trametinib
Sources réglementaires consultées
Indications approuvées
- Monothérapie uniquement pour mélanome BRAF V600E/K non résécable ou métastatique sans traitement préalable par inhibiteur BRAF. Avec dabrafénib : mélanome BRAF V600E/K non résécable/métastatique ou adjuvant après résection ganglionnaire positive ; CBNPC métastatique BRAF V600E ; cancer anaplasique thyroïdien BRAF V600E ; tumeurs solides BRAF V600E dès 1 an sans alternative, sous approbation accélérée après progression ; gliome de bas grade dès 1 an nécessitant un traitement systémique. Ne pas utiliser dans le cancer colorectal ni BRAF sauvage.
Contre-indications
Absolues
- CIMA : hypersensibilité à la substance active ou aux excipients ; l’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- Surveiller la FEVG au départ, à 1 mois puis tous les 2–3 mois. Arrêter en cas d’insuffisance cardiaque symptomatique ou baisse absolue >20 % depuis le départ et également sous la limite inférieure normale. Surveiller hémorragie, colite/perforation et MTEV ; une embolie pulmonaire menaçante impose l’arrêt. — OpenFDA, set_id 0002ad27-779d-42ab-83b5-bc65453412a1
- Examen oculaire initial et en cas de symptômes : occlusion veineuse rétinienne impose l’arrêt ; décollement de l’épithélium pigmentaire impose la suspension. Arrêter pour PID. En association, gérer la fièvre en suspendant les deux médicaments et en évaluant infection et fonction rénale. — OpenFDA, set_id 0002ad27-779d-42ab-83b5-bc65453412a1
- Toxicité cutanée : arrêter pour grade 2 intolérable ou grade 3–4 sans amélioration en 3 semaines ; surveiller SJS et DRESS. Contrôler la glycémie en cas de diabète ou hyperglycémie. En cas de suspicion de lymphohistiocytose hémophagocytaire, suspendre ; si confirmée, arrêter. — OpenFDA, set_id 0002ad27-779d-42ab-83b5-bc65453412a1
Effets indésirables
Communs (≥1%)
éruption cutanée · diarrhée · fièvre · nausées · frissons · œdème périphérique
Grossesse et allaitement
Vérifier la grossesse. Les femmes doivent utiliser une contraception pendant et 4 mois après. Ne pas allaiter pendant ni 4 mois après. Peut altérer la fertilité féminine et masculine.
Bibliographie récente (PubMed)
Melanoma, the fifth most common cancer in the US, has increased from 8.8 per 100 000 in 1975 to 28.42 per 100 000 in 2022. Cutaneous melanoma comprises 94% of cases, with 104 960 US cases projected for 2025. Cutaneous melanoma presents as a new, changing, or irregularly pigmented skin lesion. Cutaneous melanoma subtypes include superficial spreading (≈70%), lentigo maligna (≈15%), nodular (≈5%), desmoplastic (≈4%), amelanotic (2%-8%), spitzoid (<2%), and acral (≈1%). Risk factors for cutaneous melanoma include UV radiation exposure, skin type (eg, skin that always burns, never tans), presence of benign and atypical nevi, and personal or family history of melanoma. Primary prevention consists of avoiding direct sunlight and indoor tanning, and photoprotection (sunscreen and sun-protective clothing). Based on United States Cancer Statistics data from 1999 to 2021, 77% of patients with cutaneous melanoma had localized disease (involving only the primary site), 9.5% had regional (nodal) disease, 4.7% had distant metastasis, and 8.8% were unstaged. Melanoma staging, which includes tumor thickness and ulceration and presence of lymph node or distant metastasis, ranges from stage 0 (melanoma in situ) to stage IV (distant metastasis). Localized melanoma (stage IA-IIA) is surgically excised, with margins of 0.5 cm to 2 cm based on depth of invasion. Sentinel lymph node biopsy is recommended for cutaneous melanoma that is ulcerated or 0.8 mm or more thick. Following surgery, patients with stage IIB-C melanoma have improved recurrence-free survival with adjuvant anti-PD-1 immunotherapy compared with placebo (hazard ratio [HR] for recurrence or death, 0.62 [95% CI, 0.49-0.79] for pembrolizumab and 0.42 [95% CI, 0.30-0.59] for nivolumab). For stage III disease, recurrence risk is decreased with nivolumab (HR, 0.72 [95% CI, 0.60-0.86]), pembrolizumab (HR, 0.61 [95% CI, 0.51-0.72]), or BRAF + MEK inhibitor therapy (dabrafenib + trametinib) (HR, 0.52 [95% CI, 0.43-0.63]). First-lin
In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAFV600E-mutant solid tumours, except for BRAFV600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAFV600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.
Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated. Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority
The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival. We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival. The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports. After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients
Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy. In this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival. A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy. Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer pr