Trametinib (Mekinist®): A Comprehensive Clinical and Pharmacological Monograph

Introduction and Overview

Trametinib represents a landmark achievement in the field of precision oncology, establishing a new class of therapeutic agents as the first orally bioavailable, selective inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 to gain regulatory approval.[1] Its development and clinical integration exemplify the paradigm shift away from cytotoxic chemotherapy towards biomarker-driven, targeted therapies. Trametinib functions by directly intervening in the RAS/RAF/MEK/ERK (MAPK) signaling pathway, a fundamental cascade that governs cellular processes such as proliferation, differentiation, and survival, and which is frequently dysregulated in human cancers.[3]

The clinical journey of Trametinib began with its approval as a monotherapy for the treatment of unresectable or metastatic melanoma harboring specific activating mutations in the BRAF gene, namely V600E or V600K.[4] While this initial approval demonstrated proof-of-concept and provided a new option for patients, the durable benefit was often limited by the rapid development of acquired resistance, typically within six to seven months.[5] This clinical challenge spurred the development of a more robust therapeutic strategy: the combination of Trametinib with a BRAF inhibitor, dabrafenib. This dual-blockade approach, which targets the MAPK pathway at two distinct nodes, was shown to produce higher response rates, prolong progression-free and overall survival, and critically, delay the onset of resistance mechanisms that plague BRAF inhibitor monotherapy.[5] This combination has since become the standard of care in most settings where Trametinib is indicated.

The success of this targeted approach in melanoma served as a blueprint for its expansion into other malignancies driven by the same molecular aberration. The indications for Trametinib, in combination with dabrafenib, have grown to include BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC), anaplastic thyroid cancer (ATC), and pediatric low-grade glioma (LGG).[8] Culminating this expansion was a pivotal tumor-agnostic approval, which sanctions its use for any unresectable or metastatic solid tumor with a BRAF V600E mutation that has progressed on prior therapy.[9] This indication untethers the treatment from a specific organ or tissue of origin and ties it directly to the presence of a molecular biomarker, cementing Trametinib's role as a true precision medicine.

Interestingly, the potent biological activity of Trametinib was first explored beyond oncology. It was initially investigated by its original developer, Japan Tobacco, for the treatment of inflammatory conditions such as rheumatoid arthritis, owing to the central role of the MAPK pathway in mediating inflammatory responses.[1] While this indication was not pursued clinically, it provides important historical context and underscores the fundamental power of MEK inhibition in modulating key cellular signaling pathways, a property that has been successfully harnessed for the treatment of cancer.

Molecular Profile and Pharmaceutical Characteristics

Trametinib is a small molecule drug classified chemically as a pyridopyrimidine. Its structure incorporates several key functional groups, including an organofluorine and an organoiodine moiety, as well as acetamide and cyclopropane rings, which contribute to its specific binding affinity and pharmacological properties.[1] A comprehensive understanding of its molecular and pharmaceutical characteristics is essential for its proper handling, formulation, and application in both clinical and research settings.

Chemical Identity and Nomenclature

The compound is universally known by its generic name, Trametinib.[8] It is marketed globally under the brand name

Mekinist® for most indications.[5] In the European Union, a specific formulation for pediatric use is marketed as

Spexotras®.[5] During its development phase, it was identified by the codes

GSK1120212 and JTP-74057.[11] Its systematic chemical name, according to IUPAC nomenclature, is N-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-acetamide.[11]

Physicochemical and Structural Properties

Trametinib exists as a crystalline solid or powder.[12] Its molecular formula is

C26​H23​FIN5​O4​, corresponding to a molecular weight of 615.39 g/mol.[12] For research purposes, its solubility profile is well-defined; it is soluble in dimethylformamide (DMF) at 2 mg/ml and dimethyl sulfoxide (DMSO) at 3 mg/ml, with lower solubility in aqueous solutions like DMSO:PBS (pH 7.2) at 0.3 mg/ml.[11]

For unambiguous identification in chemical databases and literature, several unique identifiers are assigned to Trametinib. Its CAS (Chemical Abstracts Service) Number is 871700-17-3.[1] Its DrugBank Accession Number is DB08911.[1] The International Chemical Identifier (InChI) and its hashed version (InChIKey) provide a canonical representation of its structure:

• InChI: 1S/C26H23FIN5O4/c1−13−22−21(23(31(3)24(13)35)30−20−10−7−15(28)11−19(20)27)25(36)33(17−8−9−17)26(37)32(22)18−6−4−5−16(12−18)29−14(2)34/h4−7,10−12,17,30H,8−9H2,1−3H3,(H,29,34) [5]
• InChIKey: LIRYPHYGHXZJBZ-UHFFFAOYSA-N [5]

Pharmaceutical Formulations and Administration

Trametinib is formulated for oral use and is available in two distinct dosage forms to accommodate different patient populations and needs.[1]

1. Film-coated tablets: These are the standard formulation for adults and older pediatric patients, available in 0.5 mg (yellow, oval) and 2 mg (pink, round) strengths.[1]
2. Powder for oral solution: This formulation is designed for pediatric patients or those who cannot swallow tablets. After reconstitution, it yields a solution with a concentration of 0.05 mg/mL.[1]

It is clinically important to note that the bioequivalence between the tablet and the oral solution has not been formally demonstrated, and caution is advised when switching patients between these formulations.[17]

Table 1: Drug Identification and Chemical Properties
Attribute	Value
Generic Name	Trametinib 8
Brand Names	Mekinist®, Spexotras® 5
DrugBank ID	DB08911 8
CAS Number	871700-17-3 14
Drug Type	Small Molecule 8
Chemical Class	Pyridopyrimidine, Organofluorine Compound 1
Molecular Formula	C26​H23​FIN5​O4​ 15
Molecular Weight	615.39 g/mol 14
Systematic (IUPAC) Name	N-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-acetamide 15
InChIKey	LIRYPHYGHXZJBZ-UHFFFAOYSA-N 5

Comprehensive Pharmacological Profile

The clinical utility of Trametinib is rooted in its precise pharmacological actions. A thorough understanding of its pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drug) is fundamental to its safe and effective use, informing everything from patient selection to dosing schedules and toxicity management.

3.1. Mechanism of Action and Pharmacodynamics

Trametinib is a potent, selective, reversible, and orally available inhibitor of MEK1 and MEK2 kinase activity.[2] Its mechanism is highly specific, targeting a critical choke point in one of the most important signaling pathways in oncology.

Target and Pathway Context

The mitogen-activated protein kinase (MAPK) pathway, also known as the RAS/RAF/MEK/ERK pathway, is a central signaling cascade that transduces extracellular signals to the nucleus, regulating key cellular functions including proliferation, differentiation, survival, and angiogenesis.[3] In this cascade, growth factor receptor activation leads to the activation of RAS proteins, which in turn recruit and activate RAF kinases (ARAF, BRAF, CRAF). Activated RAF kinases then phosphorylate and activate the dual-specificity kinases MEK1 and MEK2. Finally, activated MEK1/2 phosphorylate and activate their only known substrates, the extracellular signal-regulated kinases ERK1 and ERK2. Activated ERK then translocates to the nucleus to regulate the activity of numerous transcription factors, driving the cell cycle forward.[4]

In many human cancers, this pathway is constitutively activated due to mutations in upstream components, most notably RAS or BRAF genes. Activating mutations in BRAF, which occur in approximately 50% of melanomas and at lower frequencies in other cancers like NSCLC and thyroid cancer, lock the BRAF protein in a permanently "on" state.[3] This leads to persistent, uncontrolled signaling through MEK and ERK, driving malignant cell growth and survival.[3]

Allosteric Inhibition of MEK1/MEK2

Trametinib exerts its effect by binding with high affinity to a unique allosteric (non-ATP-competitive) pocket on the MEK1 and MEK2 enzymes.[13] This binding occurs on the unphosphorylated, inactive form of MEK, effectively locking it in a catalytically inactive conformation.[8] This prevents its subsequent phosphorylation and activation by the upstream BRAF kinase.[4] By blocking this critical step, Trametinib effectively shuts down the entire downstream signaling cascade, leading to a decrease in the phosphorylation and activity of ERK.[4]

The potency of this inhibition is high, with in vitro cell-free assays demonstrating half-maximal inhibitory concentrations (IC50​) of 0.92 nM for MEK1 and 1.8 nM for MEK2.[12] Importantly, Trametinib is highly selective and does not inhibit the kinase activity of upstream proteins like c-Raf or B-Raf, which underscores its targeted nature.[12] The downstream consequences of this pathway blockade in BRAF-mutant cancer cells are profound: a decrease in cell proliferation, induction of G1-phase cell-cycle arrest, and ultimately, apoptosis (programmed cell death).[1]

Rationale for Combination Therapy with Dabrafenib

While Trametinib is effective as a monotherapy, its greatest clinical impact is realized in combination with a BRAF inhibitor such as dabrafenib. The rationale for this dual blockade is multifaceted and addresses the primary mechanism of acquired resistance to BRAF inhibitors.

When a BRAF inhibitor is used alone, cancer cells can develop resistance by reactivating the MAPK pathway through alternative mechanisms. A common route is "paradoxical activation," where the BRAF inhibitor, while blocking the mutant BRAF in cancer cells, can inadvertently activate the pathway in BRAF wild-type cells (including some cancer cells that develop secondary mutations or normal cells like keratinocytes) via other RAF isoforms like CRAF.[1] This not only leads to tumor progression but also causes toxicities like the development of cutaneous squamous cell carcinomas.[6]

By adding Trametinib, a MEK inhibitor, the pathway is blocked at a downstream node. This strategy achieves a more profound and durable suppression of MAPK signaling, regardless of how the pathway is being activated upstream.[3] This has several key benefits:

1. Overcoming Resistance: It directly counteracts the MAPK pathway reactivation that mediates resistance to BRAF inhibitors, significantly delaying the time to disease progression.[3]
2. Enhanced Efficacy: The dual blockade results in superior clinical outcomes, including higher objective response rates (ORR), longer progression-free survival (PFS), and improved overall survival (OS) compared to either agent alone.[5]
3. Improved Safety Profile (in some aspects): By preventing the paradoxical activation in skin cells, the combination of dabrafenib and Trametinib significantly reduces the incidence of BRAF inhibitor-associated cutaneous malignancies.[6] However, as will be discussed, this combination gives rise to its own unique set of emergent toxicities, such as pyrexia.[20]

3.2. Pharmacokinetics

The pharmacokinetic (PK) profile of Trametinib dictates its dosing regimen, administration guidelines, and potential for drug interactions. Its properties are characterized by rapid absorption, high bioavailability, extensive distribution, metabolism primarily by non-CYP enzymes, and a long elimination half-life.[8]

Table 2: Summary of Pharmacokinetic Parameters
Parameter	Value / Description
Absorption
Bioavailability (Absolute)	72% (tablets); 81% (oral solution) 8
Time to Peak Concentration (Tmax​)	1.5 hours (fasted) 8
Effect of Food	High-fat meal decreases AUC by 24% and Cmax​ by 70% 8
Distribution
Apparent Volume of Distribution (Vc​/F)	214 L 8
Plasma Protein Binding	97.4% 8
Metabolism
Primary Pathway	Deacetylation via hydrolytic enzymes (e.g., carboxylesterases) 8
Minor Pathway	CYP3A4-mediated oxidation 8
Active Metabolites	M5 metabolite exposure is clinically insignificant 20
Excretion
Major Route of Elimination	Feces (>80% of dose) 8
Minor Route of Elimination	Urine (<19% of dose; <0.1% as unchanged drug) 8
Elimination
Elimination Half-Life (t1/2​)	~127 hours (4-5 days) 8
Apparent Clearance	4.9 L/h 8
Steady State	Achieved by Day 15-20 8

Absorption

Following oral administration, Trametinib is rapidly absorbed, reaching peak plasma concentrations (Tmax​) in approximately 1.5 hours under fasted conditions.[8] Its absolute bioavailability is high, measured at 72% for the tablet formulation and 81% for the oral solution.[8] The pharmacokinetic profile is dose-proportional following repeated dosing.[20]

A critical aspect of its absorption is a significant negative food effect. Administration with a high-fat, high-calorie meal (approximately 1000 calories) results in a substantial reduction in drug exposure, decreasing the maximum concentration (Cmax​) by 70% and the total exposure (AUC) by 24%, while delaying Tmax​ by about four hours.[8] This interaction is not merely a minor fluctuation; it is a clinically meaningful reduction in bioavailability that could compromise therapeutic efficacy. This finding is the direct basis for the stringent administration guideline that Trametinib must be taken on an empty stomach, at least one hour before or two hours after a meal.[4] Adherence to this rule is paramount for ensuring consistent and adequate drug exposure.

Distribution

Trametinib is widely distributed throughout the body tissues, as indicated by its large apparent volume of distribution of 214 L.[8] It is highly bound to human plasma proteins, with a binding fraction of 97.4%.[8] This extensive protein binding means that only a small fraction of the drug is free and pharmacologically active at any given time, but it also contributes to its long retention in the body.

Metabolism

The metabolism of Trametinib is a key feature that distinguishes it from many other kinase inhibitors. The primary metabolic pathway is deacetylation, which is mediated by hydrolytic enzymes such as carboxylesterases (CES1b/c and CES2).[8] This initial step may be followed by further modifications like mono-oxygenation or glucuronidation. Oxidation mediated by the cytochrome P450 system, specifically CYP3A4, is only a minor metabolic pathway.[8]

This metabolic profile has significant clinical implications. Because Trametinib does not rely heavily on the CYP450 system for its clearance, it has a much lower potential for pharmacokinetic drug-drug interactions with concomitant medications that are potent inhibitors or inducers of these enzymes.[24] This simplifies the management of polypharmacy in cancer patients, who often require numerous supportive care medications. While several metabolites have been identified, the parent drug accounts for the vast majority (≥75%) of circulating drug-related material at steady state, and the primary active metabolite (M5) has exposure levels that are considered clinically insignificant.[8]

Excretion

Elimination of Trametinib and its metabolites occurs predominantly through the feces, with over 80% of an administered radiolabeled dose recovered in fecal matter over a 10-day period.[8] Renal excretion is a minor route, accounting for less than 19% of the dose, and very little of the drug (<0.1%) is excreted unchanged in the urine.[8] This excretion profile suggests that mild to moderate renal impairment is unlikely to significantly affect Trametinib exposure, and thus dose adjustments are not typically required in these patients.[25] However, data in patients with severe renal impairment is lacking.

Half-life and Steady State

Trametinib exhibits a long terminal elimination half-life of approximately 127 hours, or 4 to 5 days.[8] This long half-life, combined with once-daily dosing, leads to drug accumulation, with a mean accumulation ratio of 6.0 at the standard 2 mg daily dose.[8] Steady-state plasma concentrations are achieved by day 15 to 20 of continuous dosing.[8] The prolonged half-life is advantageous as it supports a convenient once-daily dosing regimen and ensures sustained levels of MEK inhibition throughout the dosing interval, which is crucial for maintaining continuous pressure on the MAPK signaling pathway.[3]

Clinical Efficacy Across Approved Indications

The clinical development of Trametinib has been a testament to the power of biomarker-driven therapy. Its efficacy is tightly linked to the presence of a BRAF V600 mutation, a prerequisite for treatment across all its approved indications.[3] The validation of this mutation must be performed using an FDA-approved or otherwise validated test prior to initiating therapy.[25] The drug's journey from a single-cancer monotherapy to a broad-spectrum combination agent reflects a deepening understanding of its mechanism and a strategic expansion based on robust clinical trial evidence.

4.1. Unresectable or Metastatic Melanoma

Melanoma was the first cancer type for which Trametinib was approved and remains a cornerstone indication.

Monotherapy

The initial approval of Trametinib as a single agent was supported by the Phase III METRIC trial.[28] This study randomized patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, who were either treatment-naïve or had received one prior line of chemotherapy, to receive Trametinib 2 mg once daily or standard chemotherapy (dacarbazine or paclitaxel). The trial demonstrated a clear and statistically significant superiority for Trametinib, with a median progression-free survival (PFS) of 4.8 months compared to just 1.5 months for chemotherapy (Hazard Ratio = 0.45, p<0.0001).[28] While groundbreaking at the time, the utility of monotherapy is now limited. Clinical experience and trial data show that acquired resistance develops relatively quickly, often within 6 to 7 months.[5] Furthermore, Trametinib monotherapy has not demonstrated clinical activity in patients whose disease has progressed on a prior BRAF inhibitor, indicating cross-resistance within the pathway.[28]

Combination Therapy with Dabrafenib

The combination of Trametinib with the BRAF inhibitor dabrafenib is now the established standard of care for BRAF V600-mutant melanoma, based on evidence from two pivotal Phase III trials that demonstrated superiority over single-agent targeted therapy.

The COMBI-d (NCT01584648) study compared the combination of dabrafenib plus Trametinib against dabrafenib plus placebo. The combination therapy resulted in significantly improved outcomes, with a median PFS of 11.0 months versus 8.8 months for dabrafenib alone, and a median overall survival (OS) of 25.1 months versus 18.7 months.[29]

The COMBI-v (NCT01597908) study compared the dabrafenib plus Trametinib combination against vemurafenib monotherapy, another potent BRAF inhibitor. The combination was again superior, showing a significant benefit in both PFS and OS.[29] Long-term, 5-year follow-up data from both trials have confirmed the durable benefit of the combination, solidifying its role as a first-line treatment standard for this patient population.[22]

4.2. Adjuvant Treatment of Stage III Melanoma

A major advance in melanoma treatment was the expansion of targeted therapy into the adjuvant setting, aiming to prevent recurrence after surgical resection. The approval of the dabrafenib and Trametinib combination for this indication was based on the landmark Phase III COMBI-AD (NCT01682083) trial.[5] This study enrolled patients with completely resected, high-risk Stage III melanoma with a BRAF V600E or V600K mutation. Patients were randomized to receive 12 months of combination therapy or placebo.[25]

The results were practice-changing. The combination therapy significantly reduced the risk of disease recurrence or death by 53% compared to placebo (HR: 0.47).[31] The final analysis of the trial, with a follow-up of nearly 10 years, was presented at ASCO 2024 and demonstrated a durable and sustained benefit. The 8-year landmark relapse-free survival (RFS) was 50% for the combination arm versus 35% for the placebo arm (HR: 0.52).[32] A similar sustained improvement was seen in distant metastasis-free survival (DMFS). While the overall survival curves showed a clear separation favoring the combination arm (HR: 0.80, a 20% reduction in the risk of death), the result did not meet the threshold for statistical significance (p=0.063).[32] Despite this, the profound and lasting impact on RFS has established one year of adjuvant dabrafenib and Trametinib as a standard of care for this patient population.

4.3. Metastatic Non-Small Cell Lung Cancer (NSCLC)

The success in melanoma prompted investigation in other BRAF-mutant tumors. For patients with metastatic NSCLC harboring a BRAF V600E mutation, the combination of dabrafenib and Trametinib received approval based on the results of a non-randomized, multi-cohort, open-label Phase II study (NCT01336634).[8] This study demonstrated a high and durable overall response rate (ORR) in this molecularly defined subgroup of NSCLC patients, who historically have had poor prognoses and limited effective treatment options.[9]

4.4. Anaplastic Thyroid Cancer (ATC)

Anaplastic thyroid cancer is one of the most aggressive and lethal human malignancies, with very few effective systemic therapies. The BRAF V600E mutation is found in a subset of these tumors. The approval of dabrafenib and Trametinib for locally advanced or metastatic ATC with a BRAF V600E mutation was a significant breakthrough.[8] Approval was granted based on efficacy data from the ATC cohort of the

ROAR (Rare Oncology Agnostic Research) basket trial (Study BRF117019).[9] This open-label study demonstrated a clinically meaningful and durable response rate in patients with no other satisfactory treatment options, providing a much-needed targeted therapy for this devastating disease.[33]

4.5. Tumor-Agnostic Solid Tumors

The trajectory of Trametinib's development highlights a broader shift in oncology: treating cancer based on its molecular profile rather than its tissue of origin. This culminated in the 2022 accelerated approval for the combination of dabrafenib and Trametinib for adult and pediatric patients (aged 6 years and older) with any unresectable or metastatic solid tumor that possesses a BRAF V600E mutation and has progressed following prior treatment.[9]

This landmark tumor-agnostic (or tissue-agnostic) approval was based on pooled efficacy data from several open-label trials, including the adult ROAR and NCI-MATCH basket trials, as well as a pediatric study.[10] These trials enrolled patients with a wide variety of cancer types, including rare tumors like biliary tract cancer, small intestine cancer, and various gliomas.[10] Across 24 different tumor types in the adult studies, the combination therapy yielded an ORR of 41%.[10] In the pediatric trial, the ORR was 25%.[10] This approval validates the basket trial as an efficient model for drug development in rare, biomarker-defined populations and fundamentally alters clinical practice by mandating broad molecular testing for patients with advanced cancers to identify this actionable target. It is important to note that this indication specifically excludes colorectal cancer, which exhibits intrinsic resistance to BRAF/MEK inhibition when used without an EGFR inhibitor.[19]

4.6. Pediatric Low-Grade Glioma (LGG)

In March 2023, the combination of dabrafenib and Trametinib was approved for pediatric patients aged one year and older with low-grade glioma (WHO grades 1 and 2) with a BRAF V600E mutation who require systemic therapy.[9] This marked the first FDA approval of a systemic therapy for the first-line treatment of this specific pediatric brain tumor population.

The approval was based on the Phase II/III study CDRB436G2201 (NCT02684058), which randomized patients to receive either the dabrafenib/Trametinib combination or standard-of-care chemotherapy (carboplatin and vincristine).[36] The results overwhelmingly favored the targeted therapy combination, which demonstrated a dramatically higher ORR (46.6% vs. 10.8% for chemotherapy; p<0.001) and a significantly longer median PFS (20.1 months vs. 7.4 months; HR=0.31, p<0.001).[13] This approval, which included new child-friendly oral solution formulations of both drugs, has established a new, more effective, and less toxic standard of care for these young patients.[18]

Table 3: Summary of Pivotal Clinical Trials for Approved Indications
Indication	Trial Name / ID	Phase	Therapy	Comparator	Key Efficacy Result
Metastatic Melanoma	METRIC	III	Trametinib	Chemotherapy	Median PFS: 4.8 vs. 1.5 months (HR=0.45) 28
Metastatic Melanoma	COMBI-d (NCT01584648)	III	Dabrafenib + Trametinib	Dabrafenib + Placebo	Median OS: 25.1 vs. 18.7 months 29
Metastatic Melanoma	COMBI-v (NCT01597908)	III	Dabrafenib + Trametinib	Vemurafenib	Superior OS and PFS for combination 29
Adjuvant Stage III Melanoma	COMBI-AD (NCT01682083)	III	Dabrafenib + Trametinib	Placebo	53% reduction in risk of recurrence/death 31
Metastatic NSCLC	NCT01336634	II	Dabrafenib + Trametinib	Single-arm	ORR: 64% in treatment-naïve patients 9
Anaplastic Thyroid Cancer	ROAR (BRF117019)	II	Dabrafenib + Trametinib	Single-arm	ORR: 69% in ATC cohort 9
Tumor-Agnostic Solid Tumors	ROAR / NCI-MATCH	II	Dabrafenib + Trametinib	Single-arm	ORR: 41% across multiple rare cancers 10
Pediatric Low-Grade Glioma	CDRB436G2201 (NCT02684058)	II/III	Dabrafenib + Trametinib	Carboplatin + Vincristine	ORR: 46.6% vs. 10.8%; Median PFS: 20.1 vs. 7.4 months 36

Safety Profile and Risk Management

The clinical application of Trametinib, both as a monotherapy and in combination with dabrafenib, is associated with a distinct and significant profile of adverse events (AEs). These toxicities are largely considered "on-target," arising from the inhibition of the MAPK pathway in normal tissues where it plays a physiological role. Effective management of this safety profile through patient education, proactive monitoring, and timely dose modifications is critical to maintaining treatment tolerability and maximizing clinical benefit.

A key observation in the safety profiles is that while combining Trametinib with a BRAF inhibitor mitigates certain toxicities (e.g., cutaneous malignancies), it gives rise to a novel and often more challenging set of AEs, most notably pyrexia. This demonstrates that the safety profile of the combination is not merely an additive sum of its parts but an emergent property of the dual pathway blockade, requiring specific management strategies.

Common Adverse Events

The most frequently reported AEs (occurring in ≥20% of patients) differ between monotherapy and combination therapy.

• Trametinib Monotherapy: The most common AEs are rash, diarrhea, and lymphedema (peripheral edema).[4]
• Combination with Dabrafenib: The AE profile is broader and dominated by systemic symptoms. The most common events include pyrexia (fever), nausea, rash, chills, diarrhea, vomiting, headache, fatigue, hypertension, and peripheral edema.[5] In the adjuvant melanoma setting, arthralgia and myalgia are also very common.[23] For pediatric patients, dry skin, dermatitis acneiform, abdominal pain, and paronychia are also frequently observed.[9] Pooled analyses of the large registration trials show that the incidence of most AEs, including pyrexia, is highest within the first six months of treatment initiation and tends to decline over time with continued therapy.[37]

Serious Warnings and Precautions

Regulatory agencies have highlighted several serious risks associated with Trametinib that require careful monitoring and management.

New Primary Malignancies

When Trametinib is used in combination with dabrafenib, there is a risk of developing new primary malignancies, both cutaneous and non-cutaneous. Cutaneous malignancies, particularly cutaneous squamous cell carcinoma (cuSCC) and keratoacanthoma, are a known class effect of BRAF inhibitors due to paradoxical MAPK activation, although the incidence is reduced by the addition of Trametinib. Patients require dermatologic evaluation prior to starting therapy, every two months during therapy, and for up to six months after discontinuation.[19]

Hemorrhage

Major and fatal hemorrhagic events, including in critical areas like the brain or gastrointestinal tract, can occur, particularly with combination therapy.[19] Across clinical trials, hemorrhagic events occurred in 17% of patients on the combination, with fatal events in 0.5%.[19] The risk may be increased in patients on concomitant antiplatelet or anticoagulant therapy.[28] Monitoring for signs and symptoms of bleeding is essential, and the drug should be withheld or permanently discontinued for Grade 3 or 4 events.[19]

Venous Thromboembolism (VTE)

Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported, with fatal VTE events occurring in patients receiving the combination therapy.[19] Patients should be monitored for signs and symptoms of VTE and treated as medically appropriate.

Cardiomyopathy

Trametinib can cause cardiac toxicity, specifically cardiomyopathy manifesting as a decrease in left ventricular ejection fraction (LVEF).[20] The median onset of LVEF decrease is approximately two months.[20] Therefore, assessment of LVEF by echocardiogram or MUGA scan is mandatory for all patients before starting treatment, one month after initiation, and then every 2 to 3 months thereafter for the duration of treatment.[19] For asymptomatic LVEF decline, treatment is held and may be resumed at a lower dose if function recovers; for symptomatic cardiomyopathy or persistent LVEF decline, permanent discontinuation is required.[40]

Ocular Toxicities

A range of ocular toxicities are a significant concern with Trametinib. These include:

• Retinal Pigment Epithelial Detachment (RPED): This is a relatively common event, often presenting as blurred vision or other visual disturbances. It is typically bilateral, multifocal, and occurs in the macular region.[3] In most cases, RPED is reversible and resolves after holding the drug, though some imaging abnormalities may persist.[20] Treatment can often be resumed at a reduced dose.[40]
• Retinal Vein Occlusion (RVO): This is a rare but much more serious event that can lead to macular edema, permanent loss of vision, and glaucoma.[3] Any patient reporting new or sudden visual loss requires an urgent ophthalmological evaluation. If RVO is confirmed, Trametinib must be permanently discontinued.[25]

Interstitial Lung Disease (ILD) / Pneumonitis

Treatment-related ILD or pneumonitis has been reported and can be life-threatening.[25] Patients presenting with new or progressive pulmonary symptoms such as cough, dyspnea, or hypoxia should have Trametinib withheld pending investigation. If treatment-related ILD or pneumonitis is diagnosed, the drug must be permanently discontinued.[19]

Serious Febrile Reactions (Pyrexia)

Fever is a hallmark toxicity of the dabrafenib-Trametinib combination, occurring in over half of patients.[37] While often low-grade, it can be severe and complicated by rigors, dehydration, hypotension, and renal failure.[20] Management involves interrupting both drugs, use of antipyretics, and ensuring adequate hydration. For recurrent or severe fever, corticosteroids may be required.[41] Proactive patient education on this specific side effect is crucial for prompt reporting and management.

Serious Skin Toxicities

In addition to common rashes, severe skin toxicities can occur. These include intolerable Grade 3 or 4 rashes that may require permanent discontinuation.[23] Furthermore, rare but life-threatening Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome (SJS) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with the combination therapy.[20]

Other Significant Risks

• Hyperglycemia: Serum glucose levels should be monitored, particularly in patients with pre-existing diabetes or hyperglycemia.[19]
• Colitis and GI Perforation: Though rare (<1%), colitis and gastrointestinal perforation, including fatal cases, have been reported.[19]
• Embryo-Fetal Toxicity: Trametinib can cause fetal harm. It is teratogenic and embryotoxic in animal models. Females of reproductive potential must use effective non-hormonal contraception during treatment and for 4 months after the final dose.[23]

Contraindications

The only absolute contraindication listed is known hypersensitivity to Trametinib or any of its excipients.[17]

Table 4: Common and Serious Adverse Events (AEs) of Trametinib
System Organ Class	Adverse Event	Frequency (Monotherapy / Combination)
General	Fatigue, Pyrexia, Chills, Edema	Common / Very Common 4
Skin and Subcutaneous Tissue	Rash, Dermatitis Acneiform, Dry Skin, Pruritus	Very Common / Very Common 23
	Palmar-plantar erythrodysesthesia	- / Common 20
Gastrointestinal	Diarrhea, Nausea, Vomiting, Constipation, Dry Mouth	Very Common / Very Common 23
Cardiac	Cardiomyopathy (LVEF decrease)	Common / Common 23
Eye	Blurred Vision, RPED, Periorbital Edema	Common / Common 23
	Retinal Vein Occlusion (RVO)	Uncommon / Uncommon 3
Vascular	Hypertension, Hemorrhage	Common / Very Common 23
	Venous Thromboembolism (DVT/PE)	- / Common 20
Respiratory	Cough, Dyspnea	Very Common / Very Common 23
	Interstitial Lung Disease (ILD)/Pneumonitis	Uncommon / Uncommon 25
Nervous System	Headache	- / Very Common 23
Musculoskeletal	Arthralgia, Myalgia	- / Very Common 23
Neoplasms	New Cutaneous Malignancies (cuSCC)	- / Common (Risk from Dabrafenib) 23
Frequencies are general estimates based on prescribing information; "Very Common" ≥10%, "Common" ≥1% to <10%, "Uncommon" ≥0.1% to <1%. Serious AEs are bolded.

Dosage, Administration, and Drug Interactions

The practical application of Trametinib in the clinic requires strict adherence to guidelines for dosing, administration, and management of interactions to ensure optimal efficacy and safety.

6.1. Recommended Dosage and Formulations

Trametinib dosing is standardized for adults but is weight-based in the pediatric population.

• Adult Dosage: The recommended dosage of Trametinib for all adult indications, whether as monotherapy or in combination with dabrafenib, is 2 mg taken orally once daily.[19]
• Pediatric Dosage: The dosage for pediatric patients is determined by body weight and is intended for use in combination with dabrafenib.
• Tablets (for patients ≥26 kg):
• 26 to 37 kg: 1 mg (two 0.5 mg tablets) once daily.[19]
• 38 to 50 kg: 1.5 mg (three 0.5 mg tablets) once daily.[19]
• ≥51 kg: 2 mg once daily.[19]
• Oral Solution (for patients ≥8 kg): The powder for oral solution is available for younger children or those unable to swallow tablets.[17] A recommended dose has not been established for patients weighing less than 26 kg for tablets or less than 8 kg for the solution.[17]

6.2. Administration and Storage

Proper administration is crucial due to the drug's pharmacokinetic properties.

• Food Effect: Trametinib must be taken on an empty stomach to ensure adequate absorption. Patients should be instructed to take their dose at least 1 hour before or 2 hours after a meal.[4]
• Timing: Doses should be taken at approximately the same time each day (24 hours apart) to maintain consistent plasma levels.[19]
• Missed Dose: If a dose is missed, it should be taken only if the next scheduled dose is more than 12 hours away. If the next dose is within 12 hours, the missed dose should be skipped.[19]
• Storage: Trametinib tablets must be stored under refrigeration at 2°C to 8°C (36°F to 46°F). It should be dispensed and stored in its original bottle, which contains a desiccant to protect from moisture. The medication should not be placed in pill boxes.[4] These storage requirements can pose a challenge for patients who travel, necessitating the use of portable coolers.[4]

6.3. Dose Modifications for Adverse Events

A structured approach to dose modification is essential for managing toxicity. The general principle involves interrupting therapy for moderate to severe AEs, allowing the patient to recover, and then resuming treatment at a reduced dose level. Dose adjustment below 1 mg once daily is not recommended.[25]

Table 5: Recommended Dose Modifications for Key Adverse Events
Adverse Event	Severity / Condition	Recommended Action for Trametinib
Cardiomyopathy	Asymptomatic, LVEF decrease >10% from baseline and below lower limit of normal	Hold therapy for up to 4 weeks. If LVEF improves to normal, resume at 1 dose level lower. If not improved, permanently discontinue. 25
	Symptomatic Cardiomyopathy / Heart Failure	Permanently discontinue. 40
Ocular Toxicity	Retinal Pigment Epithelial Detachment (RPED)	Hold therapy. If improved to Grade ≤1 within 3 weeks, resume at 1 dose level lower. If not improved, permanently discontinue. 40
	Retinal Vein Occlusion (RVO)	Permanently discontinue. 25
Interstitial Lung Disease (ILD) / Pneumonitis	Suspected ILD/Pneumonitis	Withhold therapy pending investigation. 23
	Confirmed treatment-related ILD/Pneumonitis	Permanently discontinue. 23
Serious Febrile Reaction	Temperature ≥100.4°F (38°C) or any complicated fever	Interrupt therapy. May resume at same or lower dose upon resolution. 41
Serious Skin Toxicity	Intolerable Grade 2, or any Grade 3 or 4 rash not improving within 3 weeks	Permanently discontinue. 19
	Severe Cutaneous Adverse Reaction (SCAR)	Permanently discontinue. 23
Hemorrhage	Grade 3 Hemorrhage	Withhold therapy. If improved, resume at 1 dose level lower. 19
	Grade 4 Hemorrhage	Permanently discontinue. 19

6.4. Drug and Food Interactions

Food Interaction

As detailed previously, co-administration with a high-fat, high-calorie meal significantly impairs the absorption of Trametinib, making the "take on an empty stomach" rule a critical component of patient counseling.[8]

Drug-Drug Interactions

The potential for pharmacokinetic drug-drug interactions with Trametinib is relatively low compared to many other kinase inhibitors. This is because its metabolism is primarily driven by hydrolytic enzymes (carboxylesterases) rather than the cytochrome P450 (CYP) enzyme system.[8] In vitro studies show that Trametinib is not a clinically relevant inhibitor or inducer of major CYP enzymes (e.g., CYP3A4, 2C9, 1A2) or transporters (e.g., P-gp).[24] Therefore, co-administration with drugs that are substrates, inhibitors, or inducers of these pathways is unlikely to result in a significant pharmacokinetic interaction with Trametinib itself.[24]

However, it is crucial to remember that Trametinib is almost always used in combination with dabrafenib, which is a substrate and inducer of CYP enzymes. Therefore, the interaction profile of the combination therapy is dictated by dabrafenib's properties, and clinicians must consult the prescribing information for dabrafenib when considering potential interactions.

The most clinically significant interactions for Trametinib are pharmacodynamic in nature:

• Live Vaccines: Due to potential immunosuppressive effects, co-administration with live or live-attenuated vaccines (e.g., measles, mumps, rubella, varicella, yellow fever) is not recommended, as it may reduce the immune response to the vaccine and increase the risk of infection from the vaccine strain.[39]
• Other Immunosuppressive Agents: Caution is advised when co-administering Trametinib with other drugs that have immunosuppressive effects (e.g., etrasimod, ponesimod, siponimod), as there is a risk of additive immune system suppression.[40]

Regulatory History and Global Status

The regulatory journey of Trametinib from a novel investigational compound to a globally approved cornerstone of targeted therapy has been rapid and expansive. Its development was initiated by Japan Tobacco (under the code JTP-74057) before being licensed to GlaxoSmithKline (GSK) (as GSK1120212), and it is now marketed by Novartis following an asset swap between the two pharmaceutical giants.[1] This timeline reflects the swift pace of drug development in oncology when a clear biomarker-driven strategy is employed.

U.S. Food and Drug Administration (FDA)

The FDA has granted a series of approvals for Trametinib, progressively widening its therapeutic scope.

• May 29, 2013: The initial landmark approval was granted for Mekinist (Trametinib) as a monotherapy for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations.[1]
• January 9, 2014: The FDA granted accelerated approval for the combination of Trametinib with dabrafenib for the same melanoma indication, recognizing the superior efficacy of the dual blockade.[5]
• June 22, 2017: The label was expanded to include the treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, in combination with dabrafenib.[9]
• April 30 / May 4, 2018: Two major approvals were granted in quick succession: for the adjuvant treatment of Stage III melanoma with BRAF V600E or V600K mutations following complete resection, and for the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with a BRAF V600E mutation, both in combination with dabrafenib.[5]
• June 22, 2022: A pivotal tumor-agnostic accelerated approval was granted for the combination to treat adult and pediatric patients (≥6 years) with unresectable or metastatic solid tumors with a BRAF V600E mutation who have progressed on prior treatment.[9]
• March 16, 2023: The most recent approval was for the treatment of pediatric patients (≥1 year) with low-grade glioma (LGG) with a BRAF V600E mutation, in combination with dabrafenib. This approval also included new oral solution formulations of the drugs.[9]

European Medicines Agency (EMA)

The EMA's approval timeline has largely mirrored that of the FDA, establishing Trametinib as a standard of care across Europe.

• June 30, 2014: The European Commission granted the initial marketing authorisation for Mekinist (Trametinib) as a monotherapy for adults with unresectable or metastatic melanoma with a BRAF V600 mutation.[1]
• Subsequent approvals for the combination with dabrafenib followed for unresectable/metastatic melanoma, adjuvant treatment of Stage III melanoma, and advanced NSCLC with a BRAF V600 mutation.[25]
• November 2023 / January 2024: The EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, leading to the approval of the combination for pediatric patients with low- and high-grade glioma with a BRAF V600E mutation. For this indication, the oral solution formulation is marketed under the brand name Spexotras.[5]

Legal Status and Commercial Information

Trametinib is a prescription-only medication (℞-only) in all major markets, including the United States, European Union, Canada, and Australia.[5] The intellectual property surrounding the drug is protected by numerous patents covering the compound itself, its pharmaceutical composition, and its methods of use in various indications. These patents, some of which include pediatric exclusivity extensions, are expected to provide market exclusivity into the 2030s.[18] Novartis offers patient assistance and co-pay programs to help eligible patients with private insurance access the medication.[45]

Table 6: Timeline of Major FDA and EMA Regulatory Approvals
Date	Agency	Indication	Supporting Trial(s)
May 2013	FDA	Metastatic Melanoma (Monotherapy)	METRIC 9
Jan 2014	FDA	Metastatic Melanoma (Combination w/ Dabrafenib)	COMBI-d 5
Jun 2014	EMA	Metastatic Melanoma (Monotherapy)	METRIC 28
Jun 2017	FDA	Metastatic NSCLC (Combination w/ Dabrafenib)	NCT01336634 9
Apr/May 2018	FDA	Adjuvant Melanoma & Anaplastic Thyroid Cancer (Combination)	COMBI-AD & ROAR 5
Jun 2022	FDA	Tumor-Agnostic Solid Tumors (Combination)	ROAR / NCI-MATCH 9
Mar 2023	FDA	Pediatric Low-Grade Glioma (Combination)	CDRB436G2201 9
Jan 2024	EMA	Pediatric Low- & High-Grade Glioma (Combination)	CDRB436G2201 5

Future Directions and Investigational Landscape

While Trametinib, in combination with dabrafenib, is firmly established as a standard of care for multiple BRAF V600-mutant malignancies, its story is far from over. Ongoing and recent clinical trials are exploring its potential in three key areas: integration with immunotherapy, development of novel combinations to overcome resistance, and expansion into new disease indications, including non-malignant conditions. This body of research positions Trametinib not just as a standalone therapy but as a versatile combination backbone for building more effective and complex treatment regimens.

Combination with Immunotherapy

The most significant frontier in melanoma research is the combination of targeted therapy and immunotherapy (immune checkpoint inhibitors, ICIs). The rationale is compelling: targeted therapy can induce rapid tumor shrinkage, release tumor antigens, and modulate the tumor microenvironment to make it more susceptible to an immune attack, while ICIs can generate deep, durable, and potentially curative responses. Several large-scale trials have investigated this triplet approach.

• The Phase II Keynote-022 (NCT02130466) trial investigated the triplet of pembrolizumab (anti-PD-1), dabrafenib, and Trametinib versus the dabrafenib/Trametinib doublet. While the study did not meet its primary endpoint of a statistically significant improvement in PFS at the initial analysis, longer-term follow-up revealed numerically superior outcomes for the triplet arm, including a median PFS of 17 months versus 9.9 months and a median OS of 46.3 months versus 26.3 months. The complete response (CR) rate was also higher with the triplet (20% vs. 15%).[46] However, these benefits came at the cost of substantially higher rates of Grade 3-5 adverse events (70% vs. 45%), highlighting the significant toxicity challenge of this approach.[46]
• The Phase III COMBI-i (NCT02967692) trial evaluated a similar triplet using the anti-PD-1 antibody spartalizumab. This study also aimed to determine the efficacy and safety of combining targeted therapy with checkpoint inhibition.[47]
• The DREAMseq (NCT02224781) trial took a different approach, investigating the optimal sequence of therapy. It randomized patients to receive either initial treatment with immunotherapy (ipilimumab + nivolumab) followed by targeted therapy (dabrafenib + Trametinib) at progression, or the reverse sequence. This trial is critical for defining the best overall treatment strategy for patients with BRAF-mutant melanoma.[48]

Overcoming Resistance and Novel Combinations

Researchers are actively exploring new combinations to preempt or overcome the mechanisms of resistance to BRAF/MEK inhibition.

• Trials have investigated adding inhibitors of other signaling nodes, such as AKT inhibitors (GSK2141795 in trial NCT01941927) or FAK inhibitors (GSK2256098 in trial NCT01938443), to create more comprehensive pathway blockades.[49]
• An innovative approach is seen in the TraMel-WT (NCT04059224) trial. This study investigated Trametinib plus a low dose of dabrafenib in patients with advanced melanoma that is BRAF wild-type and has progressed on immunotherapy.[51] The rationale is to use Trametinib for its MEK-inhibiting anti-tumor activity while adding a sub-therapeutic dose of dabrafenib solely to mitigate the dose-limiting skin toxicities of Trametinib monotherapy. This trial demonstrated encouraging efficacy and effective management of skin toxicity, potentially opening a new therapeutic niche for the combination outside of its classic BRAF-mutant setting.[51]

New and Expanded Indications

The principle of targeting the MAPK pathway is being extended to new diseases where this pathway is a known driver.

• Vascular Malformations: A Phase II trial (NCT04258046) is evaluating Trametinib for the treatment of complicated extracranial arteriovenous malformations (AVMs).[54] These are congenital, non-cancerous conditions driven by mutations in the MAPK pathway (e.g., in MAP2K1, the gene for MEK1). This represents a potential expansion of Trametinib into non-oncologic proliferative disorders.
• Other Cancers: Ongoing trials are studying Trametinib in various other cancers, including juvenile myelomonocytic leukemia (JMML) in combination with azacitidine, and in multiple myeloma and cholangiocarcinoma in combination with other novel agents.[55]

Long-Term Safety and Efficacy

As patients live longer on targeted therapies, understanding the long-term outcomes is crucial.

• The final, nearly 10-year analysis of the COMBI-AD adjuvant trial provides invaluable data, confirming the durable RFS benefit and, importantly, showing no new or unexpected long-term safety signals.[32]
• A pooled safety analysis of the pivotal melanoma registration trials confirmed that the incidence of adverse events is highest in the first 6 months of treatment and generally declines thereafter, providing reassurance about the long-term tolerability in patients who successfully navigate the initial treatment period.[37]
• Long-term rollover studies, such as NCT03340506, are designed specifically to continue providing access to treatment and to collect long-term safety data for patients who have completed parent studies, further building the evidence base for chronic administration.[56]

Expert Synthesis and Clinical Recommendations

Trametinib has fundamentally altered the treatment landscape for cancers driven by BRAF V600 mutations. Its evolution from a single-agent therapy with transient benefit to a cornerstone of highly effective combination regimens underscores the success of rational drug design and biomarker-driven clinical development. The following synthesis provides key recommendations for its optimal use in clinical practice.

1. Patient Selection is Paramount: The efficacy of Trametinib-based therapy is exclusively confined to patients whose tumors harbor a BRAF V600E or V600K mutation. Therefore, the absolute prerequisite to considering this treatment is the confirmation of mutation status using a validated, high-sensitivity assay. The expansion of Trametinib's indications to be tumor-agnostic places a greater impetus on clinicians to perform comprehensive genomic profiling, such as next-generation sequencing (NGS), for patients with advanced or refractory solid tumors, regardless of histology. Identifying a BRAF V600 mutation can unlock a highly effective treatment option where none may have previously existed.

2. Combination Therapy is the Standard of Care: Except in exceedingly rare circumstances, Trametinib should be administered in combination with the BRAF inhibitor dabrafenib. The clinical evidence from pivotal trials like COMBI-d, COMBI-v, and COMBI-AD is unequivocal: the dual blockade provides superior efficacy in terms of response rate, progression-free survival, and overall survival compared to BRAF inhibitor monotherapy. This combination strategy more effectively suppresses the MAPK pathway, delays the onset of acquired resistance, and has become the established standard in all approved settings, from metastatic melanoma to pediatric glioma.

3. Proactive and Vigilant Toxicity Management is Essential: The success of Trametinib and dabrafenib therapy is inextricably linked to the clinician's ability to manage its unique and often challenging safety profile. The goal is to mitigate adverse events to maintain quality of life and, critically, to preserve dose intensity, which is correlated with clinical benefit. This requires a multidisciplinary effort and robust patient education on several key risks:

• Pyrexia: Patients must be educated to report fever immediately. Management protocols involving treatment interruption, antipyretics, and sometimes corticosteroids must be readily implemented.
• Ocular and Cardiac Monitoring: The mandated schedule for ophthalmologic exams and LVEF assessments must be strictly followed to detect potentially irreversible toxicities like RVO or symptomatic cardiomyopathy at the earliest possible stage.
• Administration and Storage: Clear instruction on taking the medication on an empty stomach and refrigerating the tablets is necessary to ensure consistent drug exposure and stability.

4. The Future is in Intelligent Combination and Sequencing: The investigational landscape clearly indicates that the future of Trametinib lies in its role as a versatile backbone for more complex therapeutic strategies. While the toxicity of triplet regimens with immunotherapy remains a challenge to overcome, these combinations hold the promise of achieving the rapid tumor control of targeted therapy with the durable responses of immunotherapy. Trials like DREAMseq will be crucial in defining the optimal sequence of these powerful modalities. Furthermore, the exploration of Trametinib in non-malignant conditions like AVMs, driven by the same underlying pathway biology, may open entirely new therapeutic avenues for MEK inhibition. The long-term follow-up data now available provides confidence in the durability of its benefits and the manageability of its long-term safety, solidifying its position as an indispensable tool in the armamentarium of modern oncology.

Works cited

1. Trametinib | C26H23FIN5O4 | CID 11707110 - PubChem, accessed July 15, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Trametinib
2. pmc.ncbi.nlm.nih.gov, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6570520/#:~:text=MECHANISM%20OF%20ACTION,-The%20MAP%20kinase&text=Trametinib%20is%20an%20orally%20available,cycle%20arrest%2C%20and%20induces%20apoptosis.
3. Trametinib - DermNet, accessed July 15, 2025, https://dermnetnz.org/topics/trametinib
4. Trametinib: A Targeted Therapy in Metastatic Melanoma - PMC - PubMed Central, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6570520/
5. Trametinib - Wikipedia, accessed July 15, 2025, https://en.wikipedia.org/wiki/Trametinib
6. Dabrafenib (Tafinlar®) + Trametinib (Mekinist®) - Melanoma Research Alliance, accessed July 15, 2025, https://www.curemelanoma.org/patient-eng/melanoma-treatment/options/dabrafenib-tafinlar-trametinib-mekinist
7. The history of FDA approval of dabrafenib and trametinib. Dabrafenib and trametinib have been approved by the FDA for monotherapy and combination therapy for BRAF V600 mutant solid tumors. - ResearchGate, accessed July 15, 2025, https://www.researchgate.net/figure/The-history-of-FDA-approval-of-dabrafenib-and-trametinib-Dabrafenib-and-trametinib-have_fig1_373708629
8. Trametinib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/drugs/DB08911
9. Mekinist (trametinib) FDA Approval History - Drugs.com, accessed July 15, 2025, https://www.drugs.com/history/mekinist.html
10. FDA approves dabrafenib–trametinib for BRAF-positive cancers - NCI, accessed July 15, 2025, https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors
11. Trametinib (GSK1120212, JTP-74057, CAS Number: 871700-17-3) | Cayman Chemical, accessed July 15, 2025, https://www.caymanchem.com/product/16292/trametinib
12. Trametinib (GSK1120212) | CAS:871700-17-3 | Manufacturer ChemFaces, accessed July 15, 2025, https://www.chemfaces.com/natural/Trametinib-CFN60051.html
13. EMA Recommends Granting a Marketing Authorisation for Trametinib for the Treatment of Low- and High-Grade Glioma | ESMO, accessed July 15, 2025, https://www.esmo.org/oncology-news/ema-recommends-granting-a-marketing-authorisation-for-trametinib-for-the-treatment-of-low-and-high-grade-glioma
14. Trametinib | CAS 871700-17-3 | SCBT - Santa Cruz Biotechnology, accessed July 15, 2025, https://www.scbt.com/p/trametinib-871700-17-3
15. Trametinib | CAS 871700-17-3 | Cayman Chemical | Biomol.com, accessed July 15, 2025, https://www.biomol.com/products/chemicals/biochemicals/trametinib-cay16292-25
16. Buy Online CAS Number 871700-17-3 - TRC - Trametinib | LGC Standards, accessed July 15, 2025, https://www.lgcstandards.com/US/en/p/TRC-C988930-50MG?trc=true
17. Trametinib tablets - [Product Monograph Template - Standard], accessed July 15, 2025, https://www.novartis.com/ca-en/sites/novartis_ca/files/mekinist_scrip_e_1.pdf
18. Generic Mekinist Availability - Drugs.com, accessed July 15, 2025, https://www.drugs.com/availability/generic-mekinist.html
19. This label may not be the latest approved by FDA. For current ..., accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204114s024lbl.pdf
20. trametinib - Cancer Care Ontario, accessed July 15, 2025, https://www.cancercareontario.ca/en/drugformulary/drugs/monograph/44331
21. New developments in the treatment of metastatic melanoma – role of dabrafenib–trametinib combination therapy - PubMed Central, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4075957/
22. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/28475671/
23. MEKINIST® (trametinib) tablets, for oral use - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204114s021lbl.pdf
24. Cancer Drug Interactions from Radboud UMC and University of Liverpool, accessed July 15, 2025, https://cancer-druginteractions.org/interactions/701/all
25. Mekinist, INN-trametinib - European Medicines Agency, accessed July 15, 2025, https://www.ema.europa.eu/en/documents/product-information/mekinist-epar-product-information_en.pdf
26. Drugs@FDA: Drug Product Mekinist (trametinib), NDA204114, Novartis Pharmaceuticals Corporation - PharmGKB, accessed July 15, 2025, https://www.pharmgkb.org/literature/15101887
27. Annotation of EMA Label for trametinib and BRAF - PharmGKB, accessed July 15, 2025, https://www.pharmgkb.org/labelAnnotation/PA166129450
28. GSK receives EU marketing authorisation for Mekinist™ (trametinib) for patients with unresectable or metastatic melanoma with a BRAF V600 mutation, accessed July 15, 2025, https://www.gsk.com/en-gb/media/press-releases/gsk-receives-eu-marketing-authorisation-for-mekinist-trametinib-for-patients-with-unresectable-or-metastatic-melanoma-with-a-braf-v600-mutation/
29. Mekinist | European Medicines Agency (EMA), accessed July 15, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/mekinist
30. Mekinist 2 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc), accessed July 15, 2025, https://www.medicines.org.uk/emc/product/5072/smpc
31. Novartis receives FDA approval of Tafinlar® + Mekinist® for adjuvant treatment of BRAF V600-mutant melanoma, accessed July 15, 2025, https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-tafinlar-mekinist-adjuvant-treatment-braf-v600-mutant-melanoma
32. Dr Long Highlights Long-Term Benefit of Dabrafenib/Trametinib in Melanoma, accessed July 15, 2025, https://www.targetedonc.com/view/dr-long-highlights-long-term-benefit-of-dabrafenib-trametinib-in-melanoma
33. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s009lbl.pdf
34. New Treatment Options in Oncology: FDA and EMA Drug Approvals in Q2 2022, accessed July 15, 2025, https://www.aptitudehealth.com/oncology-news/new-treatment-options-oncology-hematology-ema-fda/
35. In Brief: A New Indication for Dabrafenib (Tafinlar) and Trametinib (Mekinist) Combination Therapy (online only) - The Medical Letter, accessed July 15, 2025, https://secure.medicalletter.org/TML-article-1669f
36. FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation, accessed July 15, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation
37. Pooled analysis of safety over time and link between adverse events and efficacy across combination dabrafenib and trametinib (D+T) registration trials. - ASCO Publications, accessed July 15, 2025, https://ascopubs.org/doi/10.1200/JCO.2016.34.15_suppl.9534
38. FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma - PubMed Central, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10841289/
39. Trametinib (oral route) - Mayo Clinic, accessed July 15, 2025, https://www.mayoclinic.org/drugs-supplements/trametinib-oral-route/description/drg-20061171
40. Mekinist (trametinib) dosing, indications, interactions, adverse ..., accessed July 15, 2025, https://reference.medscape.com/drug/mekinist-trametinib-999854
41. Trametinib: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed July 15, 2025, https://www.rxlist.com/trametinib/generic-drug.htm
42. Trametinib: first global approval - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/23846731/
43. CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: APPLICATION NUMBER - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204114Orig1s000Approv.pdf
44. Trametinib (Mekinist®): RMP summary - Swissmedic, accessed July 15, 2025, https://www.swissmedic.ch/dam/swissmedic/de/dokumente/marktueberwachung/rmp/trametinib_mekinistrmpsummary.pdf.download.pdf/trametinib_mekinistrmpsummary.pdf
45. TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) | DTC and HCP, accessed July 15, 2025, https://us.tafinlarmekinist.com/
46. Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives - PMC - PubMed Central, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9688939/
47. A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma | ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT02967692
48. Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma | ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT02224781
49. Study Details | Trametinib With GSK2141795 in BRAF Wild-type Melanoma, accessed July 15, 2025, https://www.clinicaltrials.gov/study/NCT01941927?term=MEKINIST&viewType=Table&rank=4
50. A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors | ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT01938443?term=AREA%5BBasicSearch%5D(FAK)&rank=8
51. Phase II Clinical Trial of Trametinib and Low-Dose Dabrafenib in Advanced, Previously Treated BRAFV600/NRASQ61 Wild-Type Melanoma (TraMel-WT) - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/39374099/
52. Phase II Clinical Trial of Trametinib and Low-Dose Dabrafenib in Advanced, Previously Treated BRAFV600/NRASQ61 Wild-Type Melanoma (TraMel-WT) | JCO Precision Oncology - ASCO Publications, accessed July 15, 2025, https://ascopubs.org/doi/10.1200/PO.23.00493
53. Study Details | TraMel-WT: A Trial of Trametinib in Patients With Advanced Pretreated BRAFV600 Wild-type Melanoma | ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT04059224
54. Study Details | Trametinib in the Treatment of Complicated Extracranial Arterial Venous Malformation | ClinicalTrials.gov, accessed July 15, 2025, https://www.clinicaltrials.gov/study/NCT04258046
55. Clinical Trials Using Trametinib - NCI, accessed July 15, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/trametinib?pn=1
56. Dabrafenib and/or Trametinib Rollover Study - Novartis, accessed July 15, 2025, https://www.novartis.com/clinicaltrials/study/nct03340506