Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD). (COMBI-AD)

COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection

This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus 2 placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk (Stage IIIa [lymph node metastasis >1 mm], IIIb or IIIc) cutaneous melanoma were screened for eligibility. Approximately 852 patients were planned to be randomized in a 1:1 ratio, stratified by BRAF mutation status (V600E, V600K) and stage of disease (Stage IIIa, IIIb, IIIc). Patients received either dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]) combination therapy or 2 matching placebos (one each for dabrafenib and trametinib) for 12 months or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent. Patients were followed for disease recurrence and survival during and after the treatment period. The study did not permit crossover. Doses of study treatment could be modified and/or interrupted for management of toxicities associated with study treatment.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: Dabrafenib; Drug: Trametinib; Drug: Placebos

Detailed Description

The study periods were follows:

1. Screening: Assessments were to be completed within 28 days of randomization.
2. Treatment: The treatment period was 12 months. Discontinuation of study treatment could occur earlier than 12 months for disease recurrence, death, unacceptable toxicity or withdrawal of consent.
3. Post treatment follow-up (before recurrence): Patients were to be followed for disease recurrence every 3 months after the end of treatment until Month 24, every 6 months after Month 24 and annually after Month 60 (365 days +/- 14 days from last visit).
4. Post treatment follow-up (after recurrence): After disease recurrence patients remained on study for follow-up assessments every 3 months until Month 24, every 6 months after Month 24, and annually after Month 60 (365 days +/- 14 days from last visit).

• Study Type: Interventional
• Enrollment (Actual): 870
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1125ABD
    • Novartis Investigative Site
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, C1426ANZ
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Gateshead, New South Wales, Australia, 2290
      • Novartis Investigative Site
    • North Sydney, New South Wales, Australia, 2060
      • Novartis Investigative Site
    • Tweed Heads, New South Wales, Australia, 2485
      • Novartis Investigative Site
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • Queensland
    • Greenslopes, Queensland, Australia, 4120
      • Novartis Investigative Site
    • Woolloongabba, Queensland, Australia, 4102
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Novartis Investigative Site
    • Heidelberg, Victoria, Australia, 3084
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia, 3004
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Graz, Austria, 8036
    • Novartis Investigative Site
  • Linz, Austria, A-4010
    • Novartis Investigative Site
  • Salzburg, Austria, A-5020
    • Novartis Investigative Site
  • Vienna, Austria, 1090
    • Novartis Investigative Site
  • Wels, Austria, A-4600
    • Novartis Investigative Site
• Belgium
  • Brussels, Belgium, 1200
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liège, Belgium, 4000
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
• Brazil
  • Paraná
    • Curitiba, Paraná, Brazil, 81520-060
      • Novartis Investigative Site
  • Rio Grande do Sul
    • Ijuí, Rio Grande do Sul, Brazil, 98700
      • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Novartis Investigative Site
    • Oshawa, Ontario, Canada, L1G 2B9
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
  • Quebec
    • Québec, Quebec, Canada, G1J 1Z4
      • Novartis Investigative Site
• Czechia
  • Brno, Czechia, 656 53
    • Novartis Investigative Site
  • Prague, Czechia, 128 08
    • Novartis Investigative Site
  • Prague, Czechia, 100 34
    • Novartis Investigative Site
  • Zlín, Czechia, 76275
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• Denmark
  • Arhus C, Denmark, 8000
    • Novartis Investigative Site
  • Herlev, Denmark, 2730
    • Novartis Investigative Site
  • Odense, Denmark, 5000 C
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• France
  • Bordeaux, France, 33075
    • Novartis Investigative Site
  • Boulogne-Billancourt, France, 92100
    • Novartis Investigative Site
  • Brest, France, 29609
    • Novartis Investigative Site
  • Dijon, France, 21079
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
  • Marseille, France, 13385
    • Novartis Investigative Site
  • Montpellier, France, 34295
    • Novartis Investigative Site
  • Nice, France, 06202
    • Novartis Investigative Site
  • Paris, France, 75014
    • Novartis Investigative Site
  • Paris, France, 75475
    • Novartis Investigative Site
  • Pierre-Bénite, France, 69495
    • Novartis Investigative Site
  • Reims, France, 51092
    • Novartis Investigative Site
  • Rennes, France, 35042
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
  • Tours, France, 37044
    • Novartis Investigative Site
  • Villejuif, France, 94805
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10249
    • Novartis Investigative Site
  • Baden-Wurttemberg
    • Freiburg im Breisgau, Baden-Wurttemberg, Germany, 79104
      • Novartis Investigative Site
    • Heilbronn, Baden-Wurttemberg, Germany, 74078
      • Novartis Investigative Site
    • Mannheim, Baden-Wurttemberg, Germany, 68167
      • Novartis Investigative Site
    • Tübingen, Baden-Wurttemberg, Germany, 72076
      • Novartis Investigative Site
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Novartis Investigative Site
  • Bavaria
    • Munich, Bavaria, Germany, 80337
      • Novartis Investigative Site
    • Nuremberg, Bavaria, Germany, 90419
      • Novartis Investigative Site
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
    • Würzburg, Bavaria, Germany, 97080
      • Novartis Investigative Site
  • Hesse
    • Darmstadt, Hesse, Germany, 64297
      • Novartis Investigative Site
    • Marburg, Hesse, Germany, 35033
      • Novartis Investigative Site
    • Wiesbaden, Hesse, Germany, 65199
      • Novartis Investigative Site
  • Lower Saxony
    • Hanover, Lower Saxony, Germany, 30625
      • Novartis Investigative Site
  • Mecklenburg-Vorpommern
    • Schwerin, Mecklenburg-Vorpommern, Germany, 19049
      • Novartis Investigative Site
  • North Rhine-Westphalia
    • Bochum, North Rhine-Westphalia, Germany, 44791
      • Novartis Investigative Site
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Novartis Investigative Site
    • Essen, North Rhine-Westphalia, Germany, 45147
      • Novartis Investigative Site
  • Rhineland-Palatinate
    • Mainz, Rhineland-Palatinate, Germany, 55131
      • Novartis Investigative Site
  • Saxony-Anhalt
    • Magdeburg, Saxony-Anhalt, Germany, 39120
      • Novartis Investigative Site
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Novartis Investigative Site
    • Lübeck, Schleswig-Holstein, Germany, 23538
      • Novartis Investigative Site
  • Thuringia
    • Erfurt, Thuringia, Germany, 99089
      • Novartis Investigative Site
    • Gera, Thuringia, Germany, 07548
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 11527
    • Novartis Investigative Site
  • Thessaloniki, Greece, 54622
    • Novartis Investigative Site
  • Thessaloniki, Greece, 56429
    • Novartis Investigative Site
• Israel
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
• Italy
  • Lazio
    • Rome, Lazio, Italy, 00167
      • Novartis Investigative Site
  • Liguria
    • Genoa, Liguria, Italy, 16132
      • Novartis Investigative Site
  • Lombardy
    • Bergamo, Lombardy, Italy, 24127
      • Novartis Investigative Site
    • Milan, Lombardy, Italy, 20133
      • Novartis Investigative Site
    • Milan, Lombardy, Italy, 20141
      • Novartis Investigative Site
  • Piedmont
    • Candiolo, Piedmont, Italy, 10060
      • Novartis Investigative Site
  • Tuscany
    • Pisa, Tuscany, Italy, 56126
      • Novartis Investigative Site
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Novartis Investigative Site
• Japan
  • Shizuoka, Japan, 411-8777
    • Novartis Investigative Site
  • Tokyo, Japan, 104-0045
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Leeuwarden, Netherlands, 8934 AD
    • Novartis Investigative Site
  • Maastricht, Netherlands, 6229 HX
    • Novartis Investigative Site
  • Nijmegen, Netherlands, 6525 GA
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3015 GD
    • Novartis Investigative Site
• New Zealand
  • Auckland, New Zealand, 0622
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0310
    • Novartis Investigative Site
  • Ålesund, Norway, 6026
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80-215
    • Novartis Investigative Site
  • Konin, Poland, 62-500
    • Novartis Investigative Site
  • Poznan, Poland, 60-693
    • Novartis Investigative Site
  • Warsaw, Poland, 02-781
    • Novartis Investigative Site
• Russia
  • Chelyabinsk, Russia, 454087
    • Novartis Investigative Site
  • Moscow, Russia, 115478
    • Novartis Investigative Site
  • Moscow, Russia, 143423
    • Novartis Investigative Site
  • Ryazan, Russia, 390011
    • Novartis Investigative Site
  • Saint Petersburg, Russia, 197758
    • Novartis Investigative Site
  • Saint Petersburg, Russia, 198255
    • Novartis Investigative Site
  • Saint Petersburg, Russia, 191014
    • Novartis Investigative Site
  • Volgograd, Russia, 400138
    • Novartis Investigative Site
• Spain
  • Badalona, Spain, 08916
    • Novartis Investigative Site
  • Barcelona, Spain, 08035
    • Novartis Investigative Site
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Donostia / San Sebastian, Spain, 20014
    • Novartis Investigative Site
  • Las Palmas de Gran Canaria, Spain, 35016
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Palma de Mallorca, Spain, 07198
    • Novartis Investigative Site
  • Pamplona, Spain, 31008
    • Novartis Investigative Site
  • Santander, Spain, 39008
    • Novartis Investigative Site
  • Valencia, Spain, 46014
    • Novartis Investigative Site
• Sweden
  • Gothenburg, Sweden, SE-413 45
    • Novartis Investigative Site
  • Lund, Sweden, SE-221 85
    • Novartis Investigative Site
  • Stockholm, Sweden, SE-171 76
    • Novartis Investigative Site
  • Uppsala, Sweden, SE-751 85
    • Novartis Investigative Site
• Switzerland
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
  • Chur, Switzerland, 7000
    • Novartis Investigative Site
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taoyuan District, Taiwan, 33305
    • Novartis Investigative Site
• United Kingdom
  • Exeter, United Kingdom, EX2 5DW
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G12 0YN
    • Novartis Investigative Site
  • Guildford, United Kingdom, GU2 7XX
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • London, United Kingdom, SW3 6JJ
    • Novartis Investigative Site
  • London, United Kingdom, NW3 2QG
    • Novartis Investigative Site
  • London, United Kingdom, W1G 6AD
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Novartis Investigative Site
  • Norwich, United Kingdom, NR4 7UY
    • Novartis Investigative Site
  • Preston, United Kingdom, PR2 9HT
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Novartis Investigative Site
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35243
      • Novartis Investigative Site
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Novartis Investigative Site
  • California
    • San Francisco, California, United States, 94115
      • Novartis Investigative Site
    • San Francisco, California, United States, 94143
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
  • Florida
    • Lake Worth, Florida, United States, 33461
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32806
      • Novartis Investigative Site
    • Tampa, Florida, United States, 33612
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Novartis Investigative Site
    • Atlanta, Georgia, United States, 30341
      • Novartis Investigative Site
  • Maryland
    • Lutherville-Timonium, Maryland, United States, 21093
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Novartis Investigative Site
    • Boston, Massachusetts, United States, 02115
      • Novartis Investigative Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48019
      • Novartis Investigative Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Novartis Investigative Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Novartis Investigative Site
  • Oregon
    • Portland, Oregon, United States, 97123
      • Novartis Investigative Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• At least 18 years of age
• Completely resected histologically confirmed high-risk (Stage IIIa [lymph node metastasis > 1 mm], IIIb or IIIc) cutaneous melanoma determined to be V600E/K mutation positive using the bioMerieux (bMX) THxID BRAF Assay by a central laboratory. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma were eligible
• Must be surgically rendered free of disease (defined as the date of the most recent surgery) no more than 12 weeks before randomization
• Recovered from definitive surgery (e.g., no uncontrolled wound infections or indwelling drains)
• ECOG Performance Status of 0-1
• Had adequate hematologic, hepatic, renal and cardiac function.

Key Exclusion Criteria:

• Known mucosal or ocular melanoma or the presence of unresectable in-transit metastases
• Evidence of distant metastatic disease on Screening evaluation
• Prior anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) including radiotherapy for melanoma. Prior surgery for melanoma was allowed

• History of another malignancy including melanoma or a concurrent malignancy. Patients who previously had Stage III melanoma or any malignancy with confirmed activating RAS mutation at any time were not eligible. Exceptions to this include:

  • Patients with a history of any malignancy that had been disease-free for at least 5 years were eligible except those with confirmed activating RAS mutations
  • Patients with a history of completely resected non-melanoma skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma) were eligible irrespective of the time since the resection
  • Patients with successfully treated in situ carcinoma were eligible
  • Patients presenting with multiple primary melanomas were eligible only if the lesions were concurrent. Patients who had concurrent multiple primary melanomas that were "distant" were eligible provided each lesion was considered local disease or resectable regional disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dabrafenib and trametinib; Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Drug: Dabrafenib; Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt); Other Names: GSK2118436; Drug: Trametinib; Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate); Other Names: GSK1120212
Placebo Comparator: Dabrafenib and trametinib placebos; Subjects received matching placebos orally for 12 months	Drug: Placebos; The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Relapse-free Survival (RFS) Events	Relapse-Free Survival (RFS) was defined as the time from randomization to disease recurrence or death from any cause. RFS events included loco-regional recurrence, distant metastases, new primary melanoma, and death without prior documented recurrence; such deaths were counted as events and not censored. Patients without an event at the analysis cut-off (30-Jun-2017) were censored at the date of the last radiological or non-radiological efficacy assessment. Patients lost to follow-up before recurrence or who initiated subsequent anti-cancer therapy prior to recurrence were censored at the last efficacy assessment before loss to follow-up or therapy initiation. Events after prolonged loss to follow-up were handled per the analysis plan. Malignancies other than new primary melanoma were not considered RFS events and, except for basal cell carcinoma, were reported as serious adverse events. Tumor tissue from any new primary cancer was collected for biomarker analyses.	Approximately 4 years
Relapse-free Survival (RFS)	Relapse-Free Survival (RFS) was defined as the time from randomization to disease recurrence or death from any cause. RFS events included loco-regional recurrence, distant metastases, new primary melanoma, and death without prior documented recurrence; such deaths were counted as events and not censored. Patients without an event at the analysis cut-off (30-Jun-2017) were censored at the date of the last radiological or non-radiological efficacy assessment. Patients lost to follow-up before recurrence or who initiated subsequent anti-cancer therapy prior to recurrence were censored at the last efficacy assessment before loss to follow-up or therapy initiation. Events after prolonged loss to follow-up were handled per the analysis plan. Malignancies other than new primary melanoma were not considered RFS events and, except for basal cell carcinoma, were reported as serious adverse events. Tumor tissue from any new primary cancer was collected for biomarker analyses.	Approximately 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Survival (OS) Events	Censoring was performed using the date of last known contact for those who were alive at the time of analysis.	Approximately 10 years
Overall Survival (OS)	Overall Survival (OS) was defined as the interval from randomization to the date of death, irrespective of the cause of death. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.	Approximately 10 years
Percentage of Participants With Distant Metastasis-free Survival (DMFS) Events	Distant metastasis-free survival (DMFS) was defined as the time from randomization to the first occurrence of distant metastasis or death, whichever occurred first, if death preceded documented recurrence. Patients who remained alive and free of distant metastasis were censored at the date of their last assessment.	Approximately 4 years
Distant Metastasis-free Survival (DMFS)	Distant metastasis-free survival (DMFS) was defined as the time from randomization to the first occurrence of distant metastasis or death, whichever occurred first, if death preceded documented recurrence. Patients who remained alive and free of distant metastasis were censored at the date of their last assessment.	Approximately 4 years
Percentage of Participants With Freedom From Relapse (FFR) Events	The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death.	Approximately 4 years
Freedom From Relapse (FFR)	Freedom from relapse (FFR) was defined as the interval from randomization to local or distant recurrence with censoring of patients dying from causes other than melanoma or treatment -related toxicity at the date of death. The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death.	Approximately 4 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.
• Dummer R, Hauschild A, Santinami M, Atkinson V, Mandala M, Kirkwood JM, Chiarion Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Gasal E, Tan M, Long GV, Schadendorf D. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med. 2020 Sep 17;383(12):1139-1148. doi: 10.1056/NEJMoa2005493. Epub 2020 Sep 2.
• Dummer R, Brase JC, Garrett J, Campbell CD, Gasal E, Squires M, Gusenleitner D, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Flaherty K, Larkin J, Robert C, Kefford R, Kirkwood JM, Hauschild A, Schadendorf D, Long GV. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):358-372. doi: 10.1016/S1470-2045(20)30062-0. Epub 2020 Jan 30.
• Schadendorf D, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Lesimple T, Plummer R, Schachter J, Dasgupta K, Manson S, Koruth R, Mookerjee B, Kefford R, Dummer R, Kirkwood JM, Long GV. 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 Oncol. 2019 May;20(5):701-710. doi: 10.1016/S1470-2045(18)30940-9. Epub 2019 Mar 27.
• Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Haas T, Shilkrut M, Gasal E, Kefford R, Kirkwood JM, Long GV. Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma. J Clin Oncol. 2018 Dec 10;36(35):3441-3449. doi: 10.1200/JCO.18.01219. Epub 2018 Oct 22.
• Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017 Nov 9;377(19):1813-1823. doi: 10.1056/NEJMoa1708539. Epub 2017 Sep 10.
• Li SN, Wan X, Peng LB, Li YM, Li JH. Cost-effectiveness of immune checkpoint inhibition and targeted treatment in combination as adjuvant treatment of patient with BRAF-mutant advanced melanoma. BMC Health Serv Res. 2023 Jan 18;23(1):49. doi: 10.1186/s12913-023-09058-7.
• Syeda MM, Long GV, Garrett J, Atkinson V, Santinami M, Schadendorf D, Hauschild A, Millward M, Mandala M, Chiarion-Sileni V, Smylie M, Manikhas GM, Dummer R, Wiggins JM, Ali S, Adnaik SB, Tan M, Dajee M, Polsky D. Clinical validation of droplet digital PCR assays in detecting BRAFV600-mutant circulating tumour DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomised phase 3 trial. Lancet Oncol. 2025 May;26(5):641-653. doi: 10.1016/S1470-2045(25)00139-1. Epub 2025 Apr 15.
• Long GV, Hauschild A, Santinami M, Kirkwood JM, Atkinson V, Mandala M, Merelli B, Sileni VC, Nyakas M, Haydon A, Dutriaux C, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Larkin J, Tan M, Adnaik SB, Burgess P, Jandoo T, Dummer R. Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med. 2024 Nov 7;391(18):1709-1720. doi: 10.1056/NEJMoa2404139. Epub 2024 Jun 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2013
• Primary Completion (Actual): June 30, 2017
• Study Completion (Actual): July 31, 2023

Study Registration Dates

• First Submitted: September 6, 2012
• First Submitted That Met QC Criteria: September 7, 2012
• First Posted (Estimated): September 10, 2012

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Oncology; trametinib; MEK inhibitor; adjuvant melanoma; dabrafenib; dabrafenib and trametinib combination therapy; BRAF mutation-positive melanoma; BRAF inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; dabrafenib; trametinib
• Other Study ID Numbers: 115532; 2012-001266-15 (EudraCT Number); CDRB436F2301 (Other Identifier: Novartis); BRF115532 (Other Identifier: legacy GSK code)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No