Durable Response to Combined Dabrafenib and Trametinib in a Patient With BRAF K601E Mutation-Positive Lung Adenocarcinoma: A Case Report.
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SUBMITTER: Su PL
PROVIDER: S-EPMC8474392 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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
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
Project description:Dabrafenib plus trametinib is US Food and Drug Administration approved combination therapy for use in patients with BRAF V600E-mutant non-small cell lung cancer, but information on use outside of clinical trials is limited. We report the case of a 70-year-old Asian woman (never smoker) who was diagnosed with lung adenocarcinoma in May 2014. Testing at diagnosis was negative for programmed death ligand 1 or EGFR, ALK, and ROS1 alterations. She was started on carboplatin-pemetrexed-bevacizumab and maintenance bevacizumab but progressed in September 2015. Subsequently, she progressed on second-line nivolumab and third-line docetaxel. In March 2016, pleural fluid obtained at diagnosis tested positive for the BRAF V600E mutation and she received dabrafenib plus trametinib. She experienced rapid tumor shrinkage and symptom improvement and became able to participate in regular daily activities with no notable adverse events. In December 2016, she died from a hemorrhagic stroke considered unrelated to treatment. In this heavily pretreated patient with non-small cell lung cancer, dabrafenib plus trametinib elicited an excellent response.
| S-EPMC6765470 | biostudies-literature
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
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
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
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
Project description:The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAF (V600E) driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8(+) tumor infiltrating lymphocytes (TILs), as well as CD4(+) T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAF (V600E) mutant metastatic melanoma.
| S-EPMC5006894 | biostudies-literature
Project description:PurposePreclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment.Patients and methodsIn this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45).ResultsIn parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%).ConclusionDabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.
| S-EPMC4226803 | biostudies-literature
Project description:BackgroundConcurrent treatment with BRAF inhibitors and palliative radiation therapy (RT) could be associated with increased toxicity, especially skin toxicity. Current Eastern Cooperative Oncology Group (ECOG) consensus guideline recommend ceasing BRAF inhibitors during RT. There is a lack of data regarding concurrent RT with combined BRAF and MEK inhibitors. This single-arm phase I/II trial was designed to assess the safety and tolerability of palliative RT with concurrent Dabrafenib and Trametinib in patients with BRAF-mutant metastatic melanoma.Materials and methodsPatients received Dabrafenib and Trametinib before and during palliative RT to soft tissue, nodal or bony metastases. The RT dose was escalated stepwise during the study period. Toxicity data including clinical photographs of the irradiated area was collected for up to 12 months following completion of RT.ResultsBetween June 2016 to October 2019, ten patients were enrolled before the study was stopped early due to low accrual rate. Six patients were treated at level 1 (20 Gy in 5 fractions, any location) and 4 patients at level 2a (30 Gy in 10 fractions with no abdominal viscera exposed). All alive patients completed one year of post-RT follow-up. Of the 82 adverse events (AEs) documented, the majority (90%) were grade 1 and 2. Eight grade 3 events (10%) occurred in five patients, only one was treatment-related (grade 3 fever due to Dabrafenib and Trametinib). No patients experienced grade 3 or 4 RT related toxicities, including skin toxicities. One serious AE was documented in relation to a grade 3 fever due to Dabrafenib and Trametinib requiring hospitalisation.ConclusionsThe lack of grade 3 and 4 RT-related toxicities in our study suggests that Dabrafenib and Trametinib may be continued concurrently during fractionated non-visceral palliative RT to extracranial sites.
| S-EPMC8379352 | biostudies-literature