Clinical trial NCT02967692: A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma
Official title: A Randomized, Double-blind, Placebo-controlled, Phase III Study Comparing the Combination of PDR001, Dabrafenib and Trametinib Versus Placebo, Dabrafenib and Trametinib in Previously Untreated Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Melanoma
Keywords: Spartalizumab (PDR001)
dabrafenib
trametinib
melanoma
immunotherapy
PD 1 inhibitor
anti PD1
PD-1
anti-PD-1
combination treatment
malignant skin cancer
skin cancer
BRAF V600
unresectable BRAF V600 mutated melanoma
metastatic BRAF V600 mutated melanoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-11-18
Enrollment: 568
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate safety and efficacy of the combination of an anti-PD-1 antibody (PDR001), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with BRAF V600 mutant, unresectable and metastatic melanoma.

Detailed description: This study was designed as a phase III, multi-center study consisting of 3 parts:

* Part 1: Safety run-in part The safety run-in part aimed to determine the recommended regimen of PDR001 in combination with dabrafenib and trametinib for previously untreated patients with BRAF V600 mutant unresectable or metastatic melanoma (stage IIIC/IV). Spartalizumab was administered at a starting dose level (DL1) of 400 mg every 4 weeks (Q4W), along with fixed doses of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). The RP3R for Part 3 was determined using the Bayesian Logistic Regression Model (BLRM) with escalation with overdose control (EWOC) criteria.
* Part 2: Biomarker cohort Part 2 was run to explore changes in the immune microenvironment and biomarker modulations upon treatment with the combination of dabrafenib, trametinib and PDR001. Part 2 started when the fourth subject in dose level 1 (DL1) of Part 1 completed approximately 4 weeks of study treatment, and fewer than 3 dose-limiting toxicities (DLTs) were observed. Participants in Part 2 received PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).
* Part 3: Double-blind, randomized, placebo-controlled part Part 3 was comparing the efficacy and safety of spartalizumab in combination with dabrafenib and trametinib to placebo in combination with dabrafenib and trametinib. Part 3 was initiated after determining the RP3R for the combination of spartalizumab with dabrafenib and trametinib in Part 1. Subjects were randomized in a 1:1 ratio to receive either the RP3R dose of spartalizumab identified in Part 1 or placebo, along with dabrafenib (150 mg BID) and trametinib (2 mg QD).

For all parts of the study, the treatment continued until the subject experiences any of the following events: disease progression according to RECIST 1.1 as determined by the Investigator, unacceptable toxicity, initiation of a new anti-neoplastic therapy, pregnancy, withdrawal of consent, physician's decision, loss to follow-up, death, or termination of the study by the Sponsor. Safety evaluations are conducted for all subjects for up to 150 days after the last dose of spartalizumab/placebo (safety follow-up period).

Subjects who discontinued study treatment without disease progression as per RECIST 1.1 continued with tumor assessments according to the protocol until documented disease progression, withdrawal of consent, loss to follow-up, or death, regardless of the initiation of new anti-neoplastic therapy (efficacy follow-up period).

Subjects entered the survival follow-up period after completing the safety follow-up period or experiencing disease progression as per RECIST 1.1 or response criteria for immunotherapy, whichever period is longer (survival follow-up period).

Eligibility criteria: Inclusion criteria Part 1: Safety run-in

* Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
* Aspartate transaminase (AST) \< 2.5× ULN and Alanine transaminase (ALT) \< 2.5× ULN
* Measurable disease according to RECIST 1.1
* ECOG performance status ≤ 1

Part 2: Biomarker cohort

* Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
* At least two cutaneous or subcutaneous or nodal lesions for tumor sample collection
* Measurable disease according to RECIST 1.1
* ECOG performance status ≤ 2

Part 3: Double-blind, randomized, placebo-controlled part

* Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
* ECOG performance status ≤ 2
* Measurable disease according to RECIST 1.1

Exclusion Criteria:

Part 1: Safety run-in

* Subjects with uveal or mucosal melanoma
* Any history of CNS metastases
* Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
* Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollmen
* Radiation therapy within 4 weeks prior to start of study treatment
* Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment

Parts 2 \& 3: Biomarker cohort \& double-blind, randomized, placebo-controlled part

* Subjects with uveal or mucosal melanoma
* Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
* Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollment
* Radiation therapy within 4 weeks prior to start of study treatment
* Clinically active cerebral melanoma metastasis.
* Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment

Other protocol-defined Inclusion/Exclusion may apply.

Primary outcomes:
measure: Safety Run-In (Part 1): Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 8 weeks (Part 1)
measure: Biomarker Cohort (Part 2): Change From Baseline in Programmed Cell Death-ligand 1 (PD-L1) Expression Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib
timeFrame: Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
measure: Biomarker Cohort (Part 2): Change From Baseline in CD8+ Cells Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib
timeFrame: Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
measure: Randomized (Part 3): Progression-Free Survival (PFS) as Per Investigator's Assessment by RECIST 1.1
timeFrame: Up to disease progression or death due to any cause, whichever occurs first, assessed up to 2.8 years (Part 3)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to death due to any cause, assessed up to approximately 5 years
measure: Overall Response Rate (ORR) as Per Investigator's Assessment by RECIST 1.1
timeFrame: Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 years
measure: Duration of Response (DOR) as Per Investigator's Assessment by RECIST 1.1
timeFrame: From first documented response to date of first documented progression or death, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3)
measure: Disease Control Rate (DCR) as Per Investigator's Assessment by RECIST 1.1
timeFrame: Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 year
measure: Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status Scores
timeFrame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
measure: Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Physical Functioning Scale Scores
timeFrame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
measure: Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Pain Symptom Scale Scores
timeFrame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
measure: Randomized (Part 3): Time to 10 Point Definitive Deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status
timeFrame: From baseline to date of at least 10 points relative to baseline worsening of the global health status score or death due to any cause, up to 2.8 years (Part 3)
measure: Randomized (Part 3): Change From Baseline in Function Assessment Cancer Therapy-melanoma (FACT-M) Melanoma Subscale Score
timeFrame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
measure: Randomized (Part 3): Change From Baseline in EuroQoL 5-level Instrument (EQ-5D-5L)- Visual Analog Scale (VAS) Score
timeFrame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
measure: Randomized (Part 3): PFS as Per Investigator's Assessment by RECIST 1.1 by PD-L1 Expression
timeFrame: Up to disease progression or death due to any cause, up to 2.8 years (Part 3)
measure: Randomized (Part 3): OS by PD-L1 Expression
timeFrame: Up to death due to any cause, up to 5 years
measure: Spartalizumab Anti-drug Antibody (ADA) Prevalence at Baseline
timeFrame: Baseline
measure: Spartalizumab ADA Incidence
timeFrame: Throughout study until 150 days after the last dose of spartalizumab, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3).
measure: Trough Concentration (Ctrough) for Spartalizumab
timeFrame: Pre-infusion on Day 1 of each Cycle starting from Cycle 2, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
measure: Pre-dose Plasma Concentration for Dabrafenib
timeFrame: Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
measure: Pre-dose Plasma Concentration for Trametinib
timeFrame: Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
measure: Number of Participants With Dose Interruptions
timeFrame: From baseline to end of treatment, up to 5 years
measure: Number of Participants With Dose Reductions
timeFrame: From baseline to end of treatment, up to 5 years
measure: Relative Dose Intensity
timeFrame: From baseline to end of treatment, up to 5 years
Other outcomes:
Locations:
city: Encinitas
country: United States
facility: California Cancer Associates for Research and Excellence
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Lutherville
country: United States
facility: Johns Hopkins U
state: Maryland
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: New York
country: United States
facility: NYU Laura and Isaac Perlmutter Cancer Center
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh Med Center
state: Pennsylvania
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Houston
country: United States
facility: Univ of TX MD Anderson Cancer Cntr
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Caba
country: Argentina
facility: Novartis Investigative Site
city: Gateshead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: North Sydney
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Greenslopes
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
state: Tyrol
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: St Poelten
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facility: Novartis Investigative Site
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Curitiba
country: Brazil
facility: Novartis Investigative Site
state: PR
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
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city: Vancouver
country: Canada
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state: British Columbia
city: Toronto
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state: Ontario
city: Montreal
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state: Quebec
city: Montreal
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state: Quebec
city: Sherbrooke
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state: Quebec
city: Temuco
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state: Araucania
city: Santiago
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city: Santiago
country: Chile
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city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Zlin
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Hradec Kralove
country: Czechia
facility: Novartis Investigative Site
state: CZE
city: Ostrava
country: Czechia
facility: Novartis Investigative Site
state: Poruba
city: Olomouc
country: Czechia
facility: Novartis Investigative Site
city: Praha 10
country: Czechia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Aarhus N
country: Denmark
facility: Novartis Investigative Site
city: Limoges
country: France
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state: Haute Vienne
city: Amiens
country: France
facility: Novartis Investigative Site
city: Besancon Cedex
country: France
facility: Novartis Investigative Site
city: Bobigny Cedex
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city: Bordeaux Cedex
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city: Boulogne Billancourt
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facility: Novartis Investigative Site
city: Caen
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city: Grenoble
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city: Le Mans
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facility: Novartis Investigative Site
city: Lille
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facility: Novartis Investigative Site
city: Lorient
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facility: Novartis Investigative Site
city: Lyon
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facility: Novartis Investigative Site
city: Marseille
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facility: Novartis Investigative Site
city: Mulhouse cedex
country: France
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Pierre Benite
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facility: Novartis Investigative Site
city: Poitiers
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facility: Novartis Investigative Site
city: Reims
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facility: Novartis Investigative Site
city: Rouen
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Vandoeuvre-les-Nancy
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Halle Saale
country: Germany
facility: Novartis Investigative Site
state: Sachsen-Anhalt
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bonn
country: Germany
facility: Novartis Investigative Site
city: Chemnitz
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Erfurt
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Gera
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Homburg
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Minden
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Stade
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Bari
country: Italy
facility: Novartis Investigative Site
state: BA
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Meldola
country: Italy
facility: Novartis Investigative Site
state: FC
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Siena
country: Italy
facility: Novartis Investigative Site
state: SI
city: Candiolo
country: Italy
facility: Novartis Investigative Site
state: TO
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Fukuoka city
country: Japan
facility: Kyushu University Hospital
state: Fukuoka
city: Sakyo Ku
country: Japan
facility: Kyoto University Hospital
state: Kyoto
city: Osaka-city
country: Japan
facility: Osaka International Cancer Institute
state: Osaka
city: Bunkyo ku
country: Japan
facility: Tokyo Metropolitan Komagome Hospital
state: Tokyo
city: Chuo ku
country: Japan
facility: National Cancer Hospital
state: Tokyo
city: Mexico
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: Leon
country: Mexico
facility: Novartis Investigative Site
state: Guanajuato
city: Guadalajara
country: Mexico
facility: Novartis Investigative Site
state: Jalisco
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Amersfroort
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Chelyabinsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Omsk
country: Russian Federation
facility: Novartis Investigative Site
city: Samara
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Jerez
country: Spain
facility: Novartis Investigative Site
state: Cadiz
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Las Palmas de Gran Canaria
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Goteborg
country: Sweden
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Aarau
country: Switzerland
facility: Novartis Investigative Site
state: Aargau
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Truro
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: Guildford
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Middlesbrough
country: United Kingdom
facility: Novartis Investigative Site
city: Preston
country: United Kingdom
facility: Novartis Investigative Site
city: Rickmansworth Road
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Tawbi HA, Robert C, Brase JC, Gusenleitner D, Gasal E, Garrett J, Savchenko A, Gorgun G, Flaherty KT, Ribas A, Dummer R, Schadendorf D, Long GV, Nathan PD, Ascierto PA. Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i). J Immunother Cancer. 2022 Jun;10(6):e004226. doi: 10.1136/jitc-2021-004226.
citation: Dummer R, Long GV, Robert C, Tawbi HA, Flaherty KT, Ascierto PA, Nathan PD, Rutkowski P, Leonov O, Dutriaux C, Mandala M, Lorigan P, Ferrucci PF, Grob JJ, Meyer N, Gogas H, Stroyakovskiy D, Arance A, Brase JC, Green S, Haas T, Masood A, Gasal E, Ribas A, Schadendorf D. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma. J Clin Oncol. 2022 May 1;40(13):1428-1438. doi: 10.1200/JCO.21.01601. Epub 2022 Jan 14.
citation: Dummer R, Lebbe C, Atkinson V, Mandala M, Nathan PD, Arance A, Richtig E, Yamazaki N, Robert C, Schadendorf D, Tawbi HA, Ascierto PA, Ribas A, Flaherty KT, Pakhle N, Campbell CD, Gusenleitner D, Masood A, Brase JC, Gasal E, Long GV. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med. 2020 Oct;26(10):1557-1563. doi: 10.1038/s41591-020-1082-2. Epub 2020 Oct 5.