FDA Grants Breakthrough Therapy Designation for Dabrafenib for NSCLC


The FDA has granted a Breakthrough Therapy designation to dabrafenib for its potential as a treatment for patients with metastatic BRAF V600E mutation-positive NSCLC who have received at least one prior line of platinum-containing chemotherapy.

BRAF V600Emutation-positive non-small cell lung cancer (NSCLC) who have received at least one prior line of platinum-containing chemotherapy.

The new designation was based on results from the phase II study BRF113928 that showed durable antitumor activity, including an overall response rate (ORR) of 40% in patients withBRAF V600Emutation—positive pretreated NSCLC patients. The FDA's Breakthrough Therapy designation will help expedite GlaxoSmithKline's development of dabrafenib in NSCLC. The breakthrough development program is intended to speed up the review process for treatments for serious or life-threatening conditions and offers several regulatory advantages.  

The phase II study that was the basis for the designation enrolled 20 patients in the first stage of clinical development followed by an additional 20 patients in the second stage. The primary endpoint was investigator assessed ORR. Interim results from the first 20 patients were presented at the 2013 ASCO Annual Meeting in June.

“Preliminary efficacy data from the first 20 patients is the first demonstration of clinical activity of a BRAF inhibitor in BRAF V600E NSCLC,” David Planchard, MD, PhD, of Institut Gustave-Roussy in Villejuif, France, said during the presentation of the results. “[The] safety profile with dabrafenib was consistent with previous studies in melanoma.”

In the open-label study, 20 patients withBRAF V600E-mutated NSCLC of adenocarcinoma histology received dabrafenib at 150 mg twice daily. All patients were Caucasian with an ECOG performance status of 0-2 and the majority were male (64%). Patients with brain metastases larger than 1 cm were excluded from the study. All patients had progressed on at least 1 prior systemic chemotherapy agent prior to the study.

At the interim analysis, 8 patients (40%) treated with dabrafenib experienced a partial response with no complete responses observed (ORR = 40%; 95% CI, 19.1%-63.9%). Additionally, 4 patients had stable disease and 6 patients had progressive disease (disease control rate = 60%; 95% CI, 36.1%-80.9%). The median duration of treatment for all patients was 12 weeks. At the time of the presentation, 2 patients remained on dabrafenib for >1 year.

Five (20%) of the patients on the trial were heavy smokers (>40 pack years). Planchard indicated that none of these patients contrived benefit from dabrafenib.

The safety of dabrafenib in NSCLC was assessed in 25 patients from both stages of the phase II development. The most common all grade adverse events were fatigue (40%), decreased appetite (32%), rash (24%), asthenia (24%), nausea (24%) and anemia (24%). Altogether, 11 patients (44%) experienced grade 3 adverse events and 1 patient experienced a grade 5 adverse event. Altogether, 2 patients (8%) developed squamous cell carcinoma, which did not alter treatment.

“Dabrafenib shows promising clinical activity for patients with metastaticBRAF V600E-mutated NSCLC,” Planchard said in his presentation. “Study has expanded sample size and now allows enrollment of first-line patients.”

ActivatingBRAF V600Emutations are present in approximately 1.6% of patients with NSCLC, primarily in the adenocarcinoma subtype. The BRAF inhibitor dabrafenib has demonstrated clinical activity inBRAF V600mutated metastatic melanoma, which resulted in the FDA approval of the drug both as a single-agent and in combination with the MEK inhibitor trametinib.

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