Dabrafenib/Trametinib Combo Produces Strong Response in BRAF V600E–Mutated Glioma

Article

Dabrafenib plus trametinib produced clinically meaningful objective responses rates in patients with recurrent or progressive BRAF V600E mutation–positive glioma.

Dabrafenib (Tafinlar) plus trametinib (Mekinist) produced clinically meaningful objective responses rates (ORRs) in patients with recurrent or progressive BRAF V600E mutation–positive glioma, according to data from interim analysis of the phase 2 ROAR trial (NCT02034110) published in The Lancet.1

In patients with high-grade glioma (n = 45), the ORR was 33% (95% CI, 20%-49%) by investigator assessment, including 3 complete responses (CRs) and 12 partial responses (PRs). The median follow-up was 12.7 months (interquartile range [IQR], 5.4-32.3). Independent radiology review found an ORR of 31% in this cohort, including 3 CRs and 11 PRs. The median duration of response (DOR) was 36.9 months (95% CI, 7.4-44.2) per investigator assessment and 13.6 months (95% CI, 4.6-43.4) per independent radiology review.

Furthermore, investigator assessment showed a median progression-free survival (PFS) of 3.8 months (95% CI, 1.8-9.2) and a median overall survival (OS) of 17.6 months (95% CI, 9.5-45.2). Independent radiology review reported a median PFS of 4.5 months (95% CI, 1.8-7.4).

In patients with low-grade disease (n = 13), ORR was 69% (95% CI, 39%-91%) per investigator assessment and independent radiology review. Investigators observed 1 CR, 6 PRs, and 2 minor responses at a median follow-up of 32.2 months (IQR, 25.1-47.8). The median DOR by independent radiology review was 27.5 months (95% CI, 3.8-39.5).

The median PFS (95% CI, 7.4-not reached) and median OS were not reached (95% CI, 11.6-not reached) by investigator assessment. However, the median PFS was 14.0 months (95% CI, 4.7-46.9) according to independent radiology review.

“Considering the rarity of BRAF V600 mutations in other tumor types, BRAF inhibitor development beyond melanoma has been challenging, but dabrafenib plus trametinib combination therapy has subsequently shown activity in non-small-cell lung cancer, anaplastic thyroid cancer, and biliary tract cancer,” lead study author Patrick Y. Wen, MD, and colleagues wrote. “In this context, the activity of dabrafenib plus trametinib, showing actionability of the BRAF V600E mutation in high-grade glioma and low-grade glioma, is a notable finding.”

Dabrafenib, a BRAF inhibitor, has shown meaningful clinical activity in pediatric patients with BRAF V600 mutation–positive low-grade and high-grade glioma.2 Trametinib, a MEK inhibitor, has shown activity in multiple tumor types and is the standard of care in BRAF V600-mutant melanoma, non–small-cell lung cancer, and anaplastic thyroid cancer.3 Furthermore, the combination has shown superior outcomes in PFS and OS when compared with BRAF inhibitor monotherapy.

BRAF V600 mutations have been identified in 5% to 15% of low-grade gliomas and approximately 3% of high-grade gliomas. No substantial treatment advances in the treatment of these tumors have been made in recent years, in part because of the rarity of gliomas, the difficulty of penetrating the blood-brain barrier, and molecular heterogeneity.

The ROAR trial examined 9 cohorts of patients with BRAF V600E mutation-positive rare cancers, including patients with high-grade and low-grade glioma. Patients enrolled in the trial needed to be at least 18 years old with an ECOG performance status of 0 to 2, plus adequate organ function as assessed by routine chemistry, hematology, and echocardiogram.

Eligible patients had histologically confirmed recurrent or progressive high-grade (WHO grade 3 or 4) or low-grade (WHO grade 1 or 2) glioma. Those in the high-grade cohort needed to have measurable disease at baseline according to the Response Assessment in Neuro-Oncology (RANO) criteria, as well as prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy.

In the low-grade glioma cohort, patients needed measurable non-enhancing disease, excluding pilocytic astrocytoma, using RANO criteria. Patients with grade 1 low-grade glioma were required to be symptomatic and were evaluated by a panel of neurooncologists prior to enrollment.

Patients received oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. Dose adjustments and interruptions were permitted to improve tolerability for patients unable to tolerate the protocol dose. Investigators made disease assessments via contrast MRI of the brain every 8 weeks for the first 48 weeks, then every 3 months, until disease progression.

Additionally, laboratory assessments were done during patient screening, including clinical chemistry and hematological assessments, measurement of glycated hemoglobin, evaluation of coagulation factors, and urinalysis. Those assessments were also conducted monthly during treatment. Glycated hemoglobin was measured every 3 months.

The primary end point of the study was investigator-assessed ORR using RANO, defined by CR plus PR for high-grade glioma, and CR plus PR and minor response for low-grade glioma. ORR was also assessed by independent radiology review. Secondary end points included PFS, DOR, OS, and safety.

Within the high-grade glioma cohort, patients had a median age of 42 years (range, 18-72) and 51% were male. Additionally, ECOG performance status of 0, 1, and 2 were seen in 29%, 58%, and 13% of patients, respectively. Sixty-nine percent of patients had a WHO grade of 4, 29% had a grade of 3, and 1 patient’s grade was missing.

Furthermore, 93% of patients had a confirmed central BRAFV600E mutation status. One patient had a negative BRAF V600E mutation status, and the status of 2 patients was deemed insufficient or invalid. Notably, no patients were excluded from analysis due to protocol deviations.

In the low-grade glioma cohort, the median age was 33 years (range, 18-58), and 31% of patients were male. ECOG performance status of 0, 1, and 2 were measured in 38%, 54%, and 8% of patients, respectively. Additionally, 54% of patients had a WHO grade of 2 and 46% of patients had a WHO grade of 1. BRAF V600E positive-mutation status was confirmed in 62% of patients, compared with BRAF V600E negative-mutation status in 15% of patients. Twenty-three percent of patients had insufficient samples or invalid results.

Across both cohorts, 93% of patients experienced any-grade adverse events (AEs), including fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%). Additionally, 53% of patients had grade 3/4 AEs, including fatigue (9%), headache (5%), and neutropenia (5%). AEs led to dose reductions in 38% of patients, treatment interruptions in 41%, and permanent discontinuation in 9%.

The authors acknowledged the lack of a comparator group as a limitation of this trial, and pointed out that randomized trials will be needed to better measure the efficacy of this line of treatment. However, they said glioblastoma has historically shown resistance to therapies, and this combination was the first targeted therapy to shown meaningful activity.

“Molecular screening strategies that include BRAF V600E mutations will be crucial for identifying patients who might benefit from this treatment combination,” the authors wrote. “And we recommend that testing is adopted in clinical practice for patients with glioma.”

References

  1. Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet. Published online November 24, 2021. doi:10.1016/S1470-2045(21)00578-7
  2. Hargrave DR, Bouffet E, Tabori U, et al. Efficacy and safety of dabrafenib in pediatric patients with BRAFV600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa study. Clin Cancer Res. 2019;25:7303-7311. doi:10.1158/1078-0432.CCR-19-2177
  3. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877-1888. doi:10.1056/NEJMoa1406037
Related Videos
Stephen Bagley, MD, MSCE
Ashley Sumrall, MD, FACP
Varun Monga, MD
In this last episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, and Michael W. McDermott, MD, shed light on the excitement surrounding the use of low-intensity focused ultrasound in cancer and other conditions.
In this fourth episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, and Michael W. McDermott, MD, discuss the key objectives of the phase 3 LIMITLESS study (NCT05317858) examining low-intensity focused ultrasound with immunotherapy and chemotherapy in patients with lung cancer and brain metastases.
Varun Monga, MD
In this third episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, and Michael W. McDermott, MD, both of Baptist Health South Florida, discuss the LIBERATE study (NCT05383872) examining low-intensity focused ultrasound (LIFU) in patients with glioblastoma.
In this second episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, and Michael W. McDermott, MD, discuss the success observed with low-intensity focused ultrasound in essential tremors and the hope for this approach in brain cancer.
Timothy I Shaw, PhD
Katherine B. Peters, MD, PhD