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RARE-09. EFFICACY AND SAFETY OF DABRAFENIB + TRAMETINIB IN PATIENTS WITH RECURRENT/REFRACTORY BRAF V600E–MUTATED HIGH-GRADE GLIOMA (HGG)

ABSTRACT: Abstract BACKGROUND Current treatment outcomes for patients with recurrent HGG are poor, with median progression-free survival (PFS) and overall survival (OS) of 2.5 and 7.5 months, respectively. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) resulted in an intracranial overall response rate (ORR) of 58% in BRAF V600–mutated melanoma brain metastases. Dabrafenib + trametinib was evaluated as treatment for patients with BRAF V600E–mutated HGG. METHODS In this phase 2, open-label trial (NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HGG, received continuous dabrafenib (150 mg BID) + trametinib (2 mg QD) until unacceptable toxicity, disease progression, or death. For the HGG cohort, eligible patients had histologically confirmed recurrent or progressive WHO grade 3 or 4 glioma and had prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiation therapy. The primary endpoint was investigator-assessed ORR by RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. RESULTS Thirty-seven patients with HGG had enrolled at data cutoff (3 January 2018). Median age was 42 years, 31 of 37 patients were evaluable for response. Investigator-assessed confirmed ORR was 26% (8/31; 95% CI, 12%-45%), including 1 complete response (CR). Six of 8 responses were ongoing at data cutoff. Five of 8 responding patients had a DOR of ? 12 months. Median PFS was 1.9 months (95% CI, 1.7–18.5). Median OS was 11.7 months (95% CI, 6.4-not reached). Adverse events (AEs) in patients with HGG included fatigue (35%), headache (30%), and rash (24%). Grade 3/4 AEs included neutropenia (8%) and fatigue (5%). Biomarker analyses are ongoing and will be presented. CONCLUSIONS: Dabrafenib + trametinib demonstrated promising efficacy in patients with BRAF V600E-mutated recurrent/refractory HGG, as 1 patient had a CR, and most responders had a prolonged DOR.

SUBMITTER: Wen P

PROVIDER: S-EPMC6217670 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND There is a lack of treatment options for HGG and LGG patients. BRAFV600E mutations are uncommon in glioma, with a poor long-term prognosis. Combined BRAF/MEK inhibition extends progression-free survival (PFS) and overall survival (OS) in BRAF V600E–mutated melanoma, non small-cell lung cancer, and anaplastic thyroid cancer. METHODS This phase 2, open-label trial (NCT02034110) evaluated dabrafenib (BRAF inhibitor, 150mg BID) plus trametinib (MEK inhibitor, 2mg QD) in patients with BRAF V600E mutations in 9 rare tumor types, including HGG and LGG. Eligible patients had histologically-confirmed recurrent or progressive glioma (LGG:WHO grade 1 or 2; HGG:WHO grade 3 or 4), with HGG patients required to have received radiotherapy and first-line chemotherapy, or concurrent chemoradiation. Treatment continued until unacceptable toxicity, disease progression, or death. Primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. RESULTS Interim analysis (IA) #14 (data cutoff: April 2, 2018) reported additional 3 months follow-up, with 49 patients enrolled (HGG, n=39; LGG, n=10) and 3 patients not evaluable for response. In HGG patients, ORR was 27% (10/37; 95%CI: 13.8%-44.1%), including CR (n=1), PR (n=9), and SD (n=11), with 16 patients currently ongoing treatment. In LGG patients, ORR was 56% (5/9; 95%CI: 26.8%-79.3%), including PR (n=5) and SD (n=4), with 6 patients currently ongoing treatment. OS, PFS, and DOR will be presented (IA#15). In HGG patients, adverse events (AEs) included fatigue (33%), headache (31%), rash (28%), and pyrexia (23%); grade 3/4 AEs included neutropenia (8%) and fatigue (5%). In LGG patients, AEs included headache (70%), fatigue, pyrexia (60% each), nausea, and arthralgia (50% each); grade 3/4 AEs included fatigue (20%). CONCLUSIONS Dabrafenib plus trametinib demonstrated promising efficacy in patients with recurrent or refractory BRAF V600E?mutated HGG or LGG, with manageable AEs and no new safety signals.

Project description:Radioactive iodine-refractory metastatic differentiated thyroid cancer (RAIR) is associated with a poor prognosis. Multikinase inhibitors have demonstrated improvement in progression-free but not overall survival in such patients, but usage is limited by significant adverse effects and the development of resistance. Clinical research has demonstrated improvement in progression-free survival with the combined use of the BRAF/MEK inhibitor in patients with metastatic melanoma and anaplastic thyroid cancer with the BRAFV600E mutation and has shown promise in redifferentiation of BRAF-positive RAIR differentiated thyroid cancer. A 58-year-old woman went to her primary care physician for a growing mass on the left side of her neck. CT imaging noted a 6 x 8 x 6 cm mixed cystic and solid mass and lymphadenopathy. Core biopsy subsequently showed metastatic papillary thyroid cancer (Stage III, PT4a/PN1b), and she underwent a total thyroidectomy with left neck dissection. She then received 204mCi 131I post-total thyroidectomy. Unfortunately, her thyroglobulin continued to increase post-radioactive iodine (RAI) treatment, indicating persistent and/or recurrent thyroid cancer. An RAI-131 whole-body scan on the thyrogen protocol showed no significant RAI uptake. A fluorodeoxyglucose (FDG)-positron emission tomography (PET) CT scan was then performed, which showed recurrent metastatic disease with hypermetabolism noted in the left thyroid bed and FDG-avid bilateral cervical lymph nodes and pulmonary nodules. Given these findings, her cancer was classified as radioactive iodine refractory (RAIR). Molecular testing indicated the BRAFV600E mutation. After a discussion with the patient, it was decided to initiate therapy with a BRAF inhibitor (dabrafenib 150 mg twice a day) and MEK inhibitor (trametinib 2 mg once a day) in an attempt to redifferentiate RAIR. Repeat RAI-131 thyrogen whole body scan one month after initiation of therapy demonstrated left level 2 cervical lymphadenopathy radioiodine uptake. The patient subsequently received 216 mCi 131I treatment given evidence of redifferentiation. Her post-treatment scan indicated additional uptake in a left lower lobe pulmonary nodule as well as a left paratracheal mass indicating successful RAI-131 uptake by metastases. Her thyroglobulin level, six months post-RAI, decreased to 4.0 indicating an encouraging response. Further surveillance, including imaging studies, is planned. This case illustrates the re-differential potential for dabrafenib and trametinib treatment in patients with BRAFV600E-mutated RAIR differentiated thyroid cancer. This therapy has been shown to be successful in small series of patients and could potentially be offered to RAIR patients with the BRAFV600E mutation as an alternative to multikinase treatment given its favorable side-effect profile.

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RARE-09. EFFICACY AND SAFETY OF DABRAFENIB + TRAMETINIB IN PATIENTS WITH RECURRENT/REFRACTORY BRAF V600E–MUTATED HIGH-GRADE GLIOMA (HGG)

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