ABSTRACT
BACKGROUND: Langerhans cell histiocytosis (LCH) is a clonal myeloid neoplasm with inflammatory component. Refractory disease is a challenge, but vemurafenib has emerged as a therapeutic option. We will delineate the cases of two Brazilian children suffering from refractory LCH with a positive response to vemurafenib. CASES: Both cases had a diagnosis of multisystem disease with involvement of organs at risk and had not responded to standard and second-line treatment. After refractoriness to classic treatment regimens, the BRAF mutation was investigated and found to be positive in both patients, and target therapy with vemurafenib was sought. The first case has been using vemurafenib for about 2 years and the second case has been using it for about 3 years, having had an attempt to suspend the medication after concomitant use with maintenance therapy. However, the disease returned 4 months after stopping the medication. Fortunately, the disease returned to remission status after the medication was reintroduced. CONCLUSION: These cases represent the first reported instances of off-label vemurafenib use in Brazil for the treatment of LCH and both patients have demonstrated excellent responses to the medication. However, the long-term side effects are unknown in children, and prospective studies are needed. In addition, there is a lack of epidemiological data on histiocytosis in Brazil and studies evaluating the budgetary impact of incorporating BRAF mutation research and the use of vemurafenib into the public health system. These reports could be a starting point.
Subject(s)
Histiocytosis, Langerhans-Cell , Proto-Oncogene Proteins B-raf , Vemurafenib , Humans , Vemurafenib/therapeutic use , Vemurafenib/administration & dosage , Histiocytosis, Langerhans-Cell/drug therapy , Histiocytosis, Langerhans-Cell/genetics , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/pathology , Brazil , Proto-Oncogene Proteins B-raf/genetics , Male , Female , Mutation , Child, Preschool , Child , Molecular Targeted Therapy/methods , Antineoplastic Agents/therapeutic use , Treatment Outcome , InfantABSTRACT
BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (nâ =â 7) and prior BRAF inhibitor therapy (nâ =â 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).
Subject(s)
Mutation , Proto-Oncogene Proteins B-raf , Vemurafenib , Humans , Proto-Oncogene Proteins B-raf/genetics , Vemurafenib/therapeutic use , Vemurafenib/administration & dosage , Male , Female , Child , Adolescent , Young Adult , Adult , Child, Preschool , Neoplasms/drug therapy , Neoplasms/geneticsABSTRACT
BACKGROUND: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). METHODS: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. RESULTS: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. CONCLUSIONS: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzimidazoles , Carbamates , Melanoma , Mutation , Proto-Oncogene Proteins B-raf , Sulfonamides , Vemurafenib , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/mortality , Carbamates/administration & dosage , Carbamates/adverse effects , Proto-Oncogene Proteins B-raf/genetics , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Benzimidazoles/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Male , Female , Vemurafenib/administration & dosage , Vemurafenib/adverse effects , Middle Aged , Aged , Adult , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Skin Neoplasms/mortality , Aged, 80 and over , Progression-Free Survival , Young AdultABSTRACT
BACKGROUND: Hairy cell leukemia (HCL) is a rare mature B-cell malignancy that is primarily treated with purine analogues. However, relapse remains a significant challenge, prompting the search for alternative therapies. The BRAF V600E mutation prevalent in HCL patients provides a target for treatment with vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study included nine patients with relapsed/refractory (R/R) HCL from six different centers. Patient data included demographics, prior treatments, clinical outcomes, and adverse events. RESULTS: Patients received different treatment regimens between centers, including vemurafenib alone or in combination with rituximab. Despite the differences in protocols, all patients achieved at least a partial response, with seven patients achieving a complete response. Adverse events were generally mild with manageable side effects. The absence of myelotoxic effects and manageable side effects make BRAF inhibitors attractive, especially for patients ineligible for purine analogues or those with severe neutropenia. CONCLUSION: Single agent vemurafenib or in combination with rituximab appears to be a promising therapeutic option for R/R HCL. Further research is needed to establish standardized treatment protocols and to investigate long-term outcomes.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Leukemia, Hairy Cell , Rituximab , Vemurafenib , Humans , Leukemia, Hairy Cell/drug therapy , Leukemia, Hairy Cell/pathology , Vemurafenib/administration & dosage , Vemurafenib/therapeutic use , Vemurafenib/adverse effects , Rituximab/administration & dosage , Rituximab/therapeutic use , Rituximab/adverse effects , Male , Middle Aged , Female , Retrospective Studies , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adult , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Treatment Outcome , Aged, 80 and over , Drug Resistance, NeoplasmABSTRACT
The combination of BRAF kinase inhibitors (BRAFis) and MEK kinase inhibitors (MEKis) is one of the most promising chemotherapy regimens in the treatment of BRAF-mutant melanoma. Although BRAFi plus MEKi combined therapy is widely used for the treatment of BRAFV600-mutated melanoma, the incidence of uveitis caused by BRAFi plus MEKi is limited. In this report, we described five cases (two men and three women) of Vogt-Koyanagi-Harada (VKH) disease-like uveitis in melanoma patients who received BRAFi plus MEKi combined therapy. Of note, all the patients had the HLA-DRB1*04 haplotype, which is frequently detected in VKH-like non-infectious uveitis. On the other hand, among BRAFi plus MEKi-treated patients who did not develop VKH disease-like uveitis, only one of five (20%) patients had the HLA-DRB1*04 haplotype. Collectively, BRAFi/MEKi might induce severe VKH disease-like uveitis in melanoma patients with the HLA-DRB1*04 haplotype.
Subject(s)
HLA-DRB1 Chains , Melanoma , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Uveomeningoencephalitic Syndrome , Humans , HLA-DRB1 Chains/genetics , Melanoma/drug therapy , Melanoma/genetics , Male , Uveomeningoencephalitic Syndrome/chemically induced , Uveomeningoencephalitic Syndrome/diagnosis , Uveomeningoencephalitic Syndrome/genetics , Female , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Middle Aged , Protein Kinase Inhibitors/adverse effects , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adult , Sulfonamides/adverse effects , Sulfonamides/administration & dosage , Vemurafenib/adverse effects , Vemurafenib/administration & dosage , Uveitis/chemically induced , Uveitis/diagnosis , Uveitis/genetics , HaplotypesABSTRACT
Background: We report the long-term outcome of uveitis associated with cancer immunotherapy (CIT). Methods: This retrospective review included serial patients with CIT-associated uveitis treated using various regimen. Results: Eight patients treated with rituximab (anti-CD20), nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4), vemurafenib and dabrafenib (anti-BRAF), trametinib (anti-MEK) and ibritunib showed uveitis with hypopion (one patient), macular edema (five patients) and choroiditis (two patients). Various regimens of corticosteroid therapy showed a favorable ophthalmological outcome, whether the CIT was continuing or suspended. Conclusion: Local corticosteroid injections in combination with CIT could be suggested as a first-line treatment. This could help to preserve the quality of life without threatening the vital prognosis.
Lay abstract This study aims to report the long-term outcome of intra-ocular inflammation (uveitis) associated with cancer immunotherapy (CIT). Serial patients complaining of blurred vision and painful eyes showed intra-ocular inflammation that was related to CIT, after infectious, inflammatory and tumoral causes of uveitis have been ruled out. The length of follow-up was more than 12 months for most patients. Eight serial patients treated with rituximab (anti-CD20), nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4), vemurafenib and dabrafenib (anti-BRAF), trametinib (anti-MEK) and ibritunib showed intra-ocular inflammation with hypopion (one patient), macular edema (five patients) and choroiditis (two patients). Various regimens of corticosteroid therapy showed a favorable ophthalmological outcome, whether the CIT was continuing or suspended. Local corticosteroid injections in combination with CIT could be suggested as a first-line treatment. This could help to preserve the quality of life without threatening the vital prognosis.
Subject(s)
Adrenal Cortex Hormones/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Immunotherapy/adverse effects , Neoplasms/therapy , Uveitis , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Female , Humans , Imidazoles/administration & dosage , Imidazoles/adverse effects , Ipilimumab/administration & dosage , Ipilimumab/adverse effects , Male , Middle Aged , Nivolumab/administration & dosage , Nivolumab/adverse effects , Oximes/administration & dosage , Oximes/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects , Pyrimidinones/administration & dosage , Pyrimidinones/adverse effects , Retrospective Studies , Rituximab/administration & dosage , Rituximab/adverse effects , Uveitis/chemically induced , Uveitis/drug therapy , Vemurafenib/administration & dosage , Vemurafenib/adverse effectsABSTRACT
BACKGROUND: In COLUMBUS, treatment with encorafenib plus binimetinib in patients with advanced BRAF-mutant melanoma showed improved progression-free and overall survival with favourable tolerability compared to vemurafenib treatment. Here, results on health-related quality of life (HRQoL) are presented. METHODS: COLUMBUS was a two-part, open-label, randomised, phase III study in patients with BRAF-mutant melanoma. In PART-I, 577 patients were randomised (1:1:1) to encorafenib plus binimetinib, encorafenib or vemurafenib. The primary objective was to assess progression-free survival. As a secondary objective, HRQoL was assessed by the EQ-5D, the EORTC QLQ-C30 and the FACT-M questionnaires. Furthermore, time to definitive 10% deterioration was estimated with a Kaplan-Meier analysis and differences in mean scores between groups were calculated with a mixed-effect model for repeated measures. Hospitalisation rate and the impact of hospitalisation on HRQoL were also assessed. RESULTS: Patients receiving the combination treatment showed improvement of their FACT-M and EORTC QLQ-C30 global health status scores, compared to those receiving vemurafenib (post-baseline score differences: 3.03 [p < 0.0001] for FACT M and 5.28 [p = 0.0042] for EORTC QLQ-C30), indicative of a meaningful change in patient's status. Furthermore, a delay in the deterioration of QoL was observed in non-hospitalised patients compared to hospitalised patients (hazard ratio [95% CI]: 1.16 [0.80; 1.68] for EORTC QLQ-C30 and 1.27 [0.81; 1.99] for FACT-M) and a risk reduction of 10% deterioration, favoured the combination in both groups. CONCLUSION: The improved efficacy of encorafenib plus binimetinib compared to vemurafenib, translates into a positive impact on the perceived health status as assessed by the HRQoL questionnaires. The study is registered with ClinicalTrials.gov, number NCT01909453 and EudraCT number 2013-001176-38.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzimidazoles/administration & dosage , Carbamates/administration & dosage , Melanoma/drug therapy , Quality of Life , Skin Neoplasms/drug therapy , Sulfonamides/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzimidazoles/adverse effects , Carbamates/adverse effects , Female , Humans , Male , Melanoma/genetics , Melanoma/mortality , Melanoma/psychology , Middle Aged , Mutation , Progression-Free Survival , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/genetics , Skin Neoplasms/mortality , Skin Neoplasms/psychology , Sulfonamides/adverse effects , Vemurafenib/administration & dosage , Vemurafenib/adverse effects , Young AdultABSTRACT
PURPOSE: In BRAF V600MUT metastatic melanoma, cyclin D-CDK4/6-INK4-Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of cyclin-dependent kinase 4 (CDK4) inhibitors. In this phase I-II study, we aimed to establish the MTD of palbociclib when added to vemurafenib. PATIENTS AND METHODS: Patients with BRAF V600E/KMUT metastatic melanoma harboring CDKN2A loss and RB1 expression were included and stratified into two groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics, and tumor molecular profiling. RESULTS: Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were American Joint Committee on Cancer stage IVM1c (N = 16; 88.9%), high lactate dehydrogenase (N = 9; 50.0%), and median number of previous treatments of 2. One and 5 patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25 mg and vemurafenib 960 mg in strata 2. No significant evidence for drug-drug interactions was highlighted. The median progression-free survival was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib. CONCLUSIONS: Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25 mg, a significant clinical benefit was achieved in pretreated patients with melanoma. An association between the transcriptomic data and clinical response was highlighted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Checkpoint Kinase 2/physiology , Melanoma/drug therapy , Melanoma/genetics , Piperazines/administration & dosage , Proto-Oncogene Proteins B-raf/genetics , Pyridines/administration & dosage , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Vemurafenib/administration & dosage , Adult , Female , Humans , Male , Melanoma/secondary , Middle Aged , Skin Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped. METHODS: In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment. RESULTS: Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents. CONCLUSIONS: In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Hairy Cell/drug therapy , Rituximab/administration & dosage , Vemurafenib/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bone Marrow/pathology , Drug Resistance, Neoplasm , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm, Residual , Neutropenia/chemically induced , Progression-Free Survival , Recurrence , Remission Induction , Rituximab/adverse effects , Thrombocytopenia/chemically induced , Vemurafenib/adverse effectsABSTRACT
Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAFV600E -mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi-resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Dedifferentiation , Connective Tissue Growth Factor/metabolism , Drug Resistance, Neoplasm , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Neoplastic , Melanoma/drug therapy , Apoptosis , Azetidines/administration & dosage , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Proliferation , Connective Tissue Growth Factor/genetics , Forkhead Transcription Factors/genetics , Humans , Melanoma/genetics , Melanoma/metabolism , Melanoma/pathology , Molecular Targeted Therapy , Mutation , Piperidines/administration & dosage , Prognosis , Signal Transduction , Survival Rate , Tumor Cells, Cultured , Vemurafenib/administration & dosageSubject(s)
Leukemia, Hairy Cell , Rituximab/administration & dosage , Vasculitis, Leukocytoclastic, Cutaneous , Vemurafenib/administration & dosage , Humans , Leukemia, Hairy Cell/diagnosis , Leukemia, Hairy Cell/drug therapy , Leukemia, Hairy Cell/pathology , Male , Middle Aged , Vasculitis, Leukocytoclastic, Cutaneous/diagnosis , Vasculitis, Leukocytoclastic, Cutaneous/drug therapy , Vasculitis, Leukocytoclastic, Cutaneous/pathologyABSTRACT
We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on adrenocortical carcinoma cells. Here, we show that methiothepin also inhibits doxorubicin efflux and increases doxorubicin cytotoxicity in melanoma cells which endogenously overexpress Ptch1. Melanoma patients having the BRAFV600E mutation are treated with vemurafenib, an inhibitor of BRAFV600E, often in combination with trametinib, an inhibitor of MEK. Almost all patients ultimately acquire resistance to the treatment leading to disease progression. Here, we report that methiothepin overcomes the resistance of BRAFV600E melanoma cells by enhancing the cytotoxicity of vemurafenib and trametinib on these cells leading to melanoma cells death. We observe that the addition of methiothepin to vemurafenib prevents migration of resistant melanoma cells more efficiently than vemurafenib alone. Our results provide an additional proof that Ptch1 drug efflux inhibition increases the effectiveness of anti-cancer treatments and overcomes resistance of melanoma cells expressing Ptch1.
Subject(s)
Antineoplastic Agents , Drug Resistance, Neoplasm/drug effects , Melanoma/drug therapy , Methiothepin , Skin Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Doxorubicin/administration & dosage , Humans , Methiothepin/pharmacology , Methiothepin/therapeutic use , Patched-1 Receptor/metabolism , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Vemurafenib/administration & dosageABSTRACT
Most patients with treatment naïve classical hairy cell leukemia (cHCL) have durable responses with purine nucleoside analogues. In contrast, options are limited for cHCL patients with co-morbidities, purine analogue intolerance, or resistant disease. We report the utility of targeted therapy for nine cHCL patients presenting with treatment naïve cHCL and severe neutropenia and infection (n = 3), purine analogue intolerance (n = 2), or purine analogue resistant disease (n = 4). BRAF inhibitor vemurafenib was started at 240-480 mg twice daily (planned 90-day treatment) and combined with rituximab in seven patients. Therapy was tolerable with no severe adverse events. All patients responded with rapid blood count recovery (median time 1.52 months, range 0.43-4.33). Median progression free and overall survival was not reached at a median follow up of 18.1 months (range 3.2-68.9). These data suggest targeted therapy could be an option for patients unable to be treated with purine analogues.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Hairy Cell/drug therapy , Rituximab/administration & dosage , Vemurafenib/administration & dosage , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia, Hairy Cell/mortality , Male , Middle Aged , Molecular Targeted Therapy , Progression-Free SurvivalABSTRACT
Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.
Subject(s)
Antineoplastic Agents/administration & dosage , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Vemurafenib/administration & dosage , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Mice , Mice, Nude , Molecular Targeted Therapy , Mutation , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/physiopathology , Proteolysis/drug effects , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Ubiquitination/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Therapy resistance to a selective B-Raf inhibitor (BRAFi) poses a challenge in treating patients with BRAF-mutant melanomas. Here, we report that RNA interference of mortalin (HSPA9/GRP75), a mitochondrial molecular chaperone often upregulated and mislocalized in melanoma, can effectively induce death of vemurafenib-resistant progenies of human B-RafV600E melanoma cell lines, A375 and Colo-829. Mortalin depletion induced death of vemurafenib-resistant cells at similar efficacy as observed in vemurafenib-naïve parental cells. This lethality was correlated with perturbed mitochondrial permeability and was attenuated by knockdown of adenine nucleotide translocase (ANT) and cyclophilin D (CypD), the key regulators of mitochondrial permeability. Chemical inhibition of MEK1/2 and ERK1/2 also suppressed mortalin depletion-induced death and mitochondrial permeability in these cells. These data suggest that mortalin and MEK/ERK regulate an ANT/CypD-associated mitochondrial death mechanism(s) in B-RafV600E melanoma cells and that this regulation is conserved even after these cells develop BRAFi resistance. We also show that doxycycline-induced mortalin depletion can effectively suppress the xenografts of vemurafenib-resistant A375 progeny in athymic nude mice. These findings suggest that mortalin has potential as a candidate therapeutic target for BRAFi-resistant BRAF-mutant tumors.
Subject(s)
Doxycycline/administration & dosage , HSP70 Heat-Shock Proteins/genetics , Melanoma/drug therapy , Mitochondrial Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Vemurafenib/administration & dosage , Adenine Nucleotide Translocator 3/genetics , Animals , Cell Line, Tumor , Cyclophilins/genetics , Doxycycline/pharmacology , Drug Resistance, Neoplasm , Extracellular Signal-Regulated MAP Kinases/genetics , Female , Gene Knockdown Techniques , Humans , Melanoma/genetics , Mice , Mice, Nude , Mitogen-Activated Protein Kinase Kinases/genetics , Mutation , Vemurafenib/pharmacology , Xenograft Model Antitumor AssaysSubject(s)
Adenocarcinoma of Lung/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Substitution/methods , Lung Neoplasms/drug therapy , Mutation , Proto-Oncogene Proteins B-raf/genetics , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Azetidines/administration & dosage , Humans , Imidazoles/administration & dosage , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Oximes/administration & dosage , Piperidines/administration & dosage , Prognosis , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Vemurafenib/administration & dosageABSTRACT
INTRODUCTION: BRAF and MEK inhibitors have been approved for use in metastatic melanoma therapies. All of them are administered as oral capsules or pills. We report two cases treated applying an alternative method of vemurafenib or debrafenib-trametinib administration in patients unable to swallow. CASE REPORT: The first case involved a 38-year-old man who was referred to a dermatologist for dysphagia and anorexia. After a computerized tomography (CT) scan it was concluded that the dysphagia was due to compression by mediastinal metastasis in a context of metastatic BRAF mutant melanoma. The second case involved a 35-year-old man who was diagnosed in March 2017 with melanoma of the back of the hand. Several months later a positron emission tomography (PET)/CT scan was performed. It revealed multiple disseminated metastasis.Management & Outcome: The first patient presented total dysphagia and was unable to swallow pills. It was decided to dissolve vemurafenib in order to facilitate administration. Dysphagia was improved 48 hours later, and oral feeding was reintroduced. Due to severe tablet phobia, the second patient was unable to swallow pills. Dabrafenib capsules were emptied and trametinib pills were grinded. One month later, we noted improved health associated with reduction of the metastases. DISCUSSION: Our study highlights the possibility of crushing or dissolving BRAF and MEK inhibitors in metastatic melanoma patients for whom it is impossible to swallow pills, eliciting a response and achieving significant if temporary clinical benefit.
Subject(s)
Antineoplastic Agents/administration & dosage , Deglutition Disorders/drug therapy , Melanoma/drug therapy , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Skin Neoplasms/drug therapy , Adult , Antineoplastic Agents/metabolism , Deglutition Disorders/diagnostic imaging , Humans , Imidazoles/administration & dosage , Imidazoles/metabolism , Male , Melanoma/diagnostic imaging , Oximes/administration & dosage , Oximes/metabolism , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Pyridones/administration & dosage , Pyridones/metabolism , Pyrimidinones/administration & dosage , Pyrimidinones/metabolism , Skin Neoplasms/diagnostic imaging , Vemurafenib/administration & dosage , Vemurafenib/metabolismSubject(s)
Adenocarcinoma of Lung/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lung Neoplasms/drug therapy , Acrylamides/administration & dosage , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Aged , Aniline Compounds/administration & dosage , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Proto-Oncogene Proteins B-raf/genetics , Treatment Outcome , Vemurafenib/administration & dosageABSTRACT
The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAFV600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Itraconazole/administration & dosage , Melanoma/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Thyroid Neoplasms/metabolism , Vemurafenib/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Drug Interactions , Female , Humans , Itraconazole/adverse effects , Male , Melanoma/blood , Melanoma/drug therapy , Melanoma/genetics , Middle Aged , Mutation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/blood , Proto-Oncogene Proteins B-raf/genetics , Thyroid Neoplasms/blood , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/genetics , Vemurafenib/administration & dosage , Vemurafenib/adverse effects , Vemurafenib/blood , Young AdultABSTRACT
CONTEXT: Multiple mechanisms play roles in restricting the ability of T-cells to recognize and eliminate tumor cells. OBJECTIVE: To identify immune escape mechanisms involved in papillary thyroid carcinoma (PTC) to optimize immunotherapy. SETTING AND DESIGN: iTRAQ analysis was conducted to identify proteins differentially expressed in PTC samples with or without BRAFV600E mutation. Molecular mechanisms regulating tumor cell evasion were investigated by in vitro modulations of BRAF/MAPK and related pathways. The pathological significance of identified tumor-specific major histocompatibility complex class II (tsMHCII) molecules in mediating tumor cell immune escape and targeted immune therapy was further evaluated in a transgenic mouse model of spontaneous thyroid cancer. RESULTS: Proteomic analysis showed that tsMHCII level was significantly lower in BRAFV600E-associated PTCs and negatively correlated with BRAF mutation status. Constitutive activation of BRAF decreased tsMHCII surface expression on tumor cells, which inhibited activation of CD4+ T-cells and led to immune escape. Pathway analysis indicated that the transforming growth factor (TGF)-ß1/SMAD3-mediated repression of tsMHCII, which could be reversed by BRAF inhibition (BRAFi). Targeting this pathway with a combined therapy of BRAF inhibitor PLX4032 and anti-PD-1 antibody efficiently blocked tumor growth by increasing CD4+ T-cell infiltration in a transgenic PTC mouse model. CONCLUSIONS: Our results suggest that BRAFV600E mutation in PTC impairs the expression of tsMHCII through the TGF-ß1/SMAD3 pathway to enhance immune escape. Combined treatment with PLX4032 and anti-PD-1 antibody promotes recognition and elimination of PTC by the immune system in a pre-clinical mouse model, and therefore offers an effective therapeutic strategy for patients with advanced PTC.