TY - JOUR
AU - Reilly,, Sean
AB - Abstract Purpose The pharmacology, pharmacokinetics, clinical efficacy, safety, administration, cost, and place in therapy of trametinib for the treatment of metastatic melanoma are reviewed. Summary Approximately 40–60% of malignant melanomas have gene mutations at codon 600 of the BRAF gene that result in the activation of the mitogen-activated protein kinase (MAPK) pathway. Trametinib is the first-in-class mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that targets a kinase in the MAPK pathway that plays a key role in oncogenic cell proliferation, survival, invasion, tumor angiogenesis, and escape from apoptosis. It is approved by the Food and Drug Administration for use in patients whose tumors express the BRAF V600E or V600K gene mutations. Moreover, trametinib is also indicated for use in combination with dabrafenib (a BRAF inhibitor). Trametinib is not indicated in patients who have received prior BRAF-inhibitor therapy due to poor response and possible cross-resistance. The most common adverse effects associated with the use of trametinib for both monotherapy and combination therapy are rash, diarrhea, peripheral edema, fatigue, and dermatitis. The recommended dosage of trametinib monotherapy is 2 mg orally once daily until disease progression or unacceptable toxicity occurs. With a daily dose of 2 mg, an estimated 30-day course of treatment would cost approximately $9135. Conclusion Trametinib, a novel MEK inhibitor, provides an alternative therapy for patients with BRAF V600 E/K metastatic melanoma as a single agent or in combination therapy for patients not previously treated with a BRAF inhibitor. More studies are needed to determine the safe and effective combination or sequencing of trametinib with other therapies. Skin cancer is the fifth most common cancer in the United States, with an estimated 76,100 new cases and 9,710 predicted deaths in 2014.1 Most skin cancers are non-melanoma and rarely lead to mortality. However, malignant cutaneous melanoma (or simply melanoma) is a major cause of morbidity and mortality among skin cancers. Its resistance to conventional cytotoxic chemotherapy and radiation results in limited treatment options available to patients. Melanoma arises from the pigment-producing melanocytes located in the basal layer of the epidermis. During embryonic development, melanocytes originate from the neural crest and migrate to the epidermis, uveal tract, meninges, and ectodermal mucosa. Consequently, melanomas are commonly found in the epidermis and less frequently in the eyes and oral, nasal, rectal, and vaginal mucosal surfaces. Melanoma follows an unpredictable course; patients with early-stage disease can be treated successfully with surgical resection. However, recurrence and metastasis may not appear for more than five years after resection of the primary lesion. Major risk factors for melanoma include a personal or family history of melanoma, exposure to intense and intermittent ultraviolet irradiation, phenotypic characteristics (fair skin or red hair), and multiple nevi.2 The prognosis for patients with distant metastases from melanoma remains poor, with a median survival time of less than one year.2 Before 2011, only a few agents were approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma, namely dacarbazine3 and immunomodulators such as interferon or high-dose interleukin.4 Response rates for these agents were generally low (less than 15–20%)3,4 and did not lead to improvement in overall survival for metastatic melanoma patients. In the past decade, significant advances in molecular biology enabled the identification of a number of oncogenes that contribute to the development and progression of melanomas. There is now evidence that 50% of melanomas harbor gene mutations that result in the activation of the protein kinase signaling pathway (also known as the mitogen-activated protein kinase, or MAPK, pathway).5,–7 This article focuses on trametinib (tra me′ ti nib; Mekinist, GlaxoSmithKline), the first-in-class MEK (mitogen-activated, extracellular signal-regulated kinase) inhibitor approved by FDA for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K gene mutations as detected by an FDA-approved genetic test. Ras-Raf-MEK-ERK pathway The MAPK pathway is one of the most important pathways for regulating cellular functions in normal cells.5 It consists of molecules that sequentially transfer signals from the cell surface receptor to the nucleus via a series of phosphorylation events: after the binding of various ligands (e.g., growth factors, mitogen, hormones, other proliferative signals), receptor tyrosine kinases on the cell membrane dimerize and trigger the activation of Ras. Ras is a family of guanosine triphosphatase proteins that acts as molecular switches in regulating the activation of Raf proteins, which are the downstream effectors that phosphorylate MEK1 and MEK2, which in turn cause the activation of extracellular signal–regulated kinase 1 and 2 (ERK1 and ERK2). Phosphorylated ERK1 and ERK2 enter the nucleus and activate transcriptional factors and regulatory proteins of the cell cycle.5 Approximately 40–60% of cutaneous melanomas have an activating gene mutation at codon 600 of exon 15 in the catalytic domain of the intracellular serine threonine kinase known as BRAF that results in the substitution of glutamic acid for valine.6 This mutation is known as the V600E mutation (V = valine, E = glutamic acid). On the other hand, the V600K mutation occurs in another 3–20% of BRAF mutations in which the substitution of lysine for valine (K = lysine) occurs.6,7 Other rare BRAF mutations occur in about 6–7% of patients with melanoma.8,9 Collectively, these genetic mutations render the MAPK pathway constitutively active and result in the phosphorylation of MEK and other downstream targets that leads to oncogenic cell proliferation, survival, invasion, tumor angiogenesis, and escape from apoptosis.10,–12 Dual BRAF and MEK inhibition Despite the remarkable initial response to BRAF inhibitors, tumor regrowth occurs in most patients.13 Half of patients who are treated with the BRAF inhibitors experience disease progression within six to seven months after the initiation of treatment.6,7 Resistance to chronic BRAF inhibition often involves reactivation of the downstream MAPK pathway.14 In some rare melanomas, such as uveal melanoma, BRAF gene mutations are rare, but MAPK-activating mutations are common.15 Therefore, researchers hypothesized that combined MEK and BRAF inhibition may overcome resistance to some tumor types.16,17 Importantly, recent findings of a Phase II trial by Flaherty and colleagues18 revealed that such a combination may indeed provide a more durable and prolonged clinical response. However, it remains unclear whether MEK inhibition represents a valid clinical target in patients who have received prior treatment with BRAF inhibitors. A study by Gowrishhanker and colleagues19 revealed that acquired resistance to BRAF inhibitors can also confer cross-resistance to combined BRAF-MEK inhibition. Because of this observation as well as the poor response rate of MEK-inhibitor therapy in patients who had received prior treatment with a BRAF inhibitor,20 the label for trametinib warns that the drug is not indicated in patients who have received prior BRAF therapy. Treatment with an MEK inhibitor in patients whose cancer has progressed on a BRAF inhibitor is unlikely to have any clinical benefit. Pharmacology Trametinib is an orally bioavailable small molecule that inhibits MAPK downstream of BRAF kinase. In the MAPK pathway, the MEK protein is the direct substrate of the activated BRAF kinase. Trametinib is a reversible, highly selective allosteric inhibitor of both MEK1 and MEK2 enzyme activity and activation, preventing BRAF-dependent MEK phosphorylation and thus allowing sustained inhibition of MEK.13,14 Through inhibition of MEK, trametinib causes decreased cellular proliferation, cell cycle arrest, and increased apoptosis in patients with melanoma.14 Pharmacokinetics Despite the plethora of clinical literature about BRAF inhibitors, there is limited evidence that MEK can be inhibited consistently at tolerable doses. Targeted therapy with MEK is generally difficult, because toxic effects may arise either at therapeutic concentrations or before these levels have been reached.21 Compared with other MEK inhibitors, trametinib exhibits a very unique pharmacokinetic profile with rapid oral absorption, low interpatient variability, dose-proportional pharmacokinetics, a prolonged half-life, and a sustained level of exposure that allows constant target inhibition with a low ratio of peak concentration (Cmax) to trough concentration.21,–23 This low peak:trough ratio translates to a sustained level of drug exposure and potentially avoiding that may result from transient peak levels. In a multicenter, Phase I, pharmacokinetic study, Infante and colleagues22 demonstrated that at a dosage of 2 mg orally daily, the median time to maximum trametinib concentration (tmax) was 1.75 hours (range, 1–3 hours). The mean absolute bioavailability of a single 2-mg oral dose of trametinib was 72%. Trametinib’s half-life was approximately four days.8,22 Trametinib was absorbed rapidly and metabolized predominantly via oxygenation, glucuronidation, or deacetylation. The increase in exposure (measured by the area under the concentration–time curve [AUC]) was generally dose proportional with daily doses of 0.125–4 mg. At 2 mg, the Cmax was 22.2 ng/mL; after 24 hours, the Cmax was 12.1 ng/mL.22 Both concentrations exceeded the preclinical target concentration of 10.4 ng/mL.22 In addition, trametinib is highly protein bound (97.4%), with an apparent volume of distribution of 214 L,8 indicating that hemodialysis would not likely be effective in treating an overdose of the drug. Thus, available pharmacokinetics data demonstrated that a dosage of 2 mg daily resulted in a relatively long half-life, a high serum drug concentration to maintain effective MEK inhibition and potential avoidance of high peak levels with other trial doses. Cox and colleagues23 conducted a food-effect study and found that administration of a single dose of trametinib with a high-fat, high-calorie meal (50% fat) decreased the trametinib AUC by 24%, decreased Cmax by 70%, and delayed tmax by approximately four hours compared with fasting conditions. Administration with food decreases the rate and, to a lesser degree, the extent of absorption of a single dose of trametinib, supporting the recommendation to administer trametinib one hour before or two hours after a meal.8,23 Of note, a patient’s age, sex, and body weight do not seem to affect the pharmacokinetics of trametinib. Current data are insufficient to evaluate the potential differences in the pharmacokinetics of trametinib by race or ethnicity.8 Together, these studies demonstrated that trametinib has sustained levels of drug concentrations and that 2 mg daily orally is an appropriate dosage for use in subsequent clinical trials.18,–22 Clinical efficacy Monotherapy: Phase I trials The safety and dose determination of trametinib monotherapy were explored in a dose-escalation trial by Infante and colleagues22 in which 206 patients (median age, 58.5 years [range, 19–92 years]) with advanced solid tumors and adequate organ function were enrolled. Over 50% of the patients had received three or more previous regimens. Patients had no history of retinal vein occlusion or central retinopathy. Patients with brain metastases previously treated with radiosurgery or surgery were eligible for study enrollment. Disease responses were measured by the Response Evaluation Criteria in Solid Tumors (RECIST), and adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Dose-limiting toxicities were defined as one of the following: grade 4 hematologic toxicity, grade 3 thrombocytopenia with bleeding, grade 3 or 4 nonhematologic toxicity (including rash, nausea, and vomiting if uncontrolled with supportive care), and other criteria as determined by the investigators. The dose-limiting toxicities experienced by patients included rash (n = 2), diarrhea (n = 1), and central retinopathy (n = 2). The most common treatment-related adverse effects were rash or dermatitis acneiform (n = 165, 80%) and diarrhea (n = 87, 42%), most of which were grades 1 and 2. The maximum tolerated dosage was 3 mg once daily. In another Phase I trial, conducted by Falchook and colleagues,24 97 patients with melanoma were enrolled (81 had cutaneous or unknown primary melanoma, and 16 had uveal melanoma). Tumors were assessed for the BRAF mutation. Responses were measured by RECIST, and adverse events were defined by CTCAE. Of these 81 patients, 36 had BRAF-mutant melanoma, and 39 had BRAF wild-type melanoma; the BRAF status of 6 patients was unknown. The most common treatment-related adverse events (grade 2 or lower) were rash or dermatitis acneiform (n = 80, 82%) and diarrhea (n = 44, 45%). No cutaneous squamous cell carcinomas were documented. Of the 36 patients with BRAF-mutant melanoma, 30 had not received prior treatment with a BRAF inhibitor; 2 had complete responses, and 10 had partial responses (confirmed response rate, 33%). The median progression-free survival of this subgroup was 5.7 months (95% confidence interval [CI], 4.0–7.4 months). Of the 6 patients with BRAF-mutant melanoma who previously received BRAF-inhibitor therapy, 1 unconfirmed partial response was recorded. Of the 39 patients with BRAF wild-type melanoma, 4 partial responses were confirmed (confirmed response rate, 10%). These findings suggest that MEK is a valid therapeutic target and that inhibition of MEK is a clinically effective mechanism to treat patients with BRAF-mutant melanoma not previously treated with a BRAF inhibitor. Monotherapy: Phase II trial The encouraging results found by Falchook and colleagues24 warranted further studies of trametinib in two separate patient populations: patients who had previously received a BRAF inhibitor and those who had not. Kim et al.20 conducted an open-label, two-cohort, multicenter Phase II study to evaluate the clinical efficacy of trametinib monotherapy in patients with metastatic BRAF-mutant melanoma previously treated with or without a BRAF inhibitor. Two groups of patients with metastatic BRAF-mutant melanoma were enrolled: cohort A (n = 40) was previously treated with a BRAF inhibitor (either vemurafenib or dabrafenib), and cohort B (n = 57) had not received prior treatment with a BRAF inhibitor but had received treatment with chemotherapy or immunotherapy. Patients received 2 mg of trametinib orally once daily. Preexisting and pretreated brain metastases were reported in 13% of cohort A and 21% of cohort B. The frequencies of V600E (81%) and V600K (12%) mutations were within the expected range. The investigators found no confirmed objective responses in cohort A, whereas patients who had previously been treated with chemotherapy or immunotherapy (cohort B) had a 25% response rate, implying that BRAF resistance develops in patients with repeated exposure. Eleven patients (28%) in cohort A had stable disease, with a median progression-free survival time of 1.8 months (range, 1.8–2 months). In cohort B, there were 1 complete response (2%) and 13 partial responses (23%). A total of 29 patients (51%) had stable disease, with a median progression-free survival time of 4.0 months (range, 3.6–5.6 months). One patient with a rare BRAF mutation had a prolonged partial response. The most frequent treatment-related adverse events were cutaneous toxicity, nausea, peripheral edema, diarrhea, pruritus, and fatigue. No cutaneous squamous cell carcinoma was observed. Results of this study demonstrated that trametinib is tolerable and has clinical efficacy in patients with metastatic BRAF mutated melanoma who have not received BRAF inhibitor therapy. Clinical activity was broad, with objective responses observed in patients with BRAF V600E, V600K, and even rare BRAF mutations. Monotherapy: Phase III trial In a Phase III open-label study (METRIC) by Flaherty et al.,25 322 patients with metastatic melanoma (281 had the V600E mutation, 40 had the V600K mutation, and 1 had both mutations) were randomly assigned to receive trametinib or cytotoxic chemotherapy (dacarbazine or paclitaxel) in a 2:1 ratio. Patients with stable brain metastases and one prior cytotoxic chemotherapy treatment were eligible for enrollment. Individuals were excluded if they had previously been treated with BRAF or MEK inhibitors or ipilimumab and had a history of active cardiovascular disease, interstitial lung disease, retinopathy, or retinal vein occlusion. Patients received trametinib 2 mg orally once daily or cytotoxic chemotherapy (dacarbazine 1000 mg/m2 i.v. every three weeks or paclitaxel 175 mg/m2 i.v. every three weeks). Patients in the cytotoxic chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary endpoint; overall survival, overall response rate, duration of response, and safety were secondary endpoints. Treatment continued until disease progression, death, or withdrawal from the study. The median progression-free survival times were 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (ranges not reported). At 6 months, the rates of overall survival were 81% in the trametinib group and 67% in the chemotherapy group despite crossover treatment with trametinib (hazard ratio for death, 0.54; 95% CI, 0.32–0.92; p = 0.01). The median overall survival was not reached at the time of study conclusion, and follow-up continues in these groups. Site investigator–confirmed response rates using RECIST revealed a complete or partial response rate of 22% in the trametinib group versus 8% in the chemotherapy group (p = 0.01). The median duration of response was 5.5 months (95% CI, 4.1–5.9 months) in 47 patients in the trametinib group but had not been reached at the time of study conclusion in the chemotherapy group (n = 9). Rash, diarrhea, and peripheral edema were the most common toxic effects associated with trametinib and were managed with dose interruption and dosage reduction. Asymptomatic and reversible reduction in the ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. The study investigators concluded that patients who had melanoma with a V600E or V600K mutation had improved progression-free survival and overall survival times when treated with trametinib versus cytotoxic chemotherapy. Based on these results, FDA approved trametinib as monotherapy in May 2013 for use in patients with BRAF V600E or V600K mutated unresectable or metastatic melanoma. In general, trametinib monotherapy continues until disease progression or intolerable toxicity occurs. Combination therapy: Phase I and II trials Although the safety of trametinib was confirmed in Phase I trials, 50% of patients who were treated with BRAF or MEK inhibitors experienced disease progression within six to seven months after the initiation of treatment.6,7,18,20 The addition of an MEK inhibitor to a BRAF inhibitor reduced the frequency of cutaneous squamous cell carcinoma (a benign form of skin cancer) associated with BRAF-inhibitor therapy.24 The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has resulted in a significant reduction in dermatological toxicities associated with BRAF inhibitors (e.g., rash, photosensitivity, hyperkeratosis, squamous cell carcinomas). These dermatological toxicities are thought to be caused by the activation of the MAPK pathway in patients receiving BRAF inhibitors. The addition of an MEK inhibitor may inhibit this paradoxical activation of the MAPK signaling pathway. In light of this information, Flaherty and colleagues18 conducted a multicenter, open-label, randomized Phase I/II trial to explore the safety of combination therapy with a BRAF inhibitor (i.e., dabrafenib) and an MEK inhibitor (i.e., trametinib) in patients with BRAF V600E (85%) or V600K (15%) metastatic melanoma. In this study, 162 patients were randomized 1:1:1 to receive trametinib 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily (n = 54), trametinib 1 mg orally once daily in combination with dabrafenib 150 mg orally twice daily (n = 54), or monotherapy with dabrafenib 150 mg orally twice daily (n = 54). Of these 162 patients, 57% were male, and the median age was 53 years (range, 18–85 years). All patients had a baseline Eastern Cooperative Oncology Group performance status of 0 or 1 (0 indicating asymptomatic status, and 1 indicating ambulatory status but restricted in strenuous activity), 67% had M1c disease (an advanced stage of melanoma with distant and visceral metastases), and 81% had not received prior therapy for unresectable or metastatic disease. Primary endpoints were the frequency of cutaneous squamous cell carcinoma, progression-free survival time, and response. Secondary endpoints included overall survival and pharmacokinetic activity. Patients with brain metastases were included. Pyrexia was more common with combination therapy than with monotherapy (71% versus 26%). The frequency of cutaneous squamous cell carcinoma (including squamous cell carcinoma and keratoacanthoma), the trial’s primary endpoint, was 7% (95% CI, 2–18%) in the combination therapy group versus 19% in the dabrafenib monotherapy group (95% CI, 9–32%). The most frequent adverse effects (frequency of ≥20%) in the combination therapy group were pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia. The most frequent grade 3 and 4 adverse events were acute renal failure, pyrexia, hemorrhage, and back pain. The rate of complete or partial response was 76% for the combination therapy group, compared with 54% for the group receiving dabrafenib monotherapy (p = 0.03). The median duration of response was 10.5 months (95% CI, 7–15 months) for patients treated with combination therapy versus 5.6 months (95% CI, 5–7 months) for patients treated with dabrafenib monotherapy. The median progression-free survival times were 9.4 months (range, 8.6–16.7 months) in the combination therapy group and 5.8 months in the dabrafenib monotherapy group (hazard ratio, 0.39; 95% CI, 0.25–0.62; p < 0.001). Overall, this study showed that dabrafenib and trametinib could be safely combined when each agent was administered at its full dose. Although the study did not evaluate trametinib monotherapy, improved survival and a reduction in skin lesions were associated with the combination of BRAF and MEK inhibitors. In January 2014, FDA granted accelerated approval to the combination therapy of trametinib–dabrafenib in patients with unresectable (stage IIIC) or metastatic (stage IV) BRAF V600E/K mutated cutaneous melanoma, based on the improved response rate and median duration of response shown with combination therapy.18 This accelerated approval is contingent on the successful completion of the ongoing randomized, double-blind, Phase III trial (Combi-D trial) to validate the clinical benefit of trametinib–dabrafenib combination therapy.26 The primary endpoint of this trial is progression-free survival; overall survival is a key secondary endpoint.8,26 To date, an improvement in overall survival has not been demonstrated with the combination of dabrafenib and trametinib relative to dabrafenib or vemurafenib alone. Safety The most common adverse effects observed in patients receiving trametinib monotherapy were rash, diarrhea, peripheral edema, fatigue, and dermatitis acneiform.20, 22, 23 These adverse effects were mostly grades 1 and 2 (based on the CTCAE) and were managed with a reduction in dosage (27% of patients) or dose interruption (35% of patients).20,23 Among these adverse effects, acneiform skin rashes, diarrhea, and ocular disturbances (most notably central retinopathy) are consistent with the mechanism-based class effects of MEK inhibitors (Table 1).18,22,23,25 Table 1 Most Common Adverse Effects in Trials of Oral Trametinib Monotherpy and Trametinib in Oral Combination Therapy Adverse Effect % Patients in Whom Adverse Effect of Any Grade Occurreda Trametinib Monotherapy vs. I.V. Chemotherapy25 Dabrafenib With or Without Trametinib18 Trametinib 2 mg Daily (n = 211) I.V. Dacarbazine or Paclitaxelb (n = 99) Trametinib 2 mg Daily + Dabrafenib 150 mg Twice Daily (n = 55) Trametinib 1 mg Daily + Dabrafenib 150 mg Twice Daily (n = 54) Dabrafenib 150 mg Twice Daily (n = 53) Acneiform dermatitis 29 1 NR NR NR Alopecia ≈11 27 5 9 34 Constipation 15 29 NR NR NR Cutaneous squamous cell carcinoma NR NR 7 2 19 Decreased ejection fraction NR NR 9 4 0 Diarrhea 49 21 36 26 28 Fatigue 35 37 53 57 40 Hypertension 30 13 9 4 4 Nausea 21 48 44 46 21 Peripheral edema 31 3 29 24 9 Pyrexia NR NR 71 69 26 Rash 84 13 27 20 36 Vomiting 15 25 40 43 15 Adverse Effect % Patients in Whom Adverse Effect of Any Grade Occurreda Trametinib Monotherapy vs. I.V. Chemotherapy25 Dabrafenib With or Without Trametinib18 Trametinib 2 mg Daily (n = 211) I.V. Dacarbazine or Paclitaxelb (n = 99) Trametinib 2 mg Daily + Dabrafenib 150 mg Twice Daily (n = 55) Trametinib 1 mg Daily + Dabrafenib 150 mg Twice Daily (n = 54) Dabrafenib 150 mg Twice Daily (n = 53) Acneiform dermatitis 29 1 NR NR NR Alopecia ≈11 27 5 9 34 Constipation 15 29 NR NR NR Cutaneous squamous cell carcinoma NR NR 7 2 19 Decreased ejection fraction NR NR 9 4 0 Diarrhea 49 21 36 26 28 Fatigue 35 37 53 57 40 Hypertension 30 13 9 4 4 Nausea 21 48 44 46 21 Peripheral edema 31 3 29 24 9 Pyrexia NR NR 71 69 26 Rash 84 13 27 20 36 Vomiting 15 25 40 43 15 a NR = not reported. b Dacarbazine 1000 mg/m2 i.v. every three weeks or paclitaxel 175 mg/m2 i.v. every three weeks. Open in new tab Table 1 Most Common Adverse Effects in Trials of Oral Trametinib Monotherpy and Trametinib in Oral Combination Therapy Adverse Effect % Patients in Whom Adverse Effect of Any Grade Occurreda Trametinib Monotherapy vs. I.V. Chemotherapy25 Dabrafenib With or Without Trametinib18 Trametinib 2 mg Daily (n = 211) I.V. Dacarbazine or Paclitaxelb (n = 99) Trametinib 2 mg Daily + Dabrafenib 150 mg Twice Daily (n = 55) Trametinib 1 mg Daily + Dabrafenib 150 mg Twice Daily (n = 54) Dabrafenib 150 mg Twice Daily (n = 53) Acneiform dermatitis 29 1 NR NR NR Alopecia ≈11 27 5 9 34 Constipation 15 29 NR NR NR Cutaneous squamous cell carcinoma NR NR 7 2 19 Decreased ejection fraction NR NR 9 4 0 Diarrhea 49 21 36 26 28 Fatigue 35 37 53 57 40 Hypertension 30 13 9 4 4 Nausea 21 48 44 46 21 Peripheral edema 31 3 29 24 9 Pyrexia NR NR 71 69 26 Rash 84 13 27 20 36 Vomiting 15 25 40 43 15 Adverse Effect % Patients in Whom Adverse Effect of Any Grade Occurreda Trametinib Monotherapy vs. I.V. Chemotherapy25 Dabrafenib With or Without Trametinib18 Trametinib 2 mg Daily (n = 211) I.V. Dacarbazine or Paclitaxelb (n = 99) Trametinib 2 mg Daily + Dabrafenib 150 mg Twice Daily (n = 55) Trametinib 1 mg Daily + Dabrafenib 150 mg Twice Daily (n = 54) Dabrafenib 150 mg Twice Daily (n = 53) Acneiform dermatitis 29 1 NR NR NR Alopecia ≈11 27 5 9 34 Constipation 15 29 NR NR NR Cutaneous squamous cell carcinoma NR NR 7 2 19 Decreased ejection fraction NR NR 9 4 0 Diarrhea 49 21 36 26 28 Fatigue 35 37 53 57 40 Hypertension 30 13 9 4 4 Nausea 21 48 44 46 21 Peripheral edema 31 3 29 24 9 Pyrexia NR NR 71 69 26 Rash 84 13 27 20 36 Vomiting 15 25 40 43 15 a NR = not reported. b Dacarbazine 1000 mg/m2 i.v. every three weeks or paclitaxel 175 mg/m2 i.v. every three weeks. Open in new tab Mechanism-based adverse effects of MEK inhibitors (e.g., peripheral edema, hypertension, decreased cardiac ejection fraction, ocular events) occurred more frequently with the combination of an MEK inhibitor with a BRAF inhibitor versus monotherapy with an MEK inhibitor.18 The most frequent adverse events observed in the combination therapy group were pyrexia (all grades, 71%; grade 3, 5%) and chills (all grades, 58%; grade 3, 2%). The combination group had more frequent toxic gastrointestinal effects (e.g., nausea, vomiting), but most of these events were grade 1 or 2. Pyrexia was generally manageable with antipyretic agents such as acetaminophen and nonsteroidal antiinflammatory drugs. The frequency of acneiform dermatitis, the most common and dose-limiting toxic effect of trametinib, was reduced when dabrafenib and trametinib were coadministered. Notably, treatment with the combination of trametinib and dabrafenib resulted in an increased rate and severity of hemorrhagic events: 16% (9 of 55 patients) for the combination versus 2% (1 of 53 patients) for dabrafenib alone.8,18 Intracranial hemorrhage was fatal in 2 patients (4%) receiving the combination. In addition, combination therapy was associated with an increased rate of deep vein thrombosis and pulmonary embolism: 7% (4 of 55 patients) versus 0 with dabrafenib monotherapy. Pulmonary embolism was fatal in 1 patient (2%) receiving combination therapy. Pregnancy Trametinib is classified as a category D drug.8 Animal studies have found maternal toxicity and an increase in postimplantation loss during the period of organogenesis. Trametinib can cause fetal harm when administered during pregnancy. Female patients of reproductive potential are advised to use highly effective contraception during treatment and for four months after completing therapy. Patients are advised to contact their healthcare provider if they become pregnant or if pregnancy is suspected while taking trametinib. Cardiomyopathy When used as monotherapy, trametinib caused asymptomatic and reversible reductions in the cardiac ejection fraction (7%, all grades).18 Furthermore, cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or a decrease in left ventricular ejection fraction [LVEF]) occurred in 9% of patients treated with the trametinib–dabrafenib combination. The manufacturer of trametinib recommends reassessing LVEF after one month of treatment and evaluating it approximately every two to three months thereafter.8 If a patient experiences an asymptomatic absolute decrease in LVEF of 10% or greater from baseline and is below the institutional lower limit of normal from the pretreatment value, the patient is recommended to withhold trametinib for up to four weeks. If the patient has improved after withholding therapy for four weeks, therapy may resume at a lower dose (reduced by 0.5 mg). It is recommended that patients discontinue therapy if they are already taking the reduced dosage of trametinib 1 mg once daily. For symptomatic heart failure, therapy must be discontinued permanently if (1) there is an absolute decrease in LVEF of greater than 20% from baseline (below the lower limit of normal) or (2) a decrease in LVEF of 10% or greater from baseline and LVEF does not improve within four weeks of treatment interruption. Ocular events Ocular events (mostly grade 1 or 2) occurred in 9% of patients receiving trametinib monotherapy, with blurred vision reported as the most frequent single ocular event (4%).25 All ocular events, except for dry eyes, were associated with dosages exceeding 2 mg once daily. The drug’s manufacturer recommends ophthalmologic evaluation for any visual disturbances and withholding therapy if retinal pigment epithelial detachment is diagnosed and discontinuation of therapy if there is no improvement in symptoms after three weeks. Retinal detachment and retinal vein occlusion were reported in 0.5% and 0.2% of patients, respectively. The manufacturer recommends discontinuing trametinib therapy when these visual problems occur.8 Interstitial lung disease Interstitial lung disease was reported in approximately 2% of patients. The drug manufacturer recommends withholding trametinib for new or progressive unexplained pulmonary symptoms or findings, such as cough, dyspnea, hypoxia, and infiltrates.8 Trametinib must be permanently discontinued if a patient develops treatment-related interstitial lung disease or pneumonitis. Serious skin toxicity Rash or dermatitis associated with trametinib use is often located on the face, scalp, and chest and is papulopustular in presentation, in contrast to the hyperkeratotic, maculopapular rash associated with the BRAF inhibitors.25,–27 In addition, secondary skin neoplasms such as cutaneous squamous cell carcinomas or hyperproliferative skin lesions were not observed during the course of treatment with trametinib.24 In fact, skin toxicity occurred much less frequently with the trametinib–dabrafenib combination than with dabrafenib monotherapy.18,25 In contrast, treatment-related squamous cell carcinomas were reported in 18% and 26% of patients in two large trials of vemurafenib (a BRAF inhibitor).28,29 The difference in the rates of these adverse cutaneous effects suggests that there is reactivation of the MAPK pathway in the normal skin with the use of a selective BRAF inhibitor (dabrafenib or vemurafenib), but coadministration of a BRAF inhibitor with an MEK inhibitor (i.e., trametinib) eliminated this MAPK activation.18,30 The manufacturer recommends monitoring for skin toxicities and secondary infections. Therapy must be discontinued in the presence of an intolerable grade 2, 3, or 4 rash that has not improved after three weeks of interruption of trametinib.8 It is imperative for pharmacists to dispel the myth that oral targeted therapies are safer and more tolerable than conventional cytotoxic chemotherapy. For instance, the first BRAF inhibitor approved by FDA for the treatment of metastatic melanoma, vemurafenib, is associated with a higher rate of adverse effects compared with dacarbazine, necessitating dosage modification in 38% of patients receiving vemurafenib versus 18% of patients receiving dacarbazine.31 Since most of these oral targeted therapies are initiated and self-administered at home, patients may not be cognizant of their adverse-effect profiles. Pharmacists can play a pivotal role in this area. Ongoing patient monitoring and education are optimal in ensuring medication safety and compliance. Dosage modification and drug–drug interactions Mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib.8 Trametinib has not been studied in patients with moderate or severe hepatic impairment. In addition, renal excretion of trametinib is low (<20%), so renal impairment is unlikely to have a clinically significant effect on the pharmacokinetics of trametinib. Mild (glomerular filtration rate [GFR], 60–89 mL/min/1.73 m2) or moderate (GFR, 30–59 mL/min/1.73 m2) renal impairment has no clinically significant effects on the systemic exposure of trametinib. Trametinib has not been studied in patients with severe renal impairment. As previously discussed, the dosage of trametinib requires adjustment in the presence of major (grade 2 or above) cutaneous, cardiac, ocular, and other toxicities that have improved after treatment interruption. No formal drug interaction studies have been conducted with trametinib. One study did confirm the absence of a drug–drug interaction with trametinib and dabrafenib. Of note, trametinib is not a substrate of cytochrome P-450 isoenzymes or the efflux transporter P-glycoprotein.18 No clinically significant drug–drug interactions between the trametinib-dabrafenib combination and another medication have been reported.8 Dosage and administration The recommended dosage of trametinib monotherapy is 2 mg orally once daily until disease progression or unacceptable toxicity occurs. Patients are advised to take trametinib at least 1 hour before or 2 hours after a meal to avoid drug–food interactions. Missed doses can be taken up to 12 hours before the next dose. Trametinib is supplied as 0.5- and 2-mg oral tablets and should be refrigerated (2–8 °C [36–46 °F]) in the original bottle.8 The recommended dosage for trametinib–dabrafenib combination therapy is trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity occurs.8 The once-daily dose of trametinib can be taken at the same time as either dose of dabrafenib. Cost For a 30-count bottle, the average wholesale acquisition costs (WACs) of trametinib are $9,135.00 for 2-mg tablets and $2,283.75 for 0.5-mg tablets.32 With a daily dose of 2 mg, an estimated 30-day course of treatment would cost approximately $9,135. A 120-count bottle of dabrafenib has average WACs of $5,320.35 for 50-mg tablets and $7,980.00 for 75-mg tablets.33 Based on the clinical trial data for combination therapy, the median duration of therapy was 9.4 months (progression-free survival), costing approximately $160,000. Trametinib use significantly increases the overall metastatic melanoma treatment expenditure, which may raise concerns among payers. Place in therapy As monotherapy, trametinib is associated with significant improvements in the overall survival rate and the progression-free survival time compared with cytotoxic chemotherapy in patients with BRAF mutated metastatic melanoma. However, trametinib appears to have less clinical benefit in patients previously treated with a BRAF inhibitor such as vemurafenib and dabrafenib. Thus, trametinib should be reserved for patients who have not previously been treated with a BRAF inhibitor. When used as combination therapy with dabrafenib (a BRAF inhibitor), trametinib has improved clinical efficacy compared with BRAF monotherapy and reduced BRAF inhibitor-induced adverse effects. Combined BRAF-MEK inhibition may overcome drug resistance and abrogate the reported toxicity of BRAF inhibitors in nontumor cells, particularly the increased frequency of squamous cell lesions.18, 24, 25 Of note, the presence of BRAF mutations in primary melanoma does not affect the overall survival, whereas the presence of BRAF mutations in metastatic melanoma is associated with poor survival in the absence of targeted therapy.34 In addition to trametinib, vemurafenib and dabrafenib are FDA-approved small-molecule inhibitors for use by patients with positive V600 E/K mutation of the BRAF gene. Patients with BRAF mutations are more likely to have brain metastases than patients without BRAF mutations. Brain metastasis occurs in 20–40% of patients with metastatic melanoma.35 The prognosis is poor for these patients. Both vemurafenib and dabrafenib have clinical activity in patients with brain metastases and have been associated with prolonged overall survival and progression-free survival times, respectively, in patients with previously untreated melanoma.34,36 Trametinib has been used in clinical trials for patients with melanoma and brain metastases, but its role in managing brain metastases has not been fully studied. Immunotherapy is based on the rationale that melanoma cells interact with T lymphocytes, where the activity of T lymphocytes is regulated by a series of molecular events. Immunotherapy with ipilimumab is the current major option for metastatic melanoma.34,36 It has demonstrated durable clinical benefit (compared with six months for the median duration of response to BRAF-targeted therapy) and long-term survival, regardless of BRAF mutational status. The current prevailing clinical opinion is that immunotherapy can be considered in patients with low volume of disease or asymptomatic disease. At present, the National Comprehensive Cancer Network (NCCN) guidelines for preferred systemic therapies for metastatic melanoma include immunotherapy (ipilimumab, high-dose interleukin-2), small-molecule inhibitors (vemurafenib and dabrafenib), and clinical trials.37 Trametinib is not a preferred agent but is an agent with active clinical activity similar to that of cytotoxic chemotherapy. NCCN recommends that the principal indication for the primary treatment of BRAF mutated melanoma with trametinib is intolerance to BRAF inhibitors. Trametinib may also be given to patients with rare BRAF gene mutations. No randomized trials have been conducted to compare targeted therapy with immunotherapy on the appropriate sequencing of therapy for metastatic melanoma. Patients with V600 BRAF gene mutations, bulky disease, or poor performance status are more likely to have rapid disease progression and shorter overall survival compared with asymptomatic patients. Thus, if a rapid response is indicated to reduce symptomatic disease burden, BRAF-inhibitor therapy or the combination of BRAF and MEK inhibitors may be the preferred first option. However, if patients are relatively asymptomatic, immunotherapy should be considered for patients with metastatic melanoma due to the possibility of durable benefit.34,36 Future studies are likely to provide more guidance on the sequencing of these small-molecule inhibitors for metastatic melanoma. Meanwhile, NCCN is expected to update its recommendation for the trametinib–dabrafenib combination therapy, after the recent accelerated approval by FDA. Nevertheless, the overall survival time associated with this drug combination remains to be determined in an ongoing validation trial.26 It is worth pointing out that combination therapy may not always work, as exemplified by the significant hepatotoxicity of the ipilimumab–vemurafenib combination.38 Future directions Combination therapy for metastatic melanoma is now advancing rapidly through clinical trials. The combination of BRAF inhibitors with inhibitors of many other oncogenic signaling pathways holds promise for new therapies.39 Studies are now ongoing to investigate the clinical efficacy of trametinib in the neoadjuvant (presurgical) and the adjuvant (postsurgical) therapy of patients with early-stage melanomas. A randomized, double-blind Phase III trial (COMBI-AD trial) of the trametinib–dabrafenib combination versus placebo is now underway for BRAF-mutant melanoma patients in the adjuvant setting.40 Such patients are at high risk of relapse, and the combination of MEK and BRAF inhibitors may shed light on whether combination therapy can delay the recurrence of melanoma and improve survival outcome compared with other therapies. An open-label, multicenter, dose-finding Phase I study on the safety of doublet therapy (dabrafenib and ipilimumab) versus triplet therapy (trametinib, dabrafenib, and ipilimumab) is currently recruiting participants with unresectable or metastatic melanoma and BRAF V600 mutations.41 Resistance to BRAF inhibitors is associated with increased expression of some transmembrane receptors involved in immune checkpoint inhibition.42 Recent studies have demonstrated the clinical significance of the blockade of the programmed cell death protein 1 (PD-1) receptor and one of its ligands, PD-L1, involved in the regulation of the antitumor immune response.43,44 PD-1 is expressed in activated T cells, memory T cells, and regulatory T cells involved in T-cell regulation. PD-L1 is highly expressed in tumor cells and has been associated with a poor prognosis in patients with cancer. Undoubtedly, results of these trials may help better delineate the efficacy, tolerability, safety, and sequencing of different classes of therapeutic agents (cytotoxic chemotherapy, targeted therapy, and new immunotherapy agents) in patients with metastatic melanoma. Recently, a new agent (pembrolizumab) that affects the PD-1 pathway in patients who have received prior immunotherapy (ipilimumab) and a BRAF inhibitor gained FDA approval. This new drug will likely expand the current available treatment options for metastatic melanoma.45 As the first-in-class MEK inhibitor, trametinib represents an attractive option for treatment of a variety of malignancies. The role of MEK inhibitors in improving the response rate and survival outcome and delaying the onset of resistance in combination therapy with cytotoxic chemotherapy or targeted therapy is emerging across a number of malignancies. Currently, trametinib is being evaluated in the management of rectal cancer,46 metastatic breast cancer,47 biliary tract cancer,48 and advanced cancers that cannot be resected.49 Conclusion Trametinib, a novel MEK inhibitor, provides an alternative therapy for patients with BRAF V600 E/K metastatic melanoma as a single agent or in combination therapy for patients not previously treated with a BRAF inhibitor. More studies are needed to determine the safe and effective combination or sequencing of trametinib with other therapies. Footnotes The authors have declared no potential conflicts of interest. References 1 American Cancer Society . Cancer facts and figures 2014 . www.cancer.gov/cancertopics/types/melanoma (accessed 2014 Apr 8). 2 Slingluff CL Jr Flaherty K Rosenberg SA et al. . Cutaneous melanoma . In: Devita VT Jr Lawrence TS Rosenberg SA , eds. DeVita, Hellman, and Rosenberg’s cancer: principles and practice of oncology . Philadelphia : Lippincott Williams & Wilkins ; 2001 : 1646 – 52 . Google Preview WorldCat COPAC 3 Lui P Cashin R Machado M et al. . Treatments for metastatic melanoma: synthesis of evidence from randomized trials . Cancer Treat Rev . 2007 ; 33 : 665 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Eggermont AM Schadendorf D . Melanoma and immunotherapy . Hematol Oncol Clin North Am . 2009 ; 23 : 547 – 64 , ix – x . Google Scholar Crossref Search ADS PubMed WorldCat 5 Cheng Y Zhang G Li G . Targeting MAPK pathway in melanoma therapy . Cancer Metastasis Rev . 2013 ; 32 : 567 – 84 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Houben R Becker JC Kappel A et al. . Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis . J Carcinog . 2004 ; 3 : 6 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Davies H Bignell GR Cox C et al. . Mutations of the BRAF gene in human cancer . Nature . 2002 ; 417 : 949 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Mekinist (trametinib) prescribing information . Research Triangle Park, NC : GlaxoSmithKline ; 2013 May . WorldCat COPAC 9 Solit DB Garraway LA Pratilas CA et al. . BRAF mutation predicts sensitivity to MEK inhibition . Nature . 2006 ; 439 : 358 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Long GV Menzies AM Nagrial AM et al. . Prognostic and clinicopathologic associations of oncogene BRAF in metastatic melanoma . J Clin Oncol . 2011 ; 29 : 1239 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Panka DJ Atkins MB Mier JW . Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma . Clin Cancer Res . 2006 ; 12 : 2371s – 2375s . Google Scholar Crossref Search ADS PubMed WorldCat 12 Gray-Schopfer V Wellbrock C Marais R . Melanoma biology and new targeted therapy . Nature . 2007 ; 445 : 851 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Frémin C Meloche S . From basic research to clinical development of MEK1/2 inhibitors for cancer therapy . J Hematol Oncol . 2010 ; 3 : 8 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Roberts PJ Der CJ . Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer . Oncogene . 2007 ; 26 : 3291 – 310 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Van Raamsdonk CD Griewank KG Crosby MB et al. . Mutations in GNA11 in uveal melanoma . N Engl J Med . 2010 ; 363 : 2191 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Emery CM Vijayendran KG Zipser MC et al. . MEK1 mutations confer resistance to MEK and B-RAF inhibition . Proc Natl Acad Sci U S A . 2009 ; 106 : 20411 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Johannessen CM Boehm JS Kim SY et al. . COT drives resistance to RAF inhibition through MAP kinase pathway reactivation . Nature . 2010 ; 468 : 968 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Flaherty KT Infante JR Daud A et al. . Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations . N Engl J Med . 2012 ; 367 : 1694 – 703 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Gowrishankar K Snoyman S Pupo GM et al. . Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition . J Invest Dermatol . 2012 ; 132 : 1850 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Kim KB Kefford R Pavlick AC et al. . Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor . J Clin Oncol . 2013 ; 31 : 482 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 21 Gilmartin AG Bleam MR Groy A et al. . GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition . Clin Cancer Res . 2011 ; 17 : 989 – 1000 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Infante JR Fecher LA Falchook GS et al. . Safety, pharmacokinetic, pharmaco-dynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial . Lancet Oncol . 2012 ; 13 : 773 – 81 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Cox DS Papadopoulos K Fang L et al. . Evaluation of the effects of food on the single-dose pharmacokinetics of trametinib, a first-in-class MEK inhibitor, in patients with cancer . J Clin Pharmacol . 2013 ; 53 : 946 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Falchook GS Lewis KD Infante JR et al. . Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial . Lancet Oncol . 2012 ; 13 : 782 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Flaherty KT Robert C Hersey P et al. . Improved survival with MEK inhibition in BRAF-mutated melanoma . N Engl J Med . 2012 ; 367 : 107 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat 26 ClinicalTrials.gov . A study comparing trametinib and dabrafenib combination therapy to dabrafenib monotherapy in subjects with BRAF-mutant melanoma . http://clinicaltrials.gov/show/NCT01584648 (accessed 2014 Apr 8). 27 Johnson DB Sosman JA . Update on the targeted therapy of melanoma . Curr Treat Options Oncol . 2013 ; 14 : 280 – 92 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Sosman JA Kim KB Schuchter L et al. . Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib . N Engl J Med . 2012 ; 366 : 707 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Su F Viros A Milagre C et al. . RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors . N Engl J Med . 2012 ; 366 : 207 – 15 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Arnault JP Mateus C Escudier B et al. . Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1 . Clin Cancer Res . 2012 ; 18 : 263 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Chapman PB Hauschild A Robert C et al. . Improved survival with vemurafenib in melanoma with BRAF V600E mutation . N Engl J Med . 2011 ; 364 : 2507 – 16 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Red Book Online . Trametinib dimethyl-sulfoxide (Mekinist) . www.micromedexsolutions.com (accessed 2014 Apr 7). 33 Red Book Online . Dabrafenib mesylate (Tafinlar) . www.micromedexsolutions.com (accessed 2014 Apr 7). 34 Jang S Atkins MB . Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol . 2013 ; 14 : e60 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Flanigan JC Jilaveanu LB Faries M et al. . Melanoma brain metastases: is it time to reassess the bias? Curr Probl Cancer . 2011 ; 35 : 200 – 10 . Google Scholar Crossref Search ADS PubMed WorldCat 36 Ascierto PA Simerone E Giannarelli D et al. . Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use . J Transl Med . 2012 ; 10 : 107 . Google Scholar Crossref Search ADS PubMed WorldCat 37 National Comprehensive Cancer Network (NCCN) . Clinical practice guidelines in oncology: Melanoma. V.4.2013 . www.nccn.org (accessed 2014 Jan 1). 38 Ribas A Hodi FS Callahan M et al. . Hepatotoxicity with combination of vemurafenib and ipilimumab . N Engl J Med . 2013 ; 368 : 1365 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 39 McArthur GA Ribas A . Targeting oncogenic drivers and the immune system in melanoma . J Clin Oncol . 2013 ; 31 : 499 – 506 . Google Scholar Crossref Search ADS PubMed WorldCat 40 ClinicalTrials.gov . A study of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in the adjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection (COMBI-AD) . http://clinicaltrials.gov/ct2/show/NCT01682083?term=trametinib&rank=3 (accessed 2014 Jan 3). 41 ClinicalTrials.gov . Study of dabrafenib +/– trametinib in combination with ipilimumab for V600E/K mutation positive metastatic or unresectable melanoma . http://clinicaltrials.gov/ct2/show/NCT01767454?term=trametinib&rank=4 (accessed 2014 Jan 3). 42 Topalian SL Hodi FS Brahmer JR et al. . Safety, activity, and immune correlates of anti-PD-1 antibody in cancer . N Engl J Med . 2012 ; 366 : 2443 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat 43 Brahmer JR Tykodi SS Chow LQ et al. . Safety and activity of anti-PD-L1 antibody in patients with advanced cancer . N Engl J Med . 2012 ; 366 : 2455 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Wolchok JD Kluger H Callahan MK et al. . Nivolumab plus ipilimumab in advanced melanoma . N Engl J Med . 2013 ; 369 : 122 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat 45 Food and Drug Administration . Pembrolizumab . www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm412861.htm (accessed 2014 Nov 12). 46 ClinicalTrials.gov . Trametinib, fluorouracil, and radiation therapy before surgery in treating patients with stage II–III rectal cancer . http://clinicaltrials.gov/ct2/show/NCT01740648?term=trametinib+and+rectal+cancer&rank=1 (accessed 2014 Jan 3). 47 ClinicalTrials.gov . Trametinib and Akt inhibitor GSK2141795 in treating patients with metastatic triple-negative breast cancer . http://clinicaltrials.gov/ct2/show/NCT01964924?term=trametinib+and+breast+cancer&rank=1 (accessed 2014 Jan 3). 48 ClinicalTrials.gov . A phase IIa study of the MEK inhibitor trametinib monotherapy in the treatment of biliary tract cancers . http://clinicaltrials.gov/ct2/show/NCT01943864?term=trametinib&rank=11 (accessed 2014 Jan 3). 49 ClinicalTrials.gov . Dabrafenib, trametinib, and navitoclax in treating patients with solid tumors that are metastatic or cannot be removed by surgery . http://clinicaltrials.gov/ct2/show/NCT01989585?term=trametinib&rank=12 (accessed 2014 Jan 3). Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Trametinib: A novel signal transduction inhibitor for the treatment of metastatic cutaneous melanoma
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp140045
DA - 2015-01-15
UR - https://www.deepdyve.com/lp/oxford-university-press/trametinib-a-novel-signal-transduction-inhibitor-for-the-treatment-of-6Pjr00j3t6
SP - 101
VL - 72
IS - 2
DP - DeepDyve
ER -