Dabrafenib, Trametinib Combination Shows Response and Duration in BRAF V600E Mutated Tumors

Patrick Y. Wen, MD

Patients with both high-grade glioma (HGG) and low-grade glioma (LGG) harboring theBRAFV600E mutation demonstrated positive benefit in response, duration of response (DOR), and progression-free survival (PFS) when given the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in a phase IIa study (NCT02034110). Given the poor treatment outcomes observed for patients with these malignancies, these findings are promising.¹

TheBRAFmutation occurs in approximately 5% of adults with HGG and up to 18% of patients with LGG, said Patrick Y. Wen, MD, during his presentation at the 24th Annual Meeting and Education Day of the Society of NeuroOncology.^1-3Historically, combined BRAF and MEK inhibition is efficacious in variousBRAFV600E-mutated tumors in the metastatic and adjuvant settings.

The study stratified patients withBRAFV600E-mutated cancers by WHO criteria into 2 cohorts, with 524 prescreened patients with HGG (WHO grade III/IV) in 1 cohort and 68 prescreened patients with LGG (WHO grade I/II) in the other.

Forty-five patients and 13 patients in the HGG and LGG cohorts, respectively, were eligible for treatment. Patients received dabrafenib (150 mg twice daily) and trametinib (2 mg daily) until disease progression, death, or unacceptable toxicity.

“A Bayesian hierarchical statistical design was used to address the small sample size,” Wen, director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and professor of Neurology at Harvard Medical School, both in Boston, Massachusetts, said during his presentation. “The percentage of patients who ended up on the study was a small percentage of the overall cohort.”

The primary end point was investigator-assessed objective response rate (ORR) and secondary end points were DOR, PFS, overall survival (OS), and safety. To be included in the study, patients had to haveBRAFV600E mutation positivity diagnosed by local assessment and am ECOG performance status ≤2. Patients were ineligible if they had previous BRAF or MEK inhibitor treatment, history of another malignancy, radiotherapy within 3 months of enrollment, or treatment with enzyme-inducing anticonvulsants within 14 days prior to enrollment.

The HGG cohort (n = 45) included 23 men (51%) and the median age was 42 years (range 18-72), whereas the LGG cohort (n = 13) included 4 men (31%) and the median age was 33 years (range 18-78). “The only [characteristic] of note is that this is a young patient population,” Wen said.

Regarding baseline histology, the most common in the HGG cohort was glioblastoma (68%), followed by anaplastic pleomorphic xanthoastrocytoma (11%) and anaplastic astrocytoma (11%). In the LGG cohort, the most common histology was ganglioglioma (31%), followed by diffuse astrocytoma (15%), and pleomorphic xanthoastrocytoma (15%).

For the HGG cohort, the ORR for both the investigator-assessed and independent radiology review was 29%. In the LGG cohort, the ORR was 62%.

Median PFS in the overall HGG cohort was 16.4 weeks (range, 7.9-39.9) and the median OS was 89.0 weeks (range 47.3-196.6). For patients with grade IV glioma, the median PFS was 12.0 weeks and the median OS was 82.7 weeks.

The HGG subgroup analysis demonstrated an ORR of 31% in patients with grade III and 29% in patients with grade IV gliomas. DOR was 100% in patients with grade III and 68.6% in patients with grade IV malignancies. ORR was 41% in patients aged 18 to 39 years. The ORR was 17% in patients aged ≥ 40 years. “Interestingly, most of the responders were under the age of 40 years. Those above the age of 40 years had a much lower response rate,” Wen said.

In the LGG cohort, median PFS was 103.4 weeks (range, 32.1-not reached [NR]) and the median OS was NR (range 50.4-NR).

Any-grade adverse events (AEs) were observed in 93% of patients in the HGG cohort and 92% of patients in the LGG cohort. Grade 3/4 AEs were 47% in the HGG cohort and 46% in the LGG cohort. Eighty-two percent of patients in the HGG cohort experienced treatment-related AEs (TRAEs), whereas 92% of patients in the LGG cohort experienced TRAEs.

“Adverse events led to discontinuation of treatment in 4 patients in the HGG cohort and 1 patient in the LGG cohort,” Wen said. Dose modification occurred in 38% of patients in the HGG cohort and 31% of patients in the LGG cohort. There were no fatal AEs.

Overall, the combination of dabrafenib and trametinib demonstrated promising efficacy in patients with HGG or LGG with recurrent/refractoryBRAFV600E-mutation.

Six patients in the HGG cohort achieving complete response (CR) with a 12-month DOR at 80%. Patients between 18 and 39 years had a higher response rate compared with patients ≥40 years. Twelve-month PFS and OS rates were 34% and 61%, respectively.

In the LGG cohort, 8 patients achieving a CR. At 24 months, rates of DOR, PFS, and OS were 56%, 43%, and 83%, respectively.

“The safety profile is not modest, but it is similar to prior studies involving dabrafenib and trametinib in melanoma and other systemic cancers,” said Wen. “BRAFV600E is an actionable mutation and it’s worth testing this patient [population] for this mutation.”

References

1. Wen PY, Stein A, et al. Updated efficacy and safety of dabrafenib plus trametinib in patients with recurrent/refractory BRAF V600E—mutated high-grade glioma (HGG) and low-grade glioma (LGG).Neuro-Oncology. 2019;21(suppl 6;abstr ACTR-30). doi: 10.1093/neuonc/noz175.073.
2. Dahiya S, Emnett RJ, Haydon DH, Leonard JR, Phillips JJ, Perry A, Gutmann DH. BRAF-V600E mutation in pediatric and adult glioblastoma.Neuro-Oncology. 2014;16(2):318-319. doi: 10.1093/neuonc/not146.
3. Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma.Acta Neuropathol. 2011;121(3):397-405. doi: 10.1007/s00401-011-0802-6.