1. Fuerst, Mark L.

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CHICAGO-A combination of dabrafenib and trametinib appears to be highly effective for patients with BRAF V600E-mutation positive (BRAF V600E+) non-small cell lung cancer (NSCLC), according to a study (Abstract 107) presented at the American Society of Clinical Oncology Annual Meeting.

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"This study confirms a fourth actionable biomarker in NSCLC-BRAFV600E-after EGFR, ALK, and ROS-1," said lead author David Planchard, MD, PhD, Thoracic Oncology Specialist, Cancer Institute Gustave-Roussy, Villejuif, France. "The potential to treat this oncogene gives hope to a very small, underserved patient population." The results of the study were published simultaneously in The Lancet Oncology.


Treating NSCLC

BRAF V600E mutations occur in 1-2 percent of patients with NSCLC, and are associated with more aggressive tumors and a poorer prognosis, independent of smoking status.


Dabrafenib and trametinib target different kinases within the serine/threonine kinase family-BRAF and MEK1/2, respectively-in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers.


In this phase II, multicenter, non-randomized, open-label study, 57 patients, median 64 years, with metastatic NSCLC who had the BRAF V600E mutation and failed at least one line of chemotherapy took 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily. The primary endpoint of the trial was investigator-assessed overall response rate (ORR), and key secondary endpoints were duration of response and progression-free survival (PFS). Independent review response rates were consistent with investigator-assessed response.


Nearly three-quarters of patients were former or current smokers, and among the smoking group, nearly half had more than 30 pack-years.


With the combination, the investigator-assessed median duration of response was 9 months. About two-thirds of patients (63%) demonstrated a clinical response; of these patients, half of them continued to respond to treatment at the time of analysis. When adding those with stable disease for at least 12 weeks, the overall disease control rate was 79 percent. The median PFS was 9.7 months.


Median overall survival data were immature at the time of the analysis. The 6-month OS rate was 82 percent. At the 11.6-month follow-up analysis, 60 percent of patients remained alive.


The study also included a single-agent dabrafenib arm that included 78 previously treated patients with metastatic BRAF V600E-mutant NSCLC. In this cohort, the ORR with single-agent dabrafenib was 33 percent and the median PFS was 5.5 months.


The results from both of these cohorts have led to FDA designation as breakthrough therapy for dabrafenib as a single agent and in combination with trametinib. This combination is also approved for the use in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation.


Safety Findings

In terms of safety, Planchard said "nearly all of the patients experienced at least one adverse event, and at least half had at least one grade 3 adverse event. Generally, it was grade 3 adverse events, with few grade 4 or 5 adverse events."


About half of the patients experienced a grade 3/4 adverse event. Serious adverse events were observed in slightly more than half of patients, and one-third of these were grade 3/4. Adverse events led to dose reductions in 35 percent of patients and discontinuation in 14 percent of patients. Dose interruptions or delays were required for 61 percent of patients.


Four patients (7%) died from fatal adverse events not related to study treatment as assessed by the investigator.


The most common all-grade adverse events were pyrexia (46%), nausea (40%), vomiting (35%), diarrhea (33%), asthenia (32%), decreased appetite (30%), peripheral edema (23%), cough (21%), and rash (21%). The most common serious adverse events were pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4 percent), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and squamous cell carcinoma of the skin (4%).


Planchard said: "Dabrafenib plus trametinib provides an important treatment option for patients with BRAF V600E-mutant NSCLC, with greater clinical activity compared with dabrafenib monotherapy. The safety profile was manageable and similar to previous experience in melanoma."


When dabrafenib is used with trametinib, the combination has been shown to slow tumor growth more than either drug alone. The combination is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.


The safety and efficacy profile of the dabrafenib plus trametinib combination has not yet been established outside of the approved indication. Because of the uncertainty of clinical trials, there is no guarantee that the combination will become commercially available with additional indications, Planchard said.


Mark L. Fuerst is a contributing writer.