RESUMO
BACKGROUND: Preclinical models of pancreatic cancer (PDAC) suggest a synergistic role for combined MEK and autophagy signaling inhibition, as well as MEK and CDK4/6 pathway targeting. Several case reports implicate clinical activity of the combination of either trametinib and hydroxychloroquine (HCQ) in patients with KRAS-mutant PDAC or trametinib with CDK4/6 inhibitors in patients with KRAS and CDKN2A/B alterations. However, prospective data from clinical trials is lacking. Here, we aim to provide clinical evidence regarding the use of these experimental regimens in the setting of dedicated precision oncology programs. METHODS: In this retrospective case series, PDAC patients who received either trametinib/HCQ (THCQ) or trametinib/palbociclib (TP) were retrospectively identified across 11 participating cancer centers in Germany. RESULTS: Overall, 34 patients were identified. 19 patients received THCQ, and 15 received TP, respectively. In patients treated with THCQ, the median duration of treatment was 46 days, median progression-free survival (PFS) was 52 days and median overall survival (OS) was 68 days. In the THCQ subgroup, all patients evaluable for response (13/19) had progressive disease (PD) within 100 days. In the TP subgroup, the median duration of treatment was 60 days, median PFS was 56 days and median OS was 195 days. In the TP subgroup, 9/15 patients were evaluable for response, of which 1/9 showed a partial response (PR) while 8/9 had PD. One patient achieved a clinical benefit despite progression under TP. CONCLUSION: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Hidroxicloroquina , Neoplasias Pancreáticas , Piperazinas , Piridinas , Piridonas , Pirimidinonas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Feminino , Idoso , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Hidroxicloroquina/uso terapêutico , Hidroxicloroquina/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Adulto , Idoso de 80 Anos ou maisRESUMO
OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.
Assuntos
Craniofaringioma , Oximas , Neoplasias Hipofisárias , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Estudos Retrospectivos , Craniofaringioma/tratamento farmacológico , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Idoso , Neoplasias Hipofisárias/tratamento farmacológico , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Oximas/uso terapêutico , Oximas/administração & dosagem , Oximas/efeitos adversos , Estudos de Coortes , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Terapia de Alvo Molecular/métodos , Imidazóis/uso terapêutico , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1â >â 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18â months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Imidazóis , Neoplasias Pulmonares , Mutação , Oximas , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas c-met , Piridonas , Pirimidinonas , Humanos , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Masculino , Oximas/administração & dosagem , Idoso , Proteínas Proto-Oncogênicas B-raf/genética , Imidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) has been reported rarely with BRAF/MEK inhibitor combinations, including dabrafenib/trametinib. Postmarketing pharmacovigilance analyses evaluating outcomes associated with dabrafenib/trametinib-induced HLH are also lacking. Herein, we report a case of dabrafenib/trametinib-induced HLH in a patient with metastatic melanoma. Recovery of HLH-related symptoms was observed following drug discontinuation, supportive care, and corticosteroids. We also conducted a pharmacovigilance analysis of the USA Food and Drug Administration Adverse Event Reporting System (FAERS) to describe postmarketing cases of HLH with dabrafenib/trametinib exposure. There were 50 reports of HLH with dabrafenib/trametinib in FAERS. Most cases occurred in the setting of melanoma ( n â =â 39; 78%) and most were reported in Europe ( n â =â 39; 74%). Hospitalization was the most common outcome ( n â =â 39; 78%) of this adverse event per FAERS. HLH is a rare complication of dabrafenib/trametinib, and clinicians should be aware and monitor for signs of this potentially serious and life-threatening adverse event.
Assuntos
Imidazóis , Linfo-Histiocitose Hemofagocítica , Melanoma , Oximas , Piridonas , Pirimidinonas , Humanos , Melanoma/tratamento farmacológico , Imidazóis/efeitos adversos , Imidazóis/administração & dosagem , Oximas/efeitos adversos , Oximas/administração & dosagem , Oximas/uso terapêutico , Pirimidinonas/efeitos adversos , Pirimidinonas/administração & dosagem , Piridonas/efeitos adversos , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Farmacovigilância , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , IdosoRESUMO
A 76-year-old female patient presented with an iodine-refractory papillary thyroid carcinoma (PTC), diagnosed eight years earlier, with several lymph node recurrences requiring successive surgeries. Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging revealed a new unresectable loco-regional recurrence. The patient was diagnosed with a somatic BRAF V600E mutation. Therefore, dabrafenib and trametinib combination therapy was introduced and closely monitored by a dedicated multidisciplinary team, involving pharmaceutical consultations. As early as six weeks after treatment initiation, the patient reported multiple adverse events (AEs) to the clinical pharmacy team, who provided advice on resolving AEs or improving tolerance. Close interprofessional collaboration among healthcare workers involved in the care pathway allowed for the identification of the most opportune times for temporary suspension of treatment (four suspensions over seven months) or dose reduction (two reductions over 3.5 months). This resulted in a total treatment duration (one year) longer than the average times reported in the literature. The patient showed a rapid and excellent response to treatment immediately after initiation, culminating in a complete metabolic response assessed by [18F]FDG PET/CT imaging at nine months. Twenty-five months after treatment discontinuation, the disease remained controlled. Overall, dabrafenib and trametinib combination could offer excellent outcomes in selected patients with refractory BRAF-mutated PTC, with additional clinical pharmacy initiatives allowing for the optimized management of AEs and prolonged treatment periods.
Assuntos
Imidazóis , Oximas , Piridonas , Pirimidinonas , Neoplasias da Glândula Tireoide , Humanos , Feminino , Oximas/uso terapêutico , Oximas/administração & dosagem , Imidazóis/uso terapêutico , Imidazóis/administração & dosagem , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Idoso , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos do Iodo/uso terapêutico , Radioisótopos do Iodo/administração & dosagem , Câncer Papilífero da Tireoide/tratamento farmacológico , Resultado do Tratamento , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAFV600-mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 .
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Imidazóis , Melanoma , Mutação , Terapia Neoadjuvante , Oximas , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Feminino , Masculino , Pessoa de Meia-Idade , Oximas/administração & dosagem , Oximas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Imidazóis/uso terapêutico , Imidazóis/administração & dosagem , Imunoterapia/métodosRESUMO
MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG-CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose-limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 µg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady-state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies.
Assuntos
Antineoplásicos , Doenças do Cão , Neoplasias , Piridonas , Pirimidinonas , Cães , Animais , Piridonas/farmacocinética , Piridonas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Piridonas/farmacologia , Pirimidinonas/farmacocinética , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/uso terapêutico , Pirimidinonas/farmacologia , Doenças do Cão/tratamento farmacológico , Feminino , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/veterinária , Antineoplásicos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a DrogaRESUMO
We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.
Assuntos
Proteínas de Ciclo Celular , Histona-Lisina N-Metiltransferase , Proteínas Tirosina Quinases , Pirazóis , Humanos , Pessoa de Meia-Idade , Histona-Lisina N-Metiltransferase/genética , Masculino , Idoso , Feminino , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Pirimidinonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/administração & dosagem , MutaçãoRESUMO
Most clinical trials investigating targeted therapies for patients harboring BRAF V600 mutations have included mostly White patients, and data for Asian patients are scarce. Although there are several retrospective studies in Japanese patients, they have investigated only the dabrafenib + trametinib regimen, and have had a short follow-up period. We conducted a single-center retrospective study to update previous studies and compare the outcomes with those in White patients. We analyzed 89 patients who received dabrafenib + trametinib or encorafenib + binimetinib, including 11 who received both treatment regimens. The overall response rate was 79.8%, with complete response in 25 patients (28.1%) and partial response in 45 patients (51.7%). The median progression-free survival was 13.7 months, and the median overall survival was 32.9 months. The 3-year progression-free and overall survival rates were 31.8% and 47.9%, respectively. Although the two regimens showed no significant differences in efficacy, their safety profiles differed, as reported in clinical trials. Therefore, the most frequent adverse event associated with the dabrafenib + trametinib regimen was pyrexia (61.3%) and that of encorafenib + binimetinib was blurred vision (32.0%). Switching directly to another targeted therapy after progressive disease showed no clinical response; however, rechallenge followed by immune checkpoint inhibitor therapy showed a certain response. As a prognostic factor, performance status was associated with progression-free survival, and performance status, serum lactate dehydrogenase level, and dose interruption were associated with overall survival in the multivariate analysis. Real-world data on targeted therapy for patients with melanoma in Japan suggest that both dabrafenib + trametinib and encorafenib + binimetinib show similar efficacy and safety in Asian and White patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Carbamatos , Imidazóis , Melanoma , Oximas , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Neoplasias Cutâneas , Sulfonamidas , Humanos , Estudos Retrospectivos , Masculino , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Feminino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Melanoma/genética , Oximas/administração & dosagem , Oximas/efeitos adversos , Pessoa de Meia-Idade , Japão , Idoso , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/genética , Adulto , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Idoso de 80 Anos ou mais , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Terapia de Alvo Molecular , Mutação , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
PURPOSE: Treatment of metastatic pancreatic neuroendocrine tumors (pancNETs), particularly grade 2 (G2) and grade 3 (G3), often presents a dilemma in choosing from multiple similarly efficacious therapies. Data on targeted therapies for these tumor types is limited, and this report presents BRAF-targeted therapy as a therapeutic option for metastatic pancNET G3. METHODS: This is a case report of a patient with G3 pancNET metastatic to the liver, lung, lymph node, and scalp (soft tissue) treated with dabrafenib/trametinib (D/T) in the presence of a BRAF V600E mutation detected in tumor tissue. RESULTS: This patient has demonstrated an ongoing partial response to therapy at all involved sites for nearly 15 months with minimal side effects attributable to D/T. CONCLUSION: Dabrafenib/trametinib therapy for BRAF-mutated metastatic pancNETs provides a novel treatment option and, especially in the G3 setting, should be considered a first-line option. Tumor testing for actionable mutations should be undertaken at the time of diagnosis and/or progression to identify novel therapeutic avenues in these rare tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Imidazóis , Mutação , Tumores Neuroendócrinos , Oximas , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Humanos , Imidazóis/uso terapêutico , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Oximas/uso terapêutico , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Feminino , Gradação de Tumores , Resultado do Tratamento , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologiaRESUMO
Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non-small cell lung cancer (NSCLC), data on its efficacy against uncommon BRAF mutations are still limited due to their rare frequency. We report a case of 70-year-old woman with BRAF V600_W604 deletion-insertion R-positive stage IVA lung adenocarcinoma, who was successfully treated with dabrafenib plus trametinib. Herein, we discuss the oncogenic role of uncommon BRAF mutations and highlight the importance of performing comprehensive genomic profiling on patients without any targetable gene alterations in companion diagnostics.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Imidazóis , Neoplasias Pulmonares , Oximas , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Idoso , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Imidazóis/uso terapêutico , Imidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Oximas/uso terapêutico , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagemRESUMO
PURPOSE: The efficacy and safety of vibegron, a ß3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. MATERIALS AND METHODS: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Scoreâstorage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). RESULTS: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Scoreâstorage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). CONCLUSIONS: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Hiperplasia Prostática , Bexiga Urinária Hiperativa , Humanos , Masculino , Hiperplasia Prostática/complicações , Hiperplasia Prostática/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Método Duplo-Cego , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Pirimidinonas/uso terapêutico , Pirimidinonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirrolidinas/uso terapêutico , Pirrolidinas/efeitos adversos , Pirrolidinas/administração & dosagem , Inibidores de 5-alfa Redutase/uso terapêutico , Inibidores de 5-alfa Redutase/efeitos adversos , Antagonistas Adrenérgicos alfa/uso terapêutico , Quimioterapia CombinadaRESUMO
BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Imidazóis , Melanoma , Terapia Neoadjuvante , Estadiamento de Neoplasias , Oximas , Piridonas , Pirimidinonas , Humanos , Oximas/administração & dosagem , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/mortalidade , Pirimidinonas/administração & dosagem , Piridonas/administração & dosagem , Imidazóis/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Adulto , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , SeguimentosRESUMO
BACKGROUND: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies. METHODS: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines. RESULTS: 16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy. CONCLUSION: Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.
Assuntos
Cistadenocarcinoma Seroso , Dasatinibe , Sinergismo Farmacológico , Ensaios de Triagem em Larga Escala , Neoplasias Ovarianas , Piridonas , Pirimidinonas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Piridonas/farmacologia , Piridonas/administração & dosagem , Pirimidinonas/farmacologia , Pirimidinonas/administração & dosagem , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Dasatinibe/administração & dosagem , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Gradação de Tumores , Inibidores de Proteínas Quinases/farmacologia , Dissulfiram/farmacologia , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.
Assuntos
Compostos de Anilina , Mutação , Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Piridonas , Pirimidinonas , Sulfonamidas , Proteína bcl-X , Humanos , Feminino , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Idoso , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/genética , Adulto , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , GTP Fosfo-Hidrolases/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.
Assuntos
Neurofibromatose 1 , Testes Neuropsicológicos , Piridonas , Pirimidinonas , Humanos , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/administração & dosagem , Masculino , Feminino , Adolescente , Criança , Neurofibromatose 1/tratamento farmacológico , Neurofibromatose 1/complicações , Neurofibromatose 1/psicologia , Adulto Jovem , Pré-Escolar , Glioma/tratamento farmacológico , Glioma/psicologia , Glioma/complicações , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/psicologia , Neoplasias Encefálicas/complicações , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/efeitos adversosRESUMO
Pralsetinib is a highly potent oral kinase inhibitor of oncogenic RET (rearranged during transfection) fusions and mutations. Pralsetinib received approval from the United States Food and Drug Administration for the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), and received accelerated approval for the treatment of patients with RET fusion-positive thyroid cancer. Exposure-response (ER) analyses of efficacy were performed separately in patients with thyroid cancer and in patients with NSCLC, but data for all patients were pooled for the safety analysis. ER models were developed with time-varying exposure; the effect of covariates was also examined. For patients with NSCLC, a higher starting dose was associated with improved progression-free survival (PFS), but this improvement did not correlate with a higher exposure overall. Significant covariates included sex and baseline Eastern Cooperative Oncology Group (ECOG) score. For patients with thyroid cancer, a higher exposure was associated with improved PFS. Significant covariates included prior systemic cancer therapy and ECOG score. For safety, higher exposure was associated with a greater risk of grade ≥3 anemia, pneumonia, and lymphopenia. Patients with an ECOG score of ≥1 had an increased risk of grade ≥3 pneumonia. Non-White patients had a lower risk of grade ≥3 lymphopenia. ER analysis revealed that higher pralsetinib exposure was associated with improved PFS in thyroid cancer, but not in NSCLC. However, a higher starting dose (ie, 400 vs ≤300 mg daily) was correlated with better PFS for all indications. Higher exposure was also associated with an increased risk of grade ≥3 adverse events (AEs); however, the overall incidence of these events was acceptably low (≤20%). This analysis supports the use of a 400 mg starting dose of pralsetinib, allowing for dose reduction in the event of AEs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Feminino , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Pessoa de Meia-Idade , Idoso , Adulto , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Pirazóis , Piridinas , PirimidinasRESUMO
We present the case of a 20-month-old girl with Schimmelpenning-Feuerstein-Mims (SFM) syndrome with extensive head, neck, and torso skin involvement successfully managed with topical trametinib. Trametinib interferes downstream of KRAS and HRAS in the MAPK signaling pathway, of which KRAS was implicated in our child's pathogenic variant. Although other dermatologic conditions have shown benefit from oral trametinib, its topical use has not been well reported. Our patient showed benefit from the use of twice-daily topical trametinib, applied to the epidermal and sebaceous nevi over a 16-month period, leading to decreased pruritus and thinning of the plaques.
Assuntos
Piridonas , Pirimidinonas , Neoplasias Cutâneas , Humanos , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Feminino , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem , Lactente , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Nevo/tratamento farmacológico , Insuficiência de Crescimento/tratamento farmacológico , Administração Tópica , Anormalidades Múltiplas/tratamento farmacológico , Nevo Sebáceo de Jadassohn/tratamento farmacológico , Síndromes Neurocutâneas/tratamento farmacológico , Síndromes Neurocutâneas/diagnóstico , Anormalidades da Pele/tratamento farmacológico , Antineoplásicos/uso terapêutico , Anormalidades do Olho/tratamento farmacológico , Doenças da Imunodeficiência Primária/tratamento farmacológicoRESUMO
Up to 71% of lung cancer patients admitted to the ICU are newly diagnosed. The decision to initiate cancer directed treatments in lung cancer patients admitted to the ICU remains complex. For those with identified oncogene driver mutations, targeted therapies with rapid and high response rates are attractive treatment options. However, mechanically ventilated patients face additional barriers in which enteral tube administration of oral therapies may require tablets or capsules to be crushed or opened and diluted. Data on the pharmacodynamics and pharmacokinetics of this alternative route of administration are often very limited. Here we describe the first case report of an intubated patient with newly diagnosed NSCLC who was successfully treated with opened dabrafenib capsules and crushed trametinib tablets administered through a nasogastric tube. We also provide a review of the existing literature on feeding tube administration of commonly used tyrosine kinase inhibitors in lung cancer. Tyrosine kinase inhibitors administered through feeding tubes can lead to a clinically meaningful recovery in critically ill patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Estado Terminal , Imidazóis , Intubação Gastrointestinal , Neoplasias Pulmonares , Oximas , Piridonas , Pirimidinonas , Humanos , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Oximas/administração & dosagem , Intubação Gastrointestinal/métodos , Imidazóis/administração & dosagem , Masculino , Nutrição Enteral/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). METHODS: Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. RESULTS: Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. CONCLUSIONS: Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.