Encorafenib/Binimetinib Exhibits Anti-Tumor Activity in Untreated BRAF-Mutant Advanced NSCLC

David Planchard, MD, PhD

Encorafenib (Braftovi) plus binimetinib (Mektovi) demonstrated anti-tumor activity in patients with treatment-naïve BRAF V600E-mutant advanced non–small cell lung cancer (NSCLC), according to data from the phase 2 ENCO-BRAF study (NCT04526782), presented at the 2024 ESMO Congress.

At a data cutoff of March 28, 2024, the investigator-assessed overall response rate (ORR) was 65.6% in 40 of 61 patients (95% CI, 53.7%-77.5%) in cohort A. Partial responses were seen in 65.6% of patients (n = 40), stable disease in 19.7% (n = 12), progressive disease in 8.2% (n = 5), and not evaluable in 6.6% (n = 4) due to death (n =2), toxicity (n =1), and patient’s decision (n = 1).

“The study was designed to test the null hypothesis of 40% or lower overall response rate in treatment-naïve patients, and the alternative [target] rate of at least 60%. Sixty-four patients have been included in first-line treatment at the data cutoff of March 2024,” David Planchard, MD, PhD, thoracic oncologist and head of the Thoracic Pathology Committee at Gustave Roussy in Villejuif, France, and president of the International Center for Thoracic Cancers, said during the presentation.

In the ongoing phase 2, open-label, single-arm study, patients previously untreated with BRAF V600E-mutant NSCLC received 450 mg of encorafenib once daily with 45 mg of binimetinib twice daily. Patients in cohort A (n = 60) — as presented in the study — were previously untreated, and patients in cohort B (n = 59) included patients who were pretreated with 1 previous line of treatment.

Patients eligible for the study must have been at least 18 years old, had a WHO performance status of 0 or 1, BRAF V600E mutation (enrollment via local assay), no prior anti-BRAF cancer therapy, stable central nervous system metastases was allowed, and were in first- or second-line of treatment.

Across 24 centers in France between March 2021 and September 2023, cohort A included 64 patients with a median age of 70.7 years (range, 39.1-90.3 years). Baseline brain metastases occurred in 17.2% of patients (n = 11), 46.9% were male (n = 30), and 35.9% were never smokers (n = 23).

The primary end point was investigator assessed confirmed ORR per RECIST v1.1 every 8 weeks for 12 months, then every 12 weeks; secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

The median DOR was 13 months (95% CI, 9.1 months-not reached [NR]) and the DCR was 85.2% (95% CI, 76.3%-94.1%). The median PFS and OS were 10.9 months (95% CI, 6.4-16.7 months) and not reached (95% CI, 20.7-NR), respectively.

Regarding safety, the most common treatment-related adverse events (TRAEs) included fatigue (42.2%), nausea (32.8%), and diarrhea (31.3%). Overall, 92.2% of patients (n = 59) experienced any grade TRAEs, with 50.0% (n = 32) who experienced grade 3 or higher TRAEs. Dose interruptions for encorafenib/binimetinib occurred in 32.8% (n = 21) and 35.9% (n = 23) of patients, respectively. Patients who received at least 1 dose reduction included 34.4% for encorafenib (n = 22) and 32.8% for binimetinib (n = 21). Permanent discontinuation of encorafenib plus binimetinib because of TRAEs occurred in 9.4% of patients (n = 4); death occurred in 3.1% (n = 2) of patients, with 1 case caused by treatment-related dyspnea and 1 case caused by pulmonary embolism not related to treatment.

The study is currently enrolling patients for cohort B to receive second-line treatment for BRAF V600E-mutant NSCLC.

“According to this trial, the ENCO-BRAF trial, and the PHAROS trial, encorafenib plus binimetinib represent a potential new option for this population with BRAF V600E-mutant, advanced non–small cell lung cancer,” Planchard concluded.

References

1. Planchard D, Mazieres J, Mascaux C, et al. Encorafenib plus binimetinib in patients (pts) with previously untreated BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): An open-label, multicenter phase II trial (IFCT-1904 ENCO-BRAF). Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1259MO.