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

NCT01682083 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: 1155322012-001266-15CDRB436F2301BRF115532
• Study Type: interventional
• Target: 870
• Locations: 24 countries
• Sites: 163

Brief Summary

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.

Conditions

Melanoma

Keywords

MEK inhibitor; trametinib; Oncology; adjuvant melanoma; dabrafenib; dabrafenib and trametinib combination therapy; BRAF mutation-positive melanoma; BRAF inhibitor

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Percentage of Participants With Overall Survival (OS) Events

  Approximately 10 years

• Overall Survival (OS)

  Approximately 10 years

• Percentage of Participants With Distant Metastasis-free Survival (DMFS) Events

  Approximately 4 years

• Distant Metastasis-free Survival (DMFS)

  Approximately 4 years

• Percentage of Participants With Freedom From Relapse (FFR) Events

  Approximately 4 years

Study Arms (2)

Dabrafenib and trametinib

EXPERIMENTAL

Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.

Drug: Dabrafenib; Drug: Trametinib

Dabrafenib and trametinib placebos

PLACEBO COMPARATOR

Subjects received matching placebos orally for 12 months

Drug: Placebos

Interventions

Dabrafenib DRUG

Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)

Also known as: GSK2118436

Dabrafenib and trametinib

Trametinib DRUG

Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)

Also known as: GSK1120212

Dabrafenib and trametinib

Placebos DRUG

The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment

Dabrafenib and trametinib placebos

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (168)

Novartis Investigative Site

Birmingham, Alabama, 35243, United States

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Tucson, Arizona, 85724, United States

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San Francisco, California, 94115, United States

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San Francisco, California, 94143, United States

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Aurora, Colorado, 80045, United States

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Lake Worth, Florida, 33461, United States

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Orlando, Florida, 32806, United States

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Tampa, Florida, 33612, United States

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Atlanta, Georgia, 30322, United States

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Atlanta, Georgia, 30341, United States

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Lutherville-Timonium, Maryland, 21093, United States

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Boston, Massachusetts, 02114, United States

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Boston, Massachusetts, 02115, United States

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Ann Arbor, Michigan, 48019, United States

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Winston-Salem, North Carolina, 27157, United States

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Columbus, Ohio, 43210, United States

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Portland, Oregon, 97123, United States

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Pittsburgh, Pennsylvania, 15232, United States

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Nashville, Tennessee, 37203, United States

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Dallas, Texas, 75390, United States

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Capital Federal, Buenos Aires, C1426ANZ, Argentina

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Buenos Aires, C1125ABD, Argentina

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Gateshead, New South Wales, 2290, Australia

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North Sydney, New South Wales, 2060, Australia

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Tweed Heads, New South Wales, 2485, Australia

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Westmead, New South Wales, 2145, Australia

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Greenslopes, Queensland, 4120, Australia

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Woolloongabba, Queensland, 4102, Australia

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Adelaide, South Australia, 5000, Australia

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Box Hill, Victoria, 3128, Australia

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Heidelberg, Victoria, 3084, Australia

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Melbourne, Victoria, 3004, Australia

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Nedlands, Western Australia, 6009, Australia

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Graz, 8036, Austria

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Linz, A-4010, Austria

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Salzburg, A-5020, Austria

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Vienna, 1090, Austria

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Wels, A-4600, Austria

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Brussels, 1200, Belgium

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Leuven, 3000, Belgium

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Liège, 4000, Belgium

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Wilrijk, 2610, Belgium

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Curitiba, Paraná, 81520-060, Brazil

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Ijuí, Rio Grande do Sul, 98700, Brazil

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Edmonton, Alberta, T6G 1Z2, Canada

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Hamilton, Ontario, L8V 5C2, Canada

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Oshawa, Ontario, L1G 2B9, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Toronto, Ontario, M5G 2M9, Canada

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Québec, Quebec, G1J 1Z4, Canada

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Brno, 656 53, Czechia

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Prague, 100 34, Czechia

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Prague, 128 08, Czechia

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Zlín, 76275, Czechia

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Arhus C, 8000, Denmark

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Herlev, 2730, Denmark

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Odense, 5000 C, Denmark

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Bordeaux, 33075, France

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Boulogne-Billancourt, 92100, France

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Brest, 29609, France

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Dijon, 21079, France

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Grenoble, 38043, France

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Lille, 59037, France

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Marseille, 13385, France

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Montpellier, 34295, France

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Nice, 06202, France

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Paris, 75014, France

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Paris, 75475, France

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Pierre-Bénite, 69495, France

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Reims, 51092, France

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Rennes, 35042, France

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Toulouse, 31059, France

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Tours, 37044, France

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Villejuif, 94805, France

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Freiburg im Breisgau, Baden-Wurttemberg, 79104, Germany

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Heilbronn, Baden-Wurttemberg, 74078, Germany

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Mannheim, Baden-Wurttemberg, 68167, Germany

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Tübingen, Baden-Wurttemberg, 72076, Germany

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Ulm, Baden-Wurttemberg, 89081, Germany

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Munich, Bavaria, 80337, Germany

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Nuremberg, Bavaria, 90419, Germany

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Regensburg, Bavaria, 93053, Germany

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Würzburg, Bavaria, 97080, Germany

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Darmstadt, Hesse, 64297, Germany

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Marburg, Hesse, 35033, Germany

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Wiesbaden, Hesse, 65199, Germany

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Hanover, Lower Saxony, 30625, Germany

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Schwerin, Mecklenburg-Vorpommern, 19049, Germany

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Bochum, North Rhine-Westphalia, 44791, Germany

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Cologne, North Rhine-Westphalia, 50937, Germany

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Essen, North Rhine-Westphalia, 45147, Germany

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Mainz, Rhineland-Palatinate, 55131, Germany

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Magdeburg, Saxony-Anhalt, 39120, Germany

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Kiel, Schleswig-Holstein, 24105, Germany

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Lübeck, Schleswig-Holstein, 23538, Germany

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Erfurt, Thuringia, 99089, Germany

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Gera, Thuringia, 07548, Germany

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Berlin, 10249, Germany

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Athens, 11527, Greece

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Thessaloniki, 54622, Greece

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Thessaloniki, 56429, Greece

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Ramat Gan, 52621, Israel

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Rome, Lazio, 00167, Italy

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Genoa, Liguria, 16132, Italy

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Bergamo, Lombardy, 24127, Italy

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Milan, Lombardy, 20133, Italy

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Milan, Lombardy, 20141, Italy

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Candiolo, Piedmont, 10060, Italy

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Pisa, Tuscany, 56126, Italy

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Padova, Veneto, 35128, Italy

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Shizuoka, 411-8777, Japan

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Tokyo, 104-0045, Japan

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Amsterdam, 1066 CX, Netherlands

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Amsterdam, 1081 HV, Netherlands

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Groningen, 9713 GZ, Netherlands

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Leeuwarden, 8934 AD, Netherlands

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Maastricht, 6229 HX, Netherlands

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Nijmegen, 6525 GA, Netherlands

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Rotterdam, 3015 GD, Netherlands

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Auckland, 0622, New Zealand

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Ålesund, 6026, Norway

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Oslo, 0310, Norway

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Gdansk, 80-215, Poland

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Konin, 62-500, Poland

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Poznan, 60-693, Poland

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Warsaw, 02-781, Poland

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Chelyabinsk, 454087, Russia

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Moscow, 115478, Russia

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Moscow, 143423, Russia

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Ryazan, 390011, Russia

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Saint Petersburg, 191014, Russia

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Saint Petersburg, 197758, Russia

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Saint Petersburg, 198255, Russia

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Volgograd, 400138, Russia

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Badalona, 08916, Spain

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Barcelona, 08035, Spain

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Barcelona, 08036, Spain

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Donostia / San Sebastian, 20014, Spain

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Las Palmas de Gran Canaria, 35016, Spain

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Madrid, 28034, Spain

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Madrid, 28041, Spain

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Madrid, 28046, Spain

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Palma de Mallorca, 07198, Spain

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Pamplona, 31008, Spain

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Santander, 39008, Spain

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Valencia, 46014, Spain

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Gothenburg, SE-413 45, Sweden

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Lund, SE-221 85, Sweden

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Stockholm, SE-171 76, Sweden

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Uppsala, SE-751 85, Sweden

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Basel, 4031, Switzerland

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Chur, 7000, Switzerland

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Zurich, 8091, Switzerland

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Taipei, 10002, Taiwan

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Taoyuan District, 33305, Taiwan

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Northwood, Middlesex, HA6 2RN, United Kingdom

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Exeter, EX2 5DW, United Kingdom

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Glasgow, G12 0YN, United Kingdom

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Guildford, GU2 7XX, United Kingdom

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Leeds, LS9 7TF, United Kingdom

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London, NW3 2QG, United Kingdom

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London, SW3 6JJ, United Kingdom

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London, W1G 6AD, United Kingdom

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Manchester, M20 4BX, United Kingdom

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Newcastle upon Tyne, NE7 7DN, United Kingdom

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Norwich, NR4 7UY, United Kingdom

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Preston, PR2 9HT, United Kingdom

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Southampton, SO16 6YD, United Kingdom

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Related Publications (9)

• 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.

  PMID: 40250457 DERIVED

• 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.

  PMID: 38899716 DERIVED

• 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.

  PMID: 36653848 DERIVED

• 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.

  PMID: 34225229 DERIVED

• 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.

  PMID: 32877599 DERIVED

• 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.

  PMID: 32007138 DERIVED

• 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.

  PMID: 30928620 DERIVED

• 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.

  PMID: 30343620 DERIVED

• 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.

  PMID: 28891408 DERIVED

MeSH Terms

Conditions

Melanoma; Neoplasms

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2012
• First Posted: September 10, 2012
• Study Start: January 8, 2013
• Primary Completion: June 30, 2017
• Study Completion: July 31, 2023
• Last Updated: April 21, 2026
• Results First Posted: September 26, 2018

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

BR (2); AR (2); CZ (4); DE (24); PL (4); DK (3); SE (4); CA (6); NL (7); RU (8); NZ (1); GB (13); CH (3); ES (12); GR (3); AU (11); IL (1); FR (17); US (20); BE (4); JP (2); TW (2); IT (8); NO (2)