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Dirk Schadendorf - One of the best experts on this subject based on the ideXlab platform.
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patient reported outcomes in patients with resected high risk melanoma with brafv600e or brafv600k mutations treated with adjuvant dabrafenib plus Trametinib combi ad a randomised placebo controlled phase 3 trial
Lancet Oncology, 2019Co-Authors: Dirk Schadendorf, James Larkin, Axel Hauschild, Victoria Atkinson, Mario Santinami, Mario Mandala, Vanna Chiarionsileni, Marta Nyakas, C Dutriaux, Andrew HaydonAbstract:Summary Background In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF V600E or BRAF V600K mutations received adjuvant dabrafenib plus Trametinib or placebo. The primary analysis showed that dabrafenib plus Trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus Trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAF V600E or BRAF V600K mutations. Here, we report the patient-reported outcomes from COMBI-AD. Methods COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAF V600E or BRAF V600K mutations, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system, stratified by mutation type and disease stage, to receive oral dabrafenib (150 mg twice daily) plus oral Trametinib (2 mg once daily) or matching placebos for 12 months. Patients, physicians, and the investigators who analysed the data were masked to treatment allocation. The primary endpoint was relapse-free survival, reported elsewhere. Health-related quality of life, reported here, was a prespecified exploratory endpoint, and was assessed with the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in the intention-to-treat population. We used a mixed-model repeated-measures analysis to assess differences in health-related quality of life between groups. This study is registered with ClinicalTrials.gov, number NCT01682083. The trial is ongoing, but is no longer recruiting participants. Findings Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus Trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28–39) in the dabrafenib plus Trametinib group and 33 months (20·5–39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus Trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15–48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus Trametinib group (mean change −6·02, SD 20·57; p=0·0032) and the placebo group (−6·84, 20·86; p Interpretation These findings show that dabrafenib plus Trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting. Funding Novartis.
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paclitaxel with or without Trametinib or pazopanib in advanced wild type braf melanoma pacmel a multicentre open label randomised controlled phase ii trial
Annals of Oncology, 2019Co-Authors: V Urbonas, Dirk Schadendorf, Lisa Zimmer, Sarah Danson, Ernie Marshall, Pippa Corrie, M Wheater, E R Plummer, Cornelia Mauch, Claire ScudderAbstract:Abstract Background Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors Trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial. Patients and methods Patients were randomised (1 : 1 : 1) to paclitaxel alone or with Trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg Trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR). Results Participants were randomised to paclitaxel alone (n = 38), paclitaxel and Trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding Trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08–2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96–1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms. Conclusion In this phase II trial, adding Trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS. This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.
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functional and symptom impact of Trametinib versus chemotherapy in braf v600e advanced or metastatic melanoma quality of life analyses of the metric study
Annals of Oncology, 2014Co-Authors: Dirk Schadendorf, Piotr Rutkowski, Reinhard Dummer, Claus Garbe, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Mayur M. Amonkar, Kelly M Grotzinger, Pascal WolterAbstract:BACKGROUND In a randomized phase III study, Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. PATIENTS AND METHODS Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. RESULTS In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with Trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, Trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for Trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of Trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent. CONCLUSIONS This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that Trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
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functional and symptom impact of Trametinib versus chemotherapy in braf v600e advanced or metastatic melanoma quality of life analyses of the metric study
Annals of Oncology, 2014Co-Authors: Dirk Schadendorf, Piotr Rutkowski, Reinhard Dummer, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Mayur M. Amonkar, Kelly M Grotzinger, C Garbe, Pascal WolterAbstract:ABSTRACT Background In a randomized phase III study, Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Patients and methods Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. Results In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4–5 points with chemotherapy but improved by 2–3 points with Trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8–11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4–8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, Trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for Trametinib decreased from baseline (symptoms improved) for pain (11–12 points), insomnia (10–12 points), and appetite loss (1–5 points), whereas those for diarrhea worsened (15–16 points). Mixed-model repeated-measures analyses showed significant (P Conclusions This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that Trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
James Larkin - One of the best experts on this subject based on the ideXlab platform.
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patient reported outcomes in patients with resected high risk melanoma with brafv600e or brafv600k mutations treated with adjuvant dabrafenib plus Trametinib combi ad a randomised placebo controlled phase 3 trial
Lancet Oncology, 2019Co-Authors: Dirk Schadendorf, James Larkin, Axel Hauschild, Victoria Atkinson, Mario Santinami, Mario Mandala, Vanna Chiarionsileni, Marta Nyakas, C Dutriaux, Andrew HaydonAbstract:Summary Background In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF V600E or BRAF V600K mutations received adjuvant dabrafenib plus Trametinib or placebo. The primary analysis showed that dabrafenib plus Trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus Trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAF V600E or BRAF V600K mutations. Here, we report the patient-reported outcomes from COMBI-AD. Methods COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAF V600E or BRAF V600K mutations, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system, stratified by mutation type and disease stage, to receive oral dabrafenib (150 mg twice daily) plus oral Trametinib (2 mg once daily) or matching placebos for 12 months. Patients, physicians, and the investigators who analysed the data were masked to treatment allocation. The primary endpoint was relapse-free survival, reported elsewhere. Health-related quality of life, reported here, was a prespecified exploratory endpoint, and was assessed with the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in the intention-to-treat population. We used a mixed-model repeated-measures analysis to assess differences in health-related quality of life between groups. This study is registered with ClinicalTrials.gov, number NCT01682083. The trial is ongoing, but is no longer recruiting participants. Findings Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus Trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28–39) in the dabrafenib plus Trametinib group and 33 months (20·5–39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus Trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15–48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus Trametinib group (mean change −6·02, SD 20·57; p=0·0032) and the placebo group (−6·84, 20·86; p Interpretation These findings show that dabrafenib plus Trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting. Funding Novartis.
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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
Annals of Oncology, 2017Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, James Larkin, Claus Garbe, T Jouary, Keith T Flaherty, F De Braud, Axel HauschildAbstract:ABSTRACT Background Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and Trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus Trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus Trametinib (n= 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus Trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus Trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and Conclusions These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus Trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
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Combination dabrafenib and Trametinib in the management of advanced melanoma with BRAFV600 mutations
Expert opinion on pharmacotherapy, 2016Co-Authors: Lavinia Spain, Maximilian Julve, James LarkinAbstract:ABSTRACTIntroduction: In the 40–50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as Trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.Areas covered: This article summarizes the mechanism of action of the combination of dabrafenib and Trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.Expert opinion: Combination therapy with dabrafenib and Trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of Trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less ...
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dabrafenib and Trametinib versus dabrafenib and placebo for val600 braf mutant melanoma a multicentre double blind phase 3 randomised controlled trial
The Lancet, 2015Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, F De Braud, James Larkin, Claus Garbe, T Jouary, Axel HauschildAbstract:Summary Background Previously, a study of ours showed that the combination of dabrafenib and Trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and Trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and Trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2–not reached) in the dabrafenib and Trametinib group versus 18·7 months (15·2–23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55–0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and Trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0–13·9) in the dabrafenib and Trametinib group and 8·8 months (5·9–9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53–0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and Trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and Trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and Trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and Trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and Trametinib in combination with immunotherapies are ongoing. Funding GlaxoSmithKline.
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PACMEL: A phase 1 dose escalation trial of Trametinib (GSK1120212) in combination with paclitaxel
European journal of cancer (Oxford England : 1990), 2014Co-Authors: Nicholas Coupe, James Larkin, Pippa Corrie, Mirela Hategan, Martin Gore, Avinash Gupta, Adelyn Wise, Sam Suter, Cristian Ciria, Sharon LoveAbstract:Abstract Background We sought to determine the maximal tolerated dose of the MEK inhibitor Trametinib with weekly paclitaxel, with a view to exploring the combination’s activity in melanoma lacking a BRAF V600 mutation. Methods In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m 2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of Trametinib (to a maximum 2 mg orally (PO) daily), following a 3 + 3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease. Findings 15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of Trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8–7.8 months) and overall survival, 14.1 months (95% CI 4.6–not reached). Interpretation Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation.
Claus Garbe - One of the best experts on this subject based on the ideXlab platform.
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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
Annals of Oncology, 2017Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, James Larkin, Claus Garbe, T Jouary, Keith T Flaherty, F De Braud, Axel HauschildAbstract:ABSTRACT Background Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and Trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus Trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus Trametinib (n= 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus Trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus Trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and Conclusions These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus Trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
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dabrafenib and Trametinib versus dabrafenib and placebo for val600 braf mutant melanoma a multicentre double blind phase 3 randomised controlled trial
The Lancet, 2015Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, F De Braud, James Larkin, Claus Garbe, T Jouary, Axel HauschildAbstract:Summary Background Previously, a study of ours showed that the combination of dabrafenib and Trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and Trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and Trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2–not reached) in the dabrafenib and Trametinib group versus 18·7 months (15·2–23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55–0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and Trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0–13·9) in the dabrafenib and Trametinib group and 8·8 months (5·9–9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53–0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and Trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and Trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and Trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and Trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and Trametinib in combination with immunotherapies are ongoing. Funding GlaxoSmithKline.
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combined braf and mek inhibition versus braf inhibition alone in melanoma
The New England Journal of Medicine, 2014Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, F De Braud, James Larkin, Claus Garbe, T Jouary, Axel Hauschild, J J GrobAbstract:BACKGROUND Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and Trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS The median progression-free survival was 9.3 months in the dabrafenib–Trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib–Trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib–Trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib–Trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib–Trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib–Trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib–Trametinib group. CONCLUSIONS A combination of dabrafenib and Trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.)
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functional and symptom impact of Trametinib versus chemotherapy in braf v600e advanced or metastatic melanoma quality of life analyses of the metric study
Annals of Oncology, 2014Co-Authors: Dirk Schadendorf, Piotr Rutkowski, Reinhard Dummer, Claus Garbe, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Mayur M. Amonkar, Kelly M Grotzinger, Pascal WolterAbstract:BACKGROUND In a randomized phase III study, Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. PATIENTS AND METHODS Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. RESULTS In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with Trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, Trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for Trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of Trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent. CONCLUSIONS This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that Trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
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improved survival with mek inhibition in braf mutated melanoma
The New England Journal of Medicine, 2012Co-Authors: Keith T Flaherty, Piotr Rutkowski, Claus Garbe, Caroline Robert, Peter Hersey, Paul C Nathan, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Peter MohrAbstract:BACKGROUND: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either Trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received Trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive Trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS: Median progression-free survival was 4.8 months in the Trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the Trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the Trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the Trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. CONCLUSIONS: Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
Piotr Rutkowski - One of the best experts on this subject based on the ideXlab platform.
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Trametinib: a MEK inhibitor for management of metastatic melanoma
OncoTargets and therapy, 2015Co-Authors: Iwona Lugowska, Hanna Koseła-paterczyk, Katarzyna Kozak, Piotr RutkowskiAbstract:This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor Trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of Trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of Trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-free survival in favor of Trametinib over standard dacarbazine or paclitaxel chemotherapy. Therefore, Trametinib was approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with V600E-mutated metastatic melanoma. Progression-free survival and response rates for Trametinib monotherapy were lower than those noted with BRAF inhibitors. The second step in developing Trametinib was to use the combination of Trametinib with the BRAF inhibitor, eg, dabrafenib, to postpone the progression on MEK or BRAF inhibitors. The recently published data showed significant improvement in overall survival and progression-free survival in favor of the combination of Trametinib and dabrafenib over vemurafenib therapy or dabrafenib alone, with good tolerance. The US Food and Drug Administration has approved the combination of dabrafenib (150 mg orally twice daily) and Trametinib (2 mg orally once daily) for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma, and their use seems to be currently the best approach. While BRAF-MEK inhibition is a standard, molecular targeted therapy in BRAF-mutated melanomas, its future utility has to be established in the rapidly changing landscape of immunotherapeutics.
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functional and symptom impact of Trametinib versus chemotherapy in braf v600e advanced or metastatic melanoma quality of life analyses of the metric study
Annals of Oncology, 2014Co-Authors: Dirk Schadendorf, Piotr Rutkowski, Reinhard Dummer, Claus Garbe, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Mayur M. Amonkar, Kelly M Grotzinger, Pascal WolterAbstract:BACKGROUND In a randomized phase III study, Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. PATIENTS AND METHODS Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. RESULTS In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with Trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, Trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for Trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of Trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent. CONCLUSIONS This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that Trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
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functional and symptom impact of Trametinib versus chemotherapy in braf v600e advanced or metastatic melanoma quality of life analyses of the metric study
Annals of Oncology, 2014Co-Authors: Dirk Schadendorf, Piotr Rutkowski, Reinhard Dummer, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Mayur M. Amonkar, Kelly M Grotzinger, C Garbe, Pascal WolterAbstract:ABSTRACT Background In a randomized phase III study, Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Patients and methods Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. Results In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4–5 points with chemotherapy but improved by 2–3 points with Trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8–11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4–8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, Trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for Trametinib decreased from baseline (symptoms improved) for pain (11–12 points), insomnia (10–12 points), and appetite loss (1–5 points), whereas those for diarrhea worsened (15–16 points). Mixed-model repeated-measures analyses showed significant (P Conclusions This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that Trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
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improved survival with mek inhibition in braf mutated melanoma
The New England Journal of Medicine, 2012Co-Authors: Keith T Flaherty, Piotr Rutkowski, Claus Garbe, Caroline Robert, Peter Hersey, Paul C Nathan, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Peter MohrAbstract:BACKGROUND: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either Trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received Trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive Trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS: Median progression-free survival was 4.8 months in the Trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the Trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the Trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the Trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. CONCLUSIONS: Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
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improved survival with mek inhibition in braf mutated melanoma for the metric study group
Flaherty K T; Robert C; Hersey P; Nathan P; Garbe C; Milhem M; Demidov L V; Hassel J C; Rutkowski P; Mohr P; Dummer R; Trefzer U; Larkin J; Utikal J; , 2012Co-Authors: Keith T Flaherty, Piotr Rutkowski, Claus Garbe, Caroline Robert, Peter Hersey, Paul C Nathan, Mohammed M Milhem, Lev V Demidov, Jessica C Hassel, Peter MohrAbstract:Background Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. Methods In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either Trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received Trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive Trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. Results Median progression-free survival was 4.8 months in the Trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the Trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the Trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54;95% CI, 0.32 to 0.92; P = 0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the Trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. Conclusions Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials .gov number, NCT01245062.)
Axel Hauschild - One of the best experts on this subject based on the ideXlab platform.
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patient reported outcomes in patients with resected high risk melanoma with brafv600e or brafv600k mutations treated with adjuvant dabrafenib plus Trametinib combi ad a randomised placebo controlled phase 3 trial
Lancet Oncology, 2019Co-Authors: Dirk Schadendorf, James Larkin, Axel Hauschild, Victoria Atkinson, Mario Santinami, Mario Mandala, Vanna Chiarionsileni, Marta Nyakas, C Dutriaux, Andrew HaydonAbstract:Summary Background In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF V600E or BRAF V600K mutations received adjuvant dabrafenib plus Trametinib or placebo. The primary analysis showed that dabrafenib plus Trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus Trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAF V600E or BRAF V600K mutations. Here, we report the patient-reported outcomes from COMBI-AD. Methods COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAF V600E or BRAF V600K mutations, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system, stratified by mutation type and disease stage, to receive oral dabrafenib (150 mg twice daily) plus oral Trametinib (2 mg once daily) or matching placebos for 12 months. Patients, physicians, and the investigators who analysed the data were masked to treatment allocation. The primary endpoint was relapse-free survival, reported elsewhere. Health-related quality of life, reported here, was a prespecified exploratory endpoint, and was assessed with the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in the intention-to-treat population. We used a mixed-model repeated-measures analysis to assess differences in health-related quality of life between groups. This study is registered with ClinicalTrials.gov, number NCT01682083. The trial is ongoing, but is no longer recruiting participants. Findings Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus Trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28–39) in the dabrafenib plus Trametinib group and 33 months (20·5–39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus Trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15–48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus Trametinib group (mean change −6·02, SD 20·57; p=0·0032) and the placebo group (−6·84, 20·86; p Interpretation These findings show that dabrafenib plus Trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting. Funding Novartis.
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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
Annals of Oncology, 2017Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, James Larkin, Claus Garbe, T Jouary, Keith T Flaherty, F De Braud, Axel HauschildAbstract:ABSTRACT Background Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and Trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus Trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus Trametinib (n= 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus Trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus Trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and Conclusions These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus Trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
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dabrafenib and Trametinib versus dabrafenib and placebo for val600 braf mutant melanoma a multicentre double blind phase 3 randomised controlled trial
The Lancet, 2015Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, F De Braud, James Larkin, Claus Garbe, T Jouary, Axel HauschildAbstract:Summary Background Previously, a study of ours showed that the combination of dabrafenib and Trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and Trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and Trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2–not reached) in the dabrafenib and Trametinib group versus 18·7 months (15·2–23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55–0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and Trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0–13·9) in the dabrafenib and Trametinib group and 8·8 months (5·9–9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53–0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and Trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and Trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and Trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and Trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and Trametinib in combination with immunotherapies are ongoing. Funding GlaxoSmithKline.
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combined braf and mek inhibition versus braf inhibition alone in melanoma
The New England Journal of Medicine, 2014Co-Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, E Levchenko, F De Braud, James Larkin, Claus Garbe, T Jouary, Axel Hauschild, J J GrobAbstract:BACKGROUND Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and Trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS The median progression-free survival was 9.3 months in the dabrafenib–Trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib–Trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib–Trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib–Trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib–Trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib–Trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib–Trametinib group. CONCLUSIONS A combination of dabrafenib and Trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.)
