Phase 2 data presented at ASCO showed that Tafinlar plus Mekinist was a highly effective treatment regimen for patients with BRAF V600E-mutant NSCLC.
The combination of Tafinlar (dabrafenib) and Mekinist (trametinib) was highly effective as a treatment for patients with BRAF V600E-mutant non—small cell lung cancer (NSCLC), according to lead investigator David Planchard, who presented the phase 2 data during the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of over 30,000 oncology professionals in Chicago. Findings from the study were also concurrently published in Lancet Oncology.
The investigator assessed objective response rate (ORR) with the combination was 63 percent, which lasted for a median duration of nine months. When adding those with stable disease for 12 weeks or greater, the overall disease control rate was 79 percent. The median progression-free survival (PFS) was 9.7 months.
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 Tafinlar was 33 percent and the median PFS was 5.5 months. Findings from both cohorts of the study have led to breakthrough therapy designations from the FDA for Tafinlar as a single agent and in combination with Mekinist.
"Tafinlar plus Mekinist provides an important treatment option for patients with BRAF V600E-mutant NSCLC, with greater clinical activity compared with Tafinlar monotherapy," said Planchard, from the Department of Cancer Medicine at the Institute Gustav Roussy in Villejuif, France. "The safety profile was manageable and similar to previous experience in melanoma."
In the study, 57 patients were treated with Tafinlar twice daily plus Mekinist once daily. Patients in the study had received at least one prior line of platinum-based chemotherapy, with 33 percent having received two or more prior regimens. The primary endpoint of the study was ORR by Response Evaluation Criteria in Solid Tumors (RECIST), 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 percent had adenocarcinoma histology. The most common ECOG performance status was one. The majority of patients were former or current smokers, 51 percent were male and 86 percent were Caucasian. In the smoking group, 46 percent of patients had greater than 30 pack years.
After a median follow-up of 11.6 months, two patients had experienced a complete response with the combination by investigator assessment. Overall, nine patients had stable disease as their best response. At the data cutoff in October 2015, 50 percent of confirmed responses remained ongoing.
By independent assessment, there were no complete responses and the stable disease rate was 7 percent. The ORR by independent review remained 63 percent; however, the disease control rate was 75 percent. Duration of response was nine months and the median PFS was 8.6 months.
At the time of the analysis, median OS data were immature. The six-month OS rate was 82 percent. At the 11.6-month follow-up analysis, 60 percent of patients remained alive.
"This study confirms a fourth actionable biomarker in NSCLC—BRAF V600E—after EGFR, ALK and ROS-1," said Planchard. "The potential to treat this oncogene gives hope to a very small, underserved patient population."
All grade adverse events (AEs) occurred in 98 percent of those treated with the combination, and 49 percent of patients experienced a grade 3/4 AE. Serious AEs were seen in 56 percent of patients, 35 percent of which were grade 3/4 in severity. AEs led to dose reductions or discontinuation for 35 percent and 14 percent of patients, respectively. Dose interruptions or delays were utilized for 61 percent of patients. There were four fatal AEs.
The most common all-grade AEs observed in the trial were pyrexia, nausea, vomiting, diarrhea, asthenia, decreased appetite, peripheral edema, cough and rash. The most common serious AEs were pyrexia, anemia, confusional state, decreased appetite, hemoptysis, hypercalcemia, nausea and squamous cell carcinoma of the skin.
“Nearly all of the patients experienced at least one adverse event, and at least half had at least one grade 3 adverse event,” Planchard said. “Generally, it was grade 3 adverse events, with few grade 4 or 5 adverse events.” BRAF alterations are present in approximately 1 percent to 2 percent of NSCLC cases. The FDA breakthrough therapy designation for the combination of Tafinlar and Mekinist was received July 2015, for patients with BRAF V600E-mutant NSCLC. This designation was based upon earlier results from 33 patients enrolled in the phase 2 study. The single-agent breakthrough designation was received in January 2014.
The multi-cohort study, which the developer of the combination Novartis called pivotal, continues to enroll participants. A third cohort is assessing the combination as a frontline therapy for patients with BRAF-mutated NSCLC. This portion of the study has fully accrued 34 patients, with results expected in the near future.v Outside of NSCLC, the combination of Tafinlar and Mekinist became the first FDA-approved combination therapy for patients with metastatic melanoma in January 2014. This approval was based on early phase data, with additional trials conducted to support the approval that showed improvements in survival and other key endpoints.