| Reference | [1]. N Engl J Med. 2020 Sep 17;383(12):1139-1148. doi: 10.1056/NEJMoa2005493. Epub 2020 Sep 2.<br />
Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.<br />
Dummer R(1), Hauschild A(1), Santinami M(1), Atkinson V(1), Mandalà M(1), Kirkwood JM(1), Chiarion Sileni V(1), Larkin J(1), Nyakas M(1), Dutriaux C(1), Haydon A(1), Robert C(1), Mortier L(1), Schachter J(1), Lesimple T(1), Plummer R(1), Dasgupta K(1), Gasal E(1), Tan M(1), Long GV(1), Schadendorf D(1).<br />
Author information: (1)From University Hospital Zurich Skin Cancer Center, Zurich, Switzerland (R.D.); University Hospital Schleswig-Holstein, Kiel (A. Hauschild), University Hospital Essen, Essen (D.S.), and German Cancer Consortium, Heidelberg (D.S.) – all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute-IRCCS, Padua (V.C.S.) – all in Italy; Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), Alfred Hospital, Melbourne, VIC (A. Haydon), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) – all in Australia; the Melanoma Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust, London (J.L.), and the Northern Centre for Cancer Care, Freeman Hospital and Newcastle University, Newcastle upon Tyne (R.P.) – both in the United Kingdom; Oslo University Hospital, the Norwegian Radium Hospital, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux (C.D.), Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Université de Lille, INSERM Unité 1189, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) – all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv – both in Israel (J.S.); Novartis Healthcare, Hyderabad, India (K.D.); and Novartis Pharmaceuticals, East Hanover, NJ (E.G., M.T.).<br />
BACKGROUND: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. METHODS: We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. RESULTS: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. CONCLUSIONS: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).<br />
DOI: 10.1056/NEJMoa2005493 PMID: 32877599 [Indexed for MEDLINE]<br />
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[2]. N Engl J Med. 2017 Nov 9;377(19):1813-1823. doi: 10.1056/NEJMoa1708539. Epub 2017 Sep 10.<br />
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.<br />
Long GV(1), Hauschild A(1), Santinami M(1), Atkinson V(1), Mandalà M(1), Chiarion-Sileni V(1), Larkin J(1), Nyakas M(1), Dutriaux C(1), Haydon A(1), Robert C(1), Mortier L(1), Schachter J(1), Schadendorf D(1), Lesimple T(1), Plummer R(1), Ji R(1), Zhang P(1), Mookerjee B(1), Legos J(1), Kefford R(1), Dummer R(1), Kirkwood JM(1).<br />
Author information: (1)From the Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals (G.V.L.), and Macquarie University, Melanoma Institute Australia, University of Sydney, and Westmead Hospital (R.K.), Sydney, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), and Alfred Hospital, Melbourne, VIC (A. Haydon) – all in Australia; University Hospital Schleswig-Holstein, Kiel (A. Hauschild), and University Hospital Essen, Essen, and the German Cancer Consortium, Heidelberg (D.S.) – all in Germany; Fondazione Istituto Nazionale Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute, Padua (V.C.-S.) – all in Italy; Rikshospitalet-Radiumhospitalet, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux (C.D.), Institute Gustave Roussy, Paris (C.R.), Université de Lille, INSERM Unité 1189, Centre Hospitalier Régional Universitaire de Lille, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) – all in France; Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel (J.S.); Royal Marsden NHS Foundation Trust, London (J. Larkin), and Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne (R.P.) – both in the United Kingdom; Novartis Pharmaceuticals, East Hanover, NJ (R.J., P.Z., B.M., J. Legos); University Hospital Zürich Skin Cancer Center, Zurich, Switzerland (R.D.); and the Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.).<br />
Comment in Nat Rev Clin Oncol. 2017 Nov;14(11):647. N Engl J Med. 2017 Nov 9;377(19):1888-1890. N Engl J Med. 2018 Feb 15;378(7):678. Br J Dermatol. 2018 Apr;178(4):817-820. N Engl J Med. 2019 Apr 4;380(14):1374-1376.<br />
BACKGROUND: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. RESULTS: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).<br />
DOI: 10.1056/NEJMoa1708539 PMID: 28891408 [Indexed for MEDLINE]<br />
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[3]. N Engl J Med. 2019 Aug 15;381(7):626-636. doi: 10.1056/NEJMoa1904059. Epub 2019 Jun 4.<br />
Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.<br />
Robert C(1), Grob JJ(1), Stroyakovskiy D(1), Karaszewska B(1), Hauschild A(1), Levchenko E(1), Chiarion Sileni V(1), Schachter J(1), Garbe C(1), Bondarenko I(1), Gogas H(1), Mandalá M(1), Haanen JBAG(1), Lebbé C(1), Mackiewicz A(1), Rutkowski P(1), Nathan PD(1), Ribas A(1), Davies MA(1), Flaherty KT(1), Burgess P(1), Tan M(1), Gasal E(1), Voi M(1), Schadendorf D(1), Long GV(1).<br />
Author information: (1)From Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Aix-Marseille University, Marseille (J.J.G.), and Assistance Publique-Hôpitaux de Paris Dermatology and Clinical Investigation Center, Unité 976, Université de Paris, Hôpital Saint-Louis, Paris (C.L.) – all in France; Moscow City Oncology Hospital, Moscow (D. Stroyakovskiy), and the Petrov Research Institute of Oncology, St. Petersburg (E.L.) – both in Russia; Przychodnia Lekarska Komed, Konin (B.K.), the University of Medical Sciences, Poznań (A.M.), and the Maria Skłodowska-Curie Institute-Oncology Center, Warsaw (P.R.) – all in Poland; the University Hospital Schleswig-Holstein, Kiel (A.H.), the Department of Dermatology, University of Tübingen, Tübingen (C.G.), University Hospital Essen, Essen (D. Schadendorf), and the German Cancer Consortium, Heidelberg (D. Schadendorf) – all in Germany; the Veneto Institute of Oncology, Padua (V.C.S.), and Papa Giovanni XXIII Hospital, Bergamo (M.M.) – both in Italy; the Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer (J.S.), and Sackler Medical School, Tel Aviv University, Tel Aviv (J.S.) – both in Israel; Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine (I.B.); Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens (H.G.); the Netherlands Cancer Institute, Amsterdam (J.B.A.G.H.); Mount Vernon Cancer Centre, Northwood, United Kingdom (P.D.N.); the University of California, Los Angeles, Los Angeles (A.R.); the University of Texas M.D. Anderson Cancer Center, Houston (M.A.D.); Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (K.T.F.); Novartis Pharma, Basel, Switzerland (P.B.); Novartis Pharmaceuticals, East Hanover, NJ (M.T., E.G., M.V.); and the Melanoma Institute Australia, the University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.).<br />
Comment in Strahlenther Onkol. 2019 Oct;195(10):940-942.<br />
BACKGROUND: Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).<br />
DOI: 10.1056/NEJMoa1904059 PMID: 31166680 [Indexed for MEDLINE]<br />
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[4]. Lancet Oncol. 2017 Oct;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4. Epub 2017 Sep 11.<br />
Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.<br />
Planchard D(1), Smit EF(2), Groen HJM(3), Mazieres J(4), Besse B(1), Helland Å(5), Giannone V(6), D'Amelio AM Jr(6), Zhang P(6), Mookerjee B(6), Johnson BE(7).<br />
Author information: (1)Gustave Roussy, Villejuif, France. (2)Vrije Universiteit VU Medical Centre, Amsterdam, Netherlands. (3)University of Groningen and University Medical Center Groningen, Groningen, Netherlands. (4)Rangueil-Larrey Hospital and Paul Sabatier University, Toulouse, France. (5)Oslo University Hospital, Department of Oncology, Norwegian Radium Hospital, Oslo, Norway. (6)Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. (7)Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: [email protected].<br />
Comment in Lancet Oncol. 2017 Oct;18(10):1286-1287. J Thorac Dis. 2018 Feb;10 (2):589-592.<br />
BACKGROUND: BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of dabrafenib plus trametinib treatment in previously untreated patients with BRAFV600E-mutant metastatic NSCLC. METHODS: In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (≥18 years of age) with previously untreated metastatic BRAFV600E-mutant NSCLC were enrolled into cohort C from 19 centres in eight countries within North America, Europe, and Asia. Patients received oral dabrafenib 150 mg twice per day plus oral trametinib 2 mg once per day until disease progression, unacceptable adverse events, consent withdrawal, or death. The primary endpoint was investigator-assessed overall response, defined as the percentage of patients who achieved a confirmed complete response or partial response per Response Evaluation Criteria In Solid Tumors version 1.1. The primary and safety analyses were by intention to treat in the protocol-defined population (previously untreated patients). The study is ongoing, but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634. FINDINGS: Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15·9 months (IQR 7·8-22·0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest). INTERPRETATION: Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAFV600E-mutant NSCLC. FUNDING: Novartis.<br />
DOI: 10.1016/S1470-2045(17)30679-4 PMID: 28919011 [Indexed for MEDLINE]<br />
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[5]. Clin Pharmacokinet. 2019 Apr;58(4):451-467. doi: 10.1007/s40262-018-0703-0.<br />
Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib.<br />
Puszkiel A(1), Noé G(2), Bellesoeur A(3)(4), Kramkimel N(5), Paludetto MN(1)(6), Thomas-Schoemann A(4)(7), Vidal M(7)(8), Goldwasser F(3), Chatelut E(1)(9)(10), Blanchet B(11)(12)(13).<br />
Author information: (1)Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France. (2)Department of Pharmacology and Toxicology, Bicetre Hospital, AP-HP, Kremlin Bicetre, France. (3)Department of Medical Oncology, CERIA, CARPEM, Cochin University Hospital, APHP, 75014, Paris, France. (4)Multidisciplinary Risk Assessment and Drug Monitoring Unit, CERIA, CARPEM, Cochin University Hospital, AP-HP, 75014, Paris, France. (5)Department of Dermatology, Cochin University Hospital, AP-HP, 75014, Paris, France. (6)Department of Pharmacy, Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France. (7)UMR8638 CNRS, Faculty of Pharmacy, University Paris Descartes, PRES Sorbonne Paris Cité, Paris, France. (8)Department of Pharmacokinetics and Pharmacochemistry, CERIA, CARPEM, Cochin University Hospital, AP-HP, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. (9)Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France. (10)Groupe de Pharmacologie Clinique Oncologique (GPCO), Paris, France. (11)UMR8638 CNRS, Faculty of Pharmacy, University Paris Descartes, PRES Sorbonne Paris Cité, Paris, France. [email protected]. (12)Department of Pharmacokinetics and Pharmacochemistry, CERIA, CARPEM, Cochin University Hospital, AP-HP, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. [email protected]. (13)Groupe de Pharmacologie Clinique Oncologique (GPCO), Paris, France. [email protected].<br />
Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75-300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug-drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.<br />
DOI: 10.1007/s40262-018-0703-0 PMID: 30094711 [Indexed for MEDLINE]
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