Frontline Dabrafenib/Trametinib Effective for BRAF+ NSCLC

David Planchard MD, PhD

Frontline treatment with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) showed promising clinical efficacy for patients with BRAF-mutant metastatic non—small cell lung cancer (NSCLC), according to findings from a cohort of a phase II study presented at the 2017 ESMO Congress.

By investigator assessment, the primary endpoint of objective response rate (ORR) was 64% (95% CI, 46%-79%) with the combination and the disease control rate (ORR + stable disease) was 75%. The median progression-free survival (PFS) was 10.9 months (95% CI, 7.0-16.6) and the 2-year overall survival (OS) rate was 51%.

"This is the first study of combination BRAF and MEK inhibition as first-line therapy in patients with BRAF V660E-mutant metastatic NSCLC," said lead investigator David Planchard, MD, PhD, Department of Medical Oncology, Thoracic Unit, Institut Gustave Roussy. "Dabrafenib plus trametinib demonstrated substantial antitumor activity and durable response in patients with treatment-naive BRAF V600E-mutant NSCLC."

The phase II study, also known as BRF113928, enrolled patients across 3 cohorts. In the first cohort, 84 patients received single-agent dabrafenib following ≥1 prior platinum-based chemotherapy. In the second cohort, 57 previously-treated patients received dabrafenib and trametinib. Finding from this cohort led to an approval for the combination for patients with advanced BRAF-mutant NSCLC earlier this year.

In these cohorts, the ORR was 67% (95% CI, 53%-79%) with the combination and 33% for the single-agent. The median duration of response was 9.8 months for the combination and 9.6 months with dabrafenib alone. The median PFS was 10.2 and 5.5 months and the median OS was 12.7 and 18.2 months, for the combination and dabrafenib alone, respectively.

Findings presented at ESMO were from the third cohort, which enrolled 36 untreated patients with BRAF-mutant stage IV NSCLC. Patients received dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily. The median age in this cohort was 67 years (range, 44-91) and most were female (61%). The ECOG performance status was primarily 1 (61%), and all but 1 patient had nonsquamous histology. Twenty-eight percent of patients were never smokers.

By independent review committee (IRC), the ORR was 64% and the disease control rate was 72%. There were 2 complete responses and 21 partial responses, both in the IRC and investigator assessments. The median duration of response by investigator assessment was 10.4 months and 15.2 months by IRC.

At the time of the ESMO analysis, 47% of the patients had died, and 31% remained on study treatment. The median PFS by IRC was 14.6 months (95% CI, 7.0-22.1). The median OS was 24.6 months with the combination, though these data were not yet mature.

All patients experienced an adverse event (AE) of any grade, with 56% having a grade 3/4 event. Serious AEs were seen in 58% of patients, with a grade 3/4 rate of 44%. Additionally, AEs led to treatment discontinuation for 19% of patients, and dose reductions or dose interruptions/delays for 31% and 69%, respectively.

The most common AEs were pyrexia (64%), nausea (56%), diarrhea (39%), fatigue (36%), peripheral edema (36%), decreased appetite (33%), vomiting (33%), dry skin (33%), chills (25%), headache (25%), rash (22%), dizziness (22%), and cough (22%). The most common grade 3/4 AEs were pyrexia (11%), vomiting (8%), rash (3%), and diarrhea (3%). There was one fatal cardiorespiratory arrest that was deemed unrelated to study treatment.

"The safety profile of the combination was manageable and similar to previous experience with the combination, with no new safety signals observed," said Planchard.

Both the EMA and FDA approved the combination for all patients with BRAF-positive NSCLC, based on the phase II results. In the United States, the combination was approved with the Oncomine Dx Target Test, a next generation sequencing (NGS) test, which detects the presence of BRAF, ROS1, and EGFR gene mutations.

Planchard D, Smit EF, Groen H, et al. Phase 2 trial (BRF113928) of dabrafenib (D) plus trametinib (T) in patients (pts) with previously untreated BRAF V600E—mutant metastatic non-small cell lung cancer (NSCLC). Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA51.