to oncology patient populations with high unmet needs," Eric Ducournau, chief executive officer of Pierre Fabre Laboratories, stated in a news release.¹

On October 11, 2023, the FDA approved encorafenib plus binimetinib for the treatment of adult patients with metastatic NSCLC harboring a BRAF V600E mutation, as detected by an FDA-approved test.3 That regulatory decision was also supported by data from PHAROS.

The single-arm, open-label, multicenter trial enrolled patients with metastatic NSCLC harboring BRAF V600 mutations who had an ECOG performance status of 0 or 1.2 Patients were not allowed to have EGFR mutations, ALK fusions, or ROS1 rearrangements, and no more than 1 prior line of therapy in the advanced setting was permitted. Prior treatment with a BRAF or MEK inhibitor was not allowed, and patients could not have brain metastases.

BRAF mutation testing was conducted by PCR- or next-generation sequencing–based assays via a central laboratory.

All patients received 450 mg of oral encorafenib once per day in combination with 45 mg of oral binimetinib twice per day in 28-day cycles. Treatment continued until disease progression or unacceptable toxicity.

ORR as assessed by an independent radiology review (IRR) served as the trial’s primary end point. Secondary end points consisted of investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), time to response (TTR), overall survival (OS), and safety.

Additional data showed that treatment-naïve patients experienced a 24-week DCR of 64% (95% CI, 51%-76%). The DOR was not evaluable (NE; 95% CI, 23.1-NE), and 59% of patients maintained a response for 12 months or longer. The median TTR was 1.9 months (range, 1.1-19.1). Additionally, encorafenib/binimetinib elicited a median PFS that was not reached (NR; 95% CI, 15.7-NE) and a median OS that was NR.

Previously treated patients achieved a 24-week DCR of 41% (95% CI, 26%-58%).2 The combination generated a median DOR of 16.7 months (9% CI, 7.4 months-NR), and 33% of patients maintained a response for at least 12 months. The median TTR was 1.7 months (range, 1.2-7.3) The median PFS was 9.3 months (95% CI, 6.2-NE), and the median OS was NR.1

Pooled data from treatment-naïve and previously treated patients (n = 98) showed that 94% of patients experienced any-grade treatment-related adverse effects (TRAEs), including 38% who had grade 3 TRAEs and 3% who had grade 4 TRAEs.2

The most common TRAEs reported in more than 10% of patients included nausea (any grade, 50%; grade 3, 3%), diarrhea (43%; 4%), fatigue (32%; 2%), vomiting (29%; 1%), anemia (18%; 3%), blurred vision (17%; 1%), constipation (13%; 0%), increased alanine aminotransferase (12%; 5%), increased aspartate aminotransferase (12%; 7%), pruritus (12%; 0%), increased blood creatine phosphokinase (11%; 0%), and peripheral edema (11%; 0%).

References

1. European Medicines Agency validates Pierre Fabre Laboratories' marketing authorisation application for combination Braftovi (encorafenib) and Mektovi (binimetinib) for patients with BRAFV600-mutant advanced non-small cell lung cancer (NSCLC). News release. Pierre Fabre Laboratories. November 2, 2023. Accessed November 2, 2023. https://www.prnewswire.com/news-releases/european-medicines-agency-validates-pierre-fabre-laboratories-marketing-authorisation-application
2. Riely GJ, Smit EF, Ahn M-J, et al. Efficacy and safety of encorafenib (enco) plus binimetinib (bini) in patients with BRAF V600E-mutant (BRAFV600E) metastatic non-small cell lung cancer (NSCLC) from the phase 2 PHAROS study. J Clin Oncol. 2023;41(suppl 16):9018. doi:10.1200/JCO.2023.41.16_suppl.9018
3. FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation. FDA. October 11, 2023. Accessed November 2, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation