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Durable Response to Combined Dabrafenib and Trametinib in a Patient With BRAF K601E Mutation-Positive Lung Adenocarcinoma: A Case Report.

ABSTRACT: Targeted therapy with combined dabrafenib and trametinib has been proven to provide clinical benefits in patients with NSCLC with a BRAF V600E mutation. Nevertheless, the treatment strategy for patients with NSCLC with BRAF non-V600E mutations remains limited. Here, we present a patient with NSCLC with a BRAF K601E mutation, a class II BRAF mutation, who had a durable response to targeted therapy with combined dabrafenib and trametinib.

SUBMITTER: Su PL

PROVIDER: S-EPMC8474392 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Durable Response to Combined Dabrafenib and Trametinib in a Patient With BRAF K601E Mutation-Positive Lung Adenocarcinoma: A Case Report.

Su Po-Lan PL Lin Chien-Yu CY Chen Yi-Lin YL Chen Wan-Li WL Lin Chien-Chung CC Su Wu-Chou WC

JTO clinical and research reports 20210703 8

Targeted therapy with combined dabrafenib and trametinib has been proven to provide clinical benefits in patients with NSCLC with a BRAF V600E mutation. Nevertheless, the treatment strategy for patients with NSCLC with BRAF non-V600E mutations remains limited. Here, we present a patient with NSCLC with a BRAF K601E mutation, a class II BRAF mutation, who had a durable response to targeted therapy with combined dabrafenib and trametinib. ...[more]

PMID: 34590045

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Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.

Project description:BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

| S-EPMC10163281 | biostudies-literature

Durable Response of Dabrafenib, Trametinib, and Capmatinib in an NSCLC Patient With Co-Existing BRAF-KIAA1549 Fusion and MET Amplification: A Case Report.

Project description:BRAF fusions are rare driver oncogenes in non-small cell lung cancer (NSCLC). Similar with BRAF V600E mutation, it could also activate the MAPK signaling pathway. There are a few case reports which had indicated the potential response to BRAF inhibitors and its important role as de novo driver mutation. In addition, the co-occurring MET amplification has been defined as a poor prognostic factor in patients with epidermal growth factor receptor (EGFR) mutant NSCLC. Currently, there are ongoing clinical trials which investigate the MET amplification as a therapeutic target in patients with EGFR mutant NSCLC and acquired resistance to osimertinib, which imply that the MET amplification also had a therapeutic significance. However, the co-occurring MET amplification had not been studied in patients with BRAF fusion before. A 67-year-old man was diagnosed with metastatic poorly-differentiated adenocarcinoma. He received first-line therapy with the combination of pembrolizumab and chemotherapy because the genomic test revealed wild-type EGFR, and negativity of ALK and ROS1 by immunohistochemical stain. Upon disease progression, the next-generation sequencing revealed co-occurring KIAA1549-BRAF fusion and MET amplification. Subsequent dabrafenib, trametinib, and capmatinib combination therapy showed a remarkable treatment effect. The combination therapy targeting the co-occurring driver mutations is a potential effective treatment for NSCLC patients. Further prospective study is still warranted to investigate the role of co-occurring driver mutations and the relevant treatment strategy.

| S-EPMC8972191 | biostudies-literature

INNV-30. RESPONSE WITH COMBINED DABRAFENIB AND TRAMETINIB AFTER BRAF INHIBITOR FAILURE IN BRAF-MUTATED GLIOBLASTOMA: A CASE REPORT

Project description:Abstract Glioblastoma (GBM) carries a poor prognosis despite aggressive multimodality therapy. Oncogenic BRAF mutations are present in < 2% of GBM, along with other glioma types (ganglioglioma, pleomorphic xanthoastrocytoma). Although oral inhibitors of the oncogenic BRAFv600 kinase have demonstrated some efficacy in GBM, several mechanisms mediating resistance to BRAF inhibitors through MAPK reactivation have been described. BRAF inhibitor monotherapy is also associated with an increased risk for hyperproliferative skin lesions. We present a case of a 44-year-old man who initially presented with headaches and seizures and was diagnosed with a left temporal, MGMT unmethylated, BRAF V600E mutant GBM. He underwent gross total resection followed by radiation therapy with concurrent temozolomide, followed by 9 cycles of adjuvant temozolomide. He presented with progression of disease (POD) and subsequently failed treatment with carboplatin after two cycles (first recurrence). He had a repeat resection, and was enrolled in a clinical trial of autologous dendritic cell vaccine and presented with POD after 10 months on this treatment (second recurrence). He was started on another clinical trial of BRAF inhibitor, achieving partial response but developed POD after 7 months on this therapy (third recurrence). He was started on BRAF inhibitor dabrafenib and MEK inhibitor trametinib (D+T), achieving complete response. At the time of this report, 8 months after initiating treatment, the patient remains clinically stable with MRI showing CR. To our knowledge, this is the first report of clinical and radiographic response to combined D+T after BRAF inhibitor failure in BRAF-mutated glioblastoma. Several ongoing trials (NCT01677741, NCT01748149, NCT02124772, NCT02684058, NCT02285439), will elucidate the precise role of these drugs as single agent and in combination in pediatric and adult brain tumors.

| S-EPMC6847586 | biostudies-literature

Dabrafenib Plus Trametinib for BRAF V600E-Mutant Non-small Cell Lung Cancer: A Patient Case Report.

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| S-EPMC6765470 | biostudies-literature

Impressive response to dabrafenib, trametinib, and osimertinib in a metastatic EGFR-mutant/BRAF V600E lung adenocarcinoma patient.

Project description:The survival outcomes of the FLAURA trial support osimertinib as the new standard of care for untreated patients harboring activating mutations in the epidermal growth factor receptor (EGFR). Despite the initial response, disease progression invariably occurs. Although uncommon, BRAF V600E mutation arises as a unique mechanism of resistance, and thus far, no prospective studies are available to support concurrent EGFR/BRAF blockade. We report a case of impressive radiological and ctDNA response under dabrafenib, trametinib, and osimertinib in an advanced EGFR-mutant lung adenocarcinoma patient who developed BRAF V600E as one of the acquired resistance mechanisms to second-line osimertinib. Moreover, the patient experienced remarkable clinical improvement and good tolerance to combination therapy. The present case suggests the importance of prospective studies evaluating both efficacy and safety of the combination in later line settings and points towards the potential of ctDNA to monitor resistance mechanisms and treatment benefit in clinical practice.

| S-EPMC7880994 | biostudies-literature

RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation.

Project description:Multiple myeloma (MM) is still considered incurable and new therapeutic approaches are therefore needed. Deep-sequencing analysis revealed the presence of BRAF mutations in up to 15% of patients. The clinical experience of BRAF-targeted therapy in myeloma patients harboring BRAF mutation is still limited. We here report the case of a patient with penta-refractory (bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab) MM with extramedullary BRAF-mutated disease that achieved clinical response to dual BRAF and MEK inhibition. At the time of disease progression, gene sequencing analysis of the tumor at the time of progression demonstrated a clonal evolution with emergence of a NRAS mutation and persistence of BRAF and TP53 mutations. Backtracking of the NRAS mutation was performed by digital polymerase chain reaction on the baseline biopsy and identified the pre-existence of the NRAS at a subclonal level. This observation is the first report of acquired NRAS mutation leading to resistance to dual BRAF/MEK inhibitors in MM. These data suggest that a systematic search for RAS mutations using highly sensitive techniques should be performed before considering targeted therapy in relapsed myeloma with BRAF mutation.

| S-EPMC9175793 | biostudies-literature

Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer.

Project description:PurposeTo evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).Patients and methodsA total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.ResultsOf 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.ConclusionThe combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

| S-EPMC4669588 | biostudies-literature

Response to Dabrafenib and Trametinib of a Patient with Metaplastic Breast Carcinoma Harboring a BRAF V600E Mutation.

Project description:Background:Metaplastic breast carcinomas are rare and carry poor prognoses. They are also more aggressive than other breast cancers and are known for their resistance to chemotherapy. Prolonged treatment with dabrafenib and trametinib is a therapy for malignant melanoma that improves the progression-free survival and overall survival. Such molecular-targeted therapies are also being developed for cancers with BRAF mutation, a driver of malignant melanoma. Case Presentation. A 57-year-old woman with metaplastic breast cancer and chemotherapy-refractory massive pleural effusion. After contained anthracycline regimen failure, her breast cancer progressed to an advanced stage. We ordered next-generation sequencing- (NGS-) based tumor molecular profiling from core needle biopsy of the breast. The NGS report indicated the presence of a BRAF V600E mutation. After initiation of dabrafenib and trametinib, her symptom and the pleural effusion were decreased. The first assessment of CT scans showed a decreased pleural effusion and shrunken subcutaneous lesions. Approximately 2 weeks later, a new lesion appeared. She died from 12 weeks after initiation of dabrafenib and trametinib treatment. Conclusion:To the best of our knowledge, this is the first report of BRAF mutation breast cancer treated with dabrafenib and trametinib and it heralds the possibility of targeted therapy for rare breast cancers.

| S-EPMC7079252 | biostudies-literature

Prolonged Complete Response With Combined Dabrafenib and Trametinib After BRAF Inhibitor Failure in BRAF-Mutant Glioblastoma.

Project description: Not available

| S-EPMC7446525 | biostudies-literature

An advanced pulmonary sarcomatoid carcinoma patient harboring a BRAFV600E mutation responds to dabrafenib and trametinib: a case report and literature review.

Project description:BackgroundThe pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of NSCLC with rapid progression and poor prognosis, and is resistant to conventional chemotherapy. Most PSC cases have potential targetable genomic alterations. Approximately 7% of PSC patients have BRAF mutations, and the efficacy of dabrafenib and trametinib in BRAFV600E mutated PSC is unclear.Case presentationOur report describes a patient with mutated BRAFV600E PSC who underwent surgery and adjuvant chemotherapy early but quickly relapsed. Both chemotherapy and immunotherapy were ineffective for him, combined dabrafenib and trametinib produced a 6-month progression-free survival, and a partial response was observed in the tumor response evaluation. As a result of financial pressure, he stopped taking the targeted drugs, and his disease rapidly progressed.ConclusionDabrafenib combined with trametinib provides partial remission in patients with advanced PSC with BRAFV600E mutations, and large-scale NGS panels could offer more options for PSC treatment.

| S-EPMC10403232 | biostudies-literature

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