Trametinib Therapy Research Articles

Abstract 4487: Effective anti-tumor effect in a rare metastatic Wilms tumor xenograft by inhibition of RAS/PI3K hyperactivation

Abstract Wilms Tumor (WT) is an embryonal renal tumor that accounts for more than 90% of kidney tumors in children. Significant advances in multidisciplinary therapeutic approaches have increased survival rates up to 90%. However, approximately 15% of patients with favorable histology and 50% of patients with anaplastic WT experience recurrence of disease. Thus, there is still a critical need to develop therapies that are effective and safe for these patients with progressive disease. To address this, we have developed a pipeline of patient derived xenograft (PDX) models from single academic institution patients with metastatic and aggressive cancers. Among these we have developed 3 xenograft models derived from patients with WT. To gain a detailed understanding of the complex array of mutations and identify therapeutic targets, molecular signatures were obtained at the DNA and protein levels via whole genome sequencing and reverse phase protein array analyses respectively. While PDX derived from encapsulated WT specimens exhibited basal levels of PI3K and MAPK pathway activation, which are well-known for promoting tumor survival, growth, and metastasis, no mutations that drive hyperactivation of these pathways were identified in these PDX. In contrast, a rare WT xenograft (PDX120) was established from a female patient with recurrent disease and metastatic cancer in the liver. -OMICS data indicated hyperactivation of PI3K (PIK3CA p.H1047R) and MAPK (KRAS p.G12_G10ins) which was validated by qPCR and immunoblotting in original tumor sample and serially passaged PDX120 xenografts. -OMICS data also confirmed the fidelity of the molecular signature between the original tumor sample and the serially passaged PDX120. The metastatic WT model was screened with two FDA approved drugs as single agents: Trametinib (MAPK pathway inhibitor; BID M-F 1mg/kg PO Day 1-35) or Alpelisib (PI3K pathway inhibitor; QD M-F 50mg/kg PO: Mice were dosed Day 1-29, followed by a gap period, and then dosing re-initiated, Day 86-103). Trametinib therapy did not effectively attenuate PDX120 tumor growth. In contrast, the PI3K inhibitor Alpelisib was well tolerated and significantly decreased PDX120 growth and prolonged survival compared to the vehicle control (Two-way ANOVA, Holm-Sidak, p<0.05). At the end of the study, histological analyses indicated a complete lack of Ki67+ and tumorigenic cells in the Alpelisb-treated tumors compared to vehicle controls, indicating a dominant growth dependency on PI3K pathway activation. While efficacy data generated in PDX derived from patients is not used to guide clinical decisions at this time, it can validate therapeutic approaches and provide rationale for future clinical trials. In conclusion, these studies provide critical feasibility data that has high translational value and great potential to improve survival and quality of life for children suffering with progressive WT. Citation Format: Mohammad Reza Saadatzadeh, Khadijeh Bijangi Vishehsaraei, Erika A. Dobrota, Barbara J. Bailey, Lauren E. Hein, Kathryn L. Coy, Melissa A. Trowbridge, Anthony L. Sinn, Troy A. Markel, Michael J. Ferguson, Pankita H. Pandya, Karen E. Pollok. Effective anti-tumor effect in a rare metastatic Wilms tumor xenograft by inhibition of RAS/PI3K hyperactivation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4487.

Bilateral Severe Panuveitis Occurring during Cancer Immunotherapy with Dabrafenib and Trametinib Therapy Due to Toxoplasmosis Reactivation

The development of cancer immunotherapy with small molecule kinase inhibitors such as BRAF inhibitors (BRAFi) or MEK inhibitors (MEKi) and immune checkpoint inhibitors allowed a major advance in the treatment of cancer. BRAF and MEK are effectors in the mitogen-activated protein kinase pathway (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway involved in cell proliferation, which is modified in cancer cells [1]. Therefore, small molecule kinase inhibitors inhibit cancer cell proliferation but also have an immune-stimulating tumor microenvironment [1]. BRAFi and MEKi in BRAF-mutant tumors could lead to an immune stimulatory microenvironment by enhancing the expression of immune stimulatory molecules and cytokines, as well as decreasing the expression of immunosuppressive molecules (such as IL-1A, IL-6, IL-8, IL-10) and reducing the number of regulatory immune cells (such as Tregs and MDSCs) [1]. They are mainly used for advanced cutaneous melanoma but also for other cancers such as non-small cell lung cancer.

Safety and rapid response of dabrafenib and trametinib therapy during hyperbilirubinemia in metastatic melanoma.

This case report describes the occurrence of hyperbilirubinemia as a complication of metastatic melanoma. A 72-year-old male patient was diagnosed with BRAF V600E-mutated melanoma with metastases in the liver, lymph nodes, lungs, pancreas, and stomach. Due to a lack of clinical data and specific guidelines for the treatment of mutated metastatic melanoma patients with hyperbilirubinemia, a conference of specialists debated between initiating treatment or providing supportive care. Ultimately, the patient was started on the combination therapy of dabrafenib and trametinib. This treatment resulted in a significant therapeutic response via normalization of bilirubin levels and an impressive radiological response of metastases just one month post-treatment initiation.

NFB-12. Effect of trametinib on leg length discrepancy in a child with NF1 related plexiform neurofibroma

INTRODUCTION: Plexiform neurofibroma(PN) is a challenging benign tumor. Recently, MEK inhibitors (MEKi) showed encouraging tumor response. We report the observed effect of Trametinib on leg length discrepancy (LLD) in a child with NF1. CASE DESCRIPTION: A 4 year old girl with sporadic NF1, developed progressive bilateral L1-L5 paraspinal PN extending to the left thigh resulting in hypertrophy of left leg and associated with LLD. At 33 months of age, length difference of 2.8 cm between both femurs was described on scanogram with a projected LLD of at 6.1- 6.2 cm LLD at bone maturity using the multiplier method, a common method of predicting LLD. At 36 months of age, treatment with Trametinib was initiated for her large PN. Ten months into therapy, parents reported impression of decrease swelling of her left thigh enlargement. MRI evaluation showed stable measurement of PN using the RECIST criteria. Repeat measurement on scanogram at 46 months of age disclosed a stable difference of 2.8 cm between both femurs, with a LLD projected at 5.2-5.3 cm at maturity by multiplier method. Bone age at study entry and at 11 months into therapy (Greulich-Pyle) was reported normal for chronologic age. DISCUSSION/CONCLUSION: LLD has not been commonly described in association with NF1 related PN. Given the PN involved mainly the left thigh in our patient, it is reasonable to suggest common underlying mechanism for the PN and faster growth of her left femur. Although with limited time point’s measurements, the early observation of stabilization of the LLD, 10 months into Trametinib therapy suggesting a final discrepancy in femurs length less than initially predicted, is encouraging. Further evaluation at completion of treatment and on follow-up are needed. Larger case series will be useful to explore this unexpected and possible clinical effect of MEKi in NF1 children.

Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition.

Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.

A case of malignant melanoma with retinal detachment due to dabrafenib and trametinib therapy

A case of malignant melanoma with retinal detachment due to dabrafenib and trametinib therapy

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis

IntroductionDabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data. MethodsPretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety. ResultsAt data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5–78.5) and 16.3 (range: 0.4–80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8–80.1) and 63.9% (46.2–79.2), median progression-free survival (95% CI) was 10.2 (6.9–16.7) and 10.8 (7.0–14.5) months, and median overall survival (95% CI) was 18.2 (14.3–28.6) and 17.3 (12.3–40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation. ConclusionsDabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment.

Acute granulomatous interstitial nephritis in a patient with metastatic melanoma on targeted therapy with dabrafenib and trametinib—A case report

BackgroundCombination molecular targeted therapy with dabrafenib plus trametinib has been shown to improve progression‐free survival and overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. In general, these agents are well tolerated. Kidney related adverse events are uncommon with only three case reports of acute interstitial nephritis and one case of a serious acute kidney injury. We report another case of interstitial nephritis related to these drugs.CaseA 37‐year‐old man diagnosed with metastatic melanoma (BRAF V600E mutation) who developed acute interstitial nephritis 5 years into his treatment with combination dabrafenib plus trametinib therapy. He presented with an asymptomatic acute kidney injury on routine surveillance pathology with a creatinine of 174 μmol/L (from baseline 80 μmol/L) and a corresponding estimated glomerular filtration rate (eGFR) of 42 ml/min/1.73 m2 (from a baseline >90 ml/min/1.73 m2) and microalbuminuria (albumin creatinine ratio [ACR] 8.5 mg/mmol). Renal biopsy revealed a granulomatous interstitial nephritis likely drug related. He was treated with prednisolone 1 mg/kg and ceased his targeted therapy with improvement in his renal function.ConclusionAlthough rare, recognition of acute interstitial nephritis, a possible serious adverse outcome due to dabrafenib and trametinib is important and needs to be incorporated into current Australian cancer therapy guidelines.

Abstract 1353: Tolerability and outcomes of trametinib treatment in KRAS mutated solid tumors

Abstract Background: RAS mutations are found in nearly one third of patients with cancer. As part of the Ras-Raf-MEK-ERK pathway, RAS mutations lead to uninhibited cell growth, proliferation, and survival. KRAS mutations account for a large majority of RAS mutations, especially in lung, colon, and pancreatic cancers. Trametinib, a MEK inhibitor, is approved at 2mg daily for the treatment of melanoma, lung, and thyroid cancers with BRAF mutations when in combination with dabrafenib, a BRAF inhibitor. However, trametinib's safety and efficacy in patients with KRAS-mutated tumors is still under investigation. The purpose of this analysis was to determine the tolerability of trametinib in patients with KRAS alterations. Methods: A retrospective, single-center, IRB-approved, cohort analysis was performed on patients with solid tumors at a regional cancer center. Patients who received at least one dose of trametinib were queried to be included in original chart review, including patients who had received trametinib as part of an IRB-approved precision oncology trial. The primary endpoint was tolerability as defined by proportion of patients who required dose reductions or complete discontinuation of therapy due to drug intolerance and by mean percent of FDA-approved dosing. Additional data collected includes patient demographics, cancer diagnosis, and outcome; number of previous therapy lines; agents combined with trametinib; and the nature of adverse events, if applicable. Results: Thirty-three patients were included for final evaluation. The average age of the patients included was 59.8 (range 32-81) years and the most common diagnoses were colon cancer, non-small cell lung cancer, and gynecological cancer. On average, patients had 2.5 (range 0-9) previous lines of therapy. Only 2 patients received single agent trametinib, while the remainder were treated in combination with additional agents (range 1-4). Seventeen (52%) patients tolerated trametinib therapy without progression for 2 months, including six (18%) who received treatment for 6 months or longer. Of these 17, three (9%) were initiated at 2mg daily, ten (30%) were initiated at half the approved dose, and the remaining patients were initiated at less than half of the approved dose. Twelve (36%) of these patients required dose reductions due to intolerance, and twelve (36%) patients ultimately discontinued trametinib therapy due to intolerance. None of these patients tolerated the full FDA-approved dose and the mean percent of recommended dose, after dose reductions, was 38%. Conclusion: This study demonstrates that trametinib therapy at 2mg daily is intolerable for most patients, especially in combination with other neoplastic therapies. The impact on efficacy of the subsequent dose reductions is unknown. Further investigation is required in order to determine the most tolerable dose of trametinib that is still efficacious. Citation Format: Julie R. Spangler, Rachel J. Elsey, Casey B. Williams. Tolerability and outcomes of trametinib treatment in KRAS mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1353.

Cost-Effectiveness Analysis of Dabrafenib Plus Trametinib and Vemurafenib as First-Line Treatment in Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma in China.

Objective: To evaluate the cost-effectiveness of dabrafenib plus trametinib combination therapy versus vemurafenib as first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a healthcare system perspective in China. Methods: This study employed a partitioned survival model with three health states (progression-free survival, post-progression survival and dead) to parameterize the data derived from Combi-v trial and extrapolated to 30 years. Health states’ utilities were measured by EQ-5D-3L, also sourced from the Combi-v trial. Costs including drug acquisition costs, disease management costs and adverse event costs were based on the Chinese Drug Bidding Database and physician survey in China. The primary outcomes of the model were lifetime costs, life-years (LYs), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted, respectively. Result: Dabrafenib plus trametinib is projected to increase a patient’s life expectancy by 0.95 life-years over vemurafenib (3.03 vs. 2.08) and 1.09 QALY gains (2.48 vs. 1.39) with an incremental cost of $3833. The incremental cost-effectiveness ratio (ICER) was $3511 per QALY. In the probabilistic sensitivity analyses, at a threshold of $33,357 per QALY (three times the gross domestic product (GDP) per capita in China in 2020), the probability of dabrafenib plus trametinib being cost-effective was 90%. In the deterministic sensitivity analyses, the results were most sensitive to the dabrafenib plus trametinib drug costs, vemurafenib drug costs and discount rate of cost. Conclusion: Dabrafenib plus trametinib therapy yields more clinical benefits than vemurafenib. Using a threshold of $33,357 per QALY, dabrafenib plus trametinib is very cost-effective as compared with vemurafenib in China.

Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.

PurposeTo describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib.MethodsWe report on six patients with NF‐1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively.ResultsSubjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4–28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life‐threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1–2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy.ConclusionTrametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF‐1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

LGG-27. TARGETED THERAPY FOR PEDIATRIC LOW-GRADE GLIOMAS AND PLEXIFORM NEUROFIBROMAS WITH TRAMETINIB

BACKGROUNDTargeted therapy aimed at modulating the RAS/RAF/MEK/ERK pathway is of increasing interest for patients with plexiform neurofibromas and low-grade gliomas. Trametinib is an FDA-approved MEK inhibitor that has little published pediatric experience to date.METHODSA retrospective chart review of patients treated with trametinib for low-grade gliomas (LGG) and/or plexiform neurofibromas (PN) between 2015–2018 was conducted at Children’s Hospital Colorado. Data collected included patient demographics, lesion location, Neurofibromatosis type 1 (NF1) status, best response of PN/LGG to trametinib, duration of trametinib therapy, and reported toxicities at least possibly attributed to trametinib.RESULTSThirty (57% male; 73% NF1) patients were identified. Sixteen (53%) patients had PN only, 12 (40%) had LGG only, and two (7%) patients had both PN and LGG. The most common LGG location was the optic pathway/hypothalamus (72%). The most common location of PN was the face (63%). Two-thirds (8/12) of patients with LGG had a BRAF alteration or NF1 mutation. The median age at start of trametinib therapy was 9.9 years (range, 2.0 – 18.8 years). The median duration of trametinib therapy was 0.8 years (range 0.1 – 2.9 years). The most commonly reported adverse event was rash. No patients developed retinal toxicity or cardiotoxicity. Only two (7%) patients discontinued for toxicity and one (3%) for progressive disease.CONCLUSIONSTrametinib can be administered without significant toxicity to children with PN or LGG. Clinical benefit is noted in this cohort; however, prospective clinical trials are necessary to characterize efficacy formally.

Enhancement of Impaired MRSA-Infected Fracture Healing by Combinatorial Antibiotics and Modulation of Sustained Inflammation.

Fracture healing is impaired in the setting of infection, which begets protracted inflammation. The most problematic causative agent of musculoskeletal infection is methicillin-resistant Staphylococcus aureus (MRSA). We hypothesized that modulation of excessive inflammation combined with cell-penetrating antibiotic treatments facilitates fracture healing in a murine MRSA-infected femoral fracture model. Sterile and MRSA-contaminated open transverse femoral osteotomies were induced in 10-week-old male C57BL/6 mice and fixed via intramedullary nailing. In the initial therapeutic cohort, empty, vancomycin (V), rifampin (R), vancomycin-rifampin (VR), or vancomycin-rifampin-trametinib (VRT) hydrogels were applied to the fracture site intraoperatively. Rifampin was included because of its ability to penetrate eukaryotic cells to target intracellular bacteria. Unbiased screening demonstrated ERK activation was upregulated in the setting of MRSA infection. As such, the FDA-approved mitogen-activated protein kinase kinase (MEK)1-pERK1/2 inhibitor trametinib was evaluated as an adjunctive therapeutic agent to selectively mitigate excessive inflammation after infected fracture. Two additional cohorts were created mimicking immediate and delayed postoperative antibiotic administration. Systemic vancomycin or VR was administered for 2 weeks, followed by 2 weeks of VRT hydrogel or oral trametinib therapy. Hematologic, histological, and cytokine analyses were performed using serum and tissue isolates obtained at distinct postoperative intervals. Radiography and micro-computed tomography (μCT) were employed to assess fracture healing. Pro-inflammatory cytokine levels remained elevated in MRSA-infected mice with antibiotic treatment alone, but increasingly normalized with trametinib therapy. Impaired callus formation and malunion were consistently observed in the MRSA-infected groups and was partially salvaged with systemic antibiotic treatment alone. Mice that received VR alongside adjuvant MEK1-pERK1/2 inhibition displayed the greatest restoration of bone and osseous union. A combinatorial approach involving adjuvant cell-penetrating antibiotic treatments alongside mitigation of excessive inflammation enhanced healing of infected fractures. © 2022 American Society for Bone and Mineral Research (ASBMR).

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II)

In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.

Synthesis of the PET Tracer 124I-Trametinib for MAPK/ERK Kinase Distribution and Resistance Monitoring.

Trametinib is an extremely potent allosteric inhibitor of mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) (MEK) 1/2, which has been approved for treatment of metastatic melanoma and anaplastic thyroid cancer in patients with confirmed BRAFV600E/K mutations. Though trametinib is highly efficacious, adverse side effects, including skin, gastrointestinal, and hepatic toxicity, are dose-limiting and can lead to treatment termination. Development of a noninvasive tool to visualize and quantify the delivery and distribution of trametinib (either as a single agent or in combination with other therapeutics) to tumors and organs would be helpful in assessing therapeutic index, personalizing individual dose, and potentially predicting resistance to therapy. Methods: To address these issues, we have developed a radiolabeled trametinib and evaluated the in vitro and in vivo properties. 123I-, 124I-, and 131I-trametinib, pure tracer analogs to trametinib, were synthesized in more than 95% purity, with an average yield of 69.7% and more than 100 GBq/μmol specific activity. Results: Overall, 124I-trametinib uptake in a panel of cancer cell lines can be blocked with cold trametinib, confirming specificity of the radiotracer in vitro and in vivo. 124I-trametinib was taken up at higher rates in KRAS and BRAF mutant cell lines than in wild-type KRAS cancer cell lines. In vivo, biodistribution revealed high uptake in the liver 2 h after injection, followed by clearance through the gastrointestinal tract over 4 d. Importantly, uptake higher than expected was observed in the lung and heart for up to 24 h. Peak uptake in the skin and gastrointestinal tract was observed between 6 and 24 h, whereas in B16F10 melanoma-bearing mice peak tumor concentrations were achieved between 24 and 48 h. Tumor uptake relative to muscle and skin was relatively low, peaking at 3.4- to 8.1-fold by 72 h, respectively. The biodistribution of 124I-trametinib was significantly reduced in mice on trametinib therapy, providing a quantitative method to observe MEK inhibition in vivo. Conclusion:124I-trametinib serves as an in vivo tool to personalize the dose instead of using the current single-fixed-dose scheme and, when combined with radiomic data, to monitor the emergence of therapy resistance. In addition, the production of iodinated trametinib affords researchers the ability to measure drug distribution for improved drug delivery studies.

Granulomatosis with polyangiitis in a patient treated with dabrafenib and trametinib for BRAF V600E positive lung adenocarcinoma

BackgroundDabrafenib and trametinib combination therapy is approved for the treatment of patients with BRAF V600E positive tumors including melanoma and lung cancer. The effect of BRAF and MEK inhibitors on the immune system is not fully understood although a number of case reports indicate autoimmune side effects related to the use of these drugs. Here, we discuss a case of a patient diagnosed with granulomatosis with polyangiitis (GPA) shortly after starting treatment with dabrafenib and trametinib for BRAF V600E positive metastatic lung adenocarcinoma.Case presentationA 57 years old female patient was diagnosed with recurrent lung adenocarcinoma following initial lobectomy for early stage disease. A BRAF V600E mutation was identified at the time of recurrence and she received combination dabrafenib and trametinib therapy. Shortly after commencement of treatment, she developed persistent fevers necessitating withholding both drugs. Pyrexia continued and was followed by left vision loss and acute kidney injury. Further rheumatological workup led to the unifying diagnosis of GPA. The patient was then treated with rituximab for GPA to the present date while all antineoplastic drugs were held. Lung cancer oligoprogression was addressed with radiation therapy and has not required further systemic treatment whereas GPA has been controlled to-date with rituximab.ConclusionsThis case report raises awareness among clinicians treating patients with lung cancer for the possibility of triggering a flare of autoimmune diseases like GPA in patients with BRAF V600E positive lung cancer receiving treatment with BRAF directed therapy.

Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists.

BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT). We provide guidance on managing adverse events likely to arise during treatment with combination BRAF and MEK inhibition with CombiDT: pyrexia, skin conditions, fatigue; and discuss management of CombiDT during surgery and radiotherapy. By improving tolerability and in particular preventing unnecessary treatment cessations or reduction in drug exposure, best outcomes can be achieved for patients undergoing CombiDT therapy.

Cardiogenic Shock and Respiratory Failure in a Patient With Metastatic Melanoma Receiving Trametinib Therapy.

Life-threatening heart failure can occur with trametinib therapy and is reversible. This article provides recommendations for evaluation of patients receiving trametinib, including those who develop severe cardiomyopathy.

Bilateral macular neurosensory retinal detachment secondary to systemic Dabrafenib and Trametinib therapy

Bilateral macular neurosensory retinal detachment secondary to systemic Dabrafenib and Trametinib therapy

Trametinib: a MEK inhibitor for management of metastatic melanoma.

This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-free survival in favor of trametinib over standard dacarbazine or paclitaxel chemotherapy. Therefore, trametinib was approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with V600E-mutated metastatic melanoma. Progression-free survival and response rates for trametinib monotherapy were lower than those noted with BRAF inhibitors. The second step in developing trametinib was to use the combination of trametinib with the BRAF inhibitor, eg, dabrafenib, to postpone the progression on MEK or BRAF inhibitors. The recently published data showed significant improvement in overall survival and progression-free survival in favor of the combination of trametinib and dabrafenib over vemurafenib therapy or dabrafenib alone, with good tolerance. The US Food and Drug Administration has approved the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma, and their use seems to be currently the best approach. While BRAF-MEK inhibition is a standard, molecular targeted therapy in BRAF-mutated melanomas, its future utility has to be established in the rapidly changing landscape of immunotherapeutics.