Bruno Strigini, CEO
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) as a treatment for patients with advanced or metastatic BRAF V600E
-mutant non–small cell lung cancer (NSCLC). The positive opinion will now be reviewed by the European Commission and a final approval decision for use in the European Union is expected in about 2 months.
The application is based on a phase II trial1,2
in which the investigator assessed objective response rate (ORR) with the combination was 63.2% (95% CI, 49.3-75.6), which lasted for a median duration of 9.0 months (95% CI, 6.9-18.3). When adding those with stable disease for ≥12 weeks, the overall disease control rate was 79% (95% CI, 66-89). The median progression-free survival (PFS) was 9.7 months (95% CI, 6.9-19.6).
In addition to the combination cohort, the study also included a single-agent arm that included 78 previously treated patients with metastatic BRAF V600E
–mutant NSCLC. In this cohort, the ORR with single-agent dabrafenib was 33% and the median PFS was 5.5 months.
"At Novartis, we are committed to finding treatments for rare cancers with an unmet need. Today's CHMP opinion marks a major milestone for NSCLC patients with the BRAF V600 mutation, who have very limited treatment options," said Bruno Strigini, CEO, Novartis Oncology. "We welcome the CHMP's opinion as a first step towards that goal, and look forward to continuing to work with European health authorities to make Tafinlar plus Mekinist available for appropriate NSCLC patients."
In the phase II study, 57 patients were treated with dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily. Patients in the study had received at least 1 prior line of platinum-based chemotherapy, with 33% having received ≥2 prior regimens. The primary endpoint of the study was ORR by RECIST criteria, with secondary outcome measures focused on PFS, duration of response, overall survival (OS), and safety.
The median age of patients was 64 years and 98% had adenocarcinoma histology. The most common ECOG performance status was 1 (61%). The majority of patients were former or current smokers (72%), 51% were male, and 86% were Caucasian. In the smoking group, 46% of patients had >30 pack years.
After a median follow-up of 11.6 months, 2 patients (4%) had experienced a complete response with the combination by investigator assessment. Overall, 9 patients had stable disease as their best response (16%). At the data cutoff in October 2015, 50% of confirmed responses remained ongoing.
By independent assessment, there were no complete responses and the stable disease rate was 7%. The ORR by independent review remained 63%; however, the disease control rate was 75%. Duration of response was 9 months (95% CI, 5.8-17.6) and the median PFS was 8.6 months (95% CI, 5.2-19.1).
At the time of the analysis, median OS data were immature. The 6-month OS rate was 82%. At the 11.6-month follow-up analysis, 60% of patients remained alive.
All grade adverse events (AEs) occurred in 98% of those treated with the combination, and 49% of patients experienced a grade 3/4 AE. Serious AEs were seen in 56% of patients, 35% of which were grade 3/4 in severity. AEs led to dose reductions or discontinuation for 35% and 14% of patients, respectively. Dose interruptions or delays were utilized for 61% of patients. There were 4 fatal AEs.
The most common all-grade AEs observed in the trial 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 AEs were pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and squamous cell carcinoma of the skin (4%).
- Planchard D, Besse B, Groen HJM, et al. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC; BRF113928). J Clin Oncol. 2016;34 (suppl; abstr 107).
- Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial [published online June 6, 2016]. Lancet Oncol. DOI: 10.1016/S1470-2045(16)30146-2.