Encorafenib/Binimetinib Combo Approved in Europe for BRAF V600E+ NSCLC

The European Commission (EC) has approved encorafenib (Braftovi) plus binimetinib (Mektovi) for use in adult patients with advanced non–small cell lung cancer (NSCLC) harboring a BRAF V600E mutation.¹

The regulatory decision is supported by data from the phase 2 PHAROS study (NCT03915951). Data from the primary analysis, which had a data cutoff date of September 22, 2022, indicated that the doublet elicited an objective response rate (ORR) of 75% (95% CI, 62%-85%) by independent radiology review (IRR) in treatment-naive patients (n = 59), meeting the trial’s primary end point. Of those who responded to the regimen, 15% achieved a complete response (CR) and 59% experienced a partial response (PR). With an additional 10 months of follow-up, 64% of these patients had maintained their response for 1 year or longer. The median duration of response (DOR) was 40 months (95% CI, 23.1-not estimable [NE]) per IRR.

Additional data from the primary analysis showed that encorafenib plus binimetinib induced an ORR of 46% (95% CI, 30%-63%) by IRR in patients who previously received treatment (n = 39); 10% of responders had CRs and 36% had PRs. With the additional 10 months of follow-up, 44% of patients had maintained their response for at least 1 year. The median DOR in this group was 16.7 months (95% CI, 7.4-NE).

“The EC approval highlights our ongoing commitment to bring meaningful change to patients with diseases such as lung cancer where there is a high unmet need” Núria Perez-Cullell, head of Medical, Patient, and Consumer Affairs, at Pierre Fabre Laboratories, stated in a news release. “Through our longstanding partnership with Pfizer, we have been able to utilize our capabilities and experience to deliver this innovative treatment combination for patients with BRAFV600Emutant advanced NSCLC. We remain committed to harnessing the full potential of our clinical development programme so that we can continue to bring promising targeted oncology compounds to patients in Europe.”

The open-label, single-arm, multicenter, phase 2 PHAROS study included patients with BRAF V600E–mutated NSCLC who had an ECOG performance status of 0 or 1.² To be eligible, patients could not have previously received more than 1 line of therapy in the advanced setting, nor could they have had prior BRAF or MEK inhibition. Those who had tumor harboring EGFR mutations, ALK fusions, or ROS1 rearrangements were excluded, as were those with symptomatic brain metastases.

Study participants were separated into two groups: those who were treatment naive and those who had received prior treatment. All patients were administered encorafenib at a once daily dose of 450 mg plus binimetinib at a twice daily dose of 45 mg in 28-day cycles. Treatment continued until disease progression or intolerable toxicity.

In addition to the trial’s primary end point being ORR by IRR, secondary end points included investigator-assessed ORR; DOR, disease control rate (DCR), progression-free survival (PFS), and time to response (TTR), all per IRR and investigator assessment; overall survival (OS); and safety. Investigators also conducted biomarker and pharmacokinetic analyses.

Data from the primary analysis of the study were shared during the 2023 ASCO Annual Meeting. Additional data from the analysis indicated that in the treatment-naive subset, the 24-week DCR was 64% (95% CI, 51%-76%) and the median TTR was 1.9 months (95% CI, 1.1-19.1). Moreover, the median DOR was NE (95% CI, 23.1-NE) with 59% of patients experiencing a DOR of at least 12 months. In the previously treated subset, the DCR at 24 weeks was 41% (95% CI, 26%-58%) and the median TTR was 1.7 months (95% CI, 1.2-7.3). The median DOR was 16.7 months (95% CI, 7.4-NE) with 23% of patients experiencing a DOR of at least 12 months. By investigator assessment, the respective ORRs with the doublet in the treatment naive and previously treated groups were 63% and 41%.

At a median follow-up of 18.2 months (95% CI, 16.4-22.3) in the treatment-naive subset, the median PFS was NE (95% CI, 15.7-NE) by IRR. At a median follow-up of 12.8 months (95% CI, 9.0-19.8) in the previously treated subset, the median PFS was 9.3 months (95% CI, 6.2-NE). At the time of the data cutoff date, the OS data were immature.

Regarding safety in the overall population (n = 98), any-grade treatment-related adverse effects occurred in 94% of patients; 38% of patients experienced grade 3 effects, and 3% experienced grade 4 effects. The most common TRAEs to occur in more than 10% of patients were 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%), and peripheral edema (11%).

In October 2023, the FDA approved encorafenib plus binimetinib for this patient population based on early PHAROS findings.³

References

1. Pierre Fabre Laboratories receives European Commission approval for BRAFTOVI® (encorafenib) in combination with MEKTOVI® (binimetinib) for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAFV600Emutation. News release. Pierre Fabre Laboratories. August 30, 2024. Accessed August 30, 2024. https://mma.prnewswire.com/media/2493283/Pierre_Fabre_Approval.pdf
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 August 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation