Dataset Information

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations.

ABSTRACT: On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open-label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B, n?=?57) or were treatment-naïve (Cohort C, n?=?36). All patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily. In Cohort B, overall response rate (ORR) was 63% (95% confidence interval [CI] 49%-76%) with response durations ?6 months in 64% of responders. In Cohort C, ORR was 61% (95% CI 44%-77%) with response durations ?6 months in 59% of responders. Results were evaluated in the context of the Intergroupe Francophone de Cancérologie Thoracique registry and a chart review of U.S. electronic health records at two academic sites, characterizing treatment outcomes data for patients with metastatic NSCLC with or without BRAF V600E mutations. The treatment effect of dabrafenib 150 mg twice daily was evaluated in 78 patients with previously treated BRAF mutant NSCLC, yielding an ORR of 27% (95% CI 18%-38%), establishing that dabrafenib alone is active, but that the addition of trametinib is necessary to achieve an ORR of >40%. The most common adverse reactions (?20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. IMPLICATIONS FOR PRACTICE:The approvals of dabrafenib and trametinib, administered concurrently, provide a new regimen for the treatment of a rare subset of non-small cell lung cancer (NSCLC) and demonstrate how drugs active for treatment of BRAF-mutant tumors in one setting predict efficacy and can provide supportive evidence for approval in another setting. The FDA also approved the first next-generation sequencing oncology panel test for simultaneous assessment of multiple actionable mutations, which will facilitate selection of optimal, personalized therapy. The test was shown to accurately and reliably select patients with NSCLC with the BRAF V600E mutation for whom treatment with dabrafenib and trametinib is the optimal treatment.

SUBMITTER: Odogwu L

PROVIDER: S-EPMC6067947 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring <i>BRAF V600E</i> Mutations.

Odogwu Lauretta L Mathieu Luckson L Blumenthal Gideon G Larkins Erin E Goldberg Kirsten B KB Griffin Norma N Bijwaard Karen K Lee Eunice Y EY Philip Reena R Jiang Xiaoping X Rodriguez Lisa L McKee Amy E AE Keegan Patricia P Pazdur Richard R

The oncologist 20180207 6

On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open-label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B, <i>n</i> = 57) or were treatment-naïv ...[more]

PMID: 29438093

Similar Datasets

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.

Project description:Background:Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after??36-month follow-up for all living patients. Patients and methods:This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150?mg twice daily) plus trametinib (2?mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results:Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n?=?211) or dabrafenib monotherapy (n?=?212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and?<3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions:These data demonstrate that durable (?3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Dataset Information

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations.

Publications

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring <i>BRAF V600E</i> Mutations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets