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Year:2015
Improvedoverallsurvivalinmelanomawithcombineddabrafeniband
trametinib
Robert,Caroline;Karaszewska,Boguslawa;Schachter,Jacob;Rutkowski,Piotr;Mackiewicz,Andrzej
;Stroiakovski,Daniil;Lichinitser,Michael;Dummer,Reinhard;Grange,Florent;Mortier,Laurent;
Chiarion-Sileni,Vanna;Drucis,Kamil;Krajsova,Ivana;Hauschild,Axel;Lorigan,Paul;Wolter,
Pascal;Long,GeorginaV;Flaherty,Keith;Nathan,Paul;Ribas,Antoni;Martin,Anne-Marie;Sun,
Peng;Crist,Wendy;Legos,Je;Rubin,StephenD;Little,ShondaM;Schadendorf,Dirk
Abstract:BACKGROUNDTheBRAFinhibitorsvemurafenibanddabrafenibhaveshownecacyas
monotherapiesinpatientswithpreviouslyuntreatedmetastaticmelanomawithBRAFV600EorV600K
mutations.CombiningdabrafenibandtheMEKinhibitortrametinib,ascomparedwithdabrafenibalone,
enhancedantitumoractivityinthispopulationofpatients.METHODSInthisopen-label,phase3trial,
werandomlyassigned704patientswithmetastaticmelanomawithaBRAFV600mutationtoreceive
eitheracombinationofdabrafenib(150mgtwicedaily)andtrametinib(2mgoncedaily)orvemurafenib
(960mgtwicedaily)orallyasrst-linetherapy.Theprimaryendpointwasoverallsurvival.RESULTS
Atthepreplannedinterimoverallsurvivalanalysis,whichwasperformedafter77%ofthetotalnumber
ofexpectedeventsoccurred,theoverallsurvivalrateat12monthswas72%(95%condenceinterval
[CI],67to77)inthecombination-therapygroupand65%(95%CI,59to70)inthevemurafenibgroup
(hazardratiofordeathinthecombination-therapygroup,0.69;95%CI,0.53to0.89;P=0.005).The
prespeciedinterimstoppingboundarywascrossed,andthestudywasstoppedforecacyinJuly2014.
Medianprogression-freesurvivalwas11.4monthsinthecombination-therapygroupand7.3monthsin
thevemurafenibgroup(hazard ratio,0.56;95%CI,0.46to 0.69; P<0.001).Theobjectiveresponse
ratewas64%inthecombination-therapygroupand51%inthevemurafenibgroup(P<0.001).Rates
ofsevereadverseeventsandstudy-drug discontinuationsweresimilarinthetwogroups.Cutaneous
squamous-cellcarcinomaandkeratoacanthomaoccurredin1%ofpatientsinthecombination-therapy
groupand 18%of thoseinthevemurafenibgroup.CONCLUSIONSDabrafenib plustrametinib, as
comparedwithvemurafenibmonotherapy,signicantlyimprovedoverallsurvivalinpreviouslyuntreated
patientswithmetastaticmelanomawithBRAFV600EorV600Kmutations,withoutincreasedoverall
toxicity.(FundedbyGlaxoSmithKline;ClinicalTrials.govnumber,NCT01597908.).
DOI:https://doi.org/10.1056/NEJMoa1412690
PostedattheZurichOpenRepositoryandArchive,UniversityofZurich
ZORAURL:https://doi.org/10.5167/uzh-107163
JournalArticle
PublishedVersion
Originallypublishedat:
Robert,Caroline;Karaszewska,Boguslawa;Schachter,Jacob;Rutkowski,Piotr;Mackiewicz,Andrzej;
Stroiakovski,Daniil;Lichinitser,Michael;Dummer,Reinhard;Grange,Florent;Mortier,Laurent;Chiarion-
Sileni,Vanna;Drucis,Kamil; Krajsova,Ivana; Hauschild,Axel; Lorigan,Paul;Wolter,Pascal;Long,
Georgina V; Flaherty,Keith;Nathan,Paul;Ribas,Antoni;Martin,Anne-Marie;Sun,Peng;Crist,
Wendy;Legos,Je;Rubin,StephenD;Little,ShondaM;Schadendorf,Dirk(2015).Improvedoverall
survivalinmelanomawithcombineddabrafenibandtrametinib.NewEnglandJournalofMedicine,
372(1):30-39.
DOI:https://doi.org/10.1056/NEJMoa1412690
2
original article
The
new england journal
of
medicine
n engl j med 372;1 nejm.org january 1, 2015
30
Improved Overall Survival in Melanoma
with Combined Dabrafenib and Trametinib
Caroline Robert, M.D., Ph.D., Boguslawa Karaszewska, M.D., Jacob Schachter, M.D.,
Piotr Rutkowski, M.D., Ph.D., Andrzej Mackiewicz, M.D., Ph.D.,
Daniil Stroiakovski, M.D., Michael Lichinitser, M.D., Reinhard Dummer, M.D.,
Florent Grange, M.D., Ph.D., Laurent Mortier, M.D., Vanna Chiarion-Sileni, M.D.,
Kamil Drucis, M.D., Ph.D., Ivana Krajsova, M.D., Axel Hauschild, M.D., Ph.D.,
Paul Lorigan, M.D., Pascal Wolter, M.D., Georgina V. Long, M.D., Ph.D.,
Keith Flaherty, M.D., Paul Nathan, M.D., Ph.D., Antoni Ribas, M.D., Ph.D.,
Anne-Marie Martin, Ph.D., Peng Sun, Ph.D., Wendy Crist, B.A., Jeff Legos, Ph.D.,
Stephen D. Rubin, M.D., Shonda M. Little, M.P.H., and Dirk Schadendorf, M.D.
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. Robert at the Dermatology Service
and INSERM Unité 981, Gustave Roussy,
114 rue Edouard Vaillant, 94 805 Villejuif-
Paris Sud, France, or at caroline.robert@
gustaveroussy.fr.
This article was published on November 16,
2014, at NEJM.org.
N Engl J Med 2015;372:30-9.
DOI: 10.1056/NEJMoa1412690
Copyright © 2014 Massachusetts Medical Society.
ABSTRACT
Background
The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as mono-
therapies in patients with previously untreated metastatic melanoma with BRAF
V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor tra-
metinib, as compared with dabrafenib alone, enhanced antitumor activity in this
population of patients.
Methods
In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic
melanoma with a BR AF V600 mutation to receive either a combination of dabrafenib
(150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice
daily) orally as first-line therapy. The primary end point was overall survival.
Result s
At the preplanned interim overall survival analysis, which was performed after 77%
of the total number of expected events occurred, the overall survival rate at 12 months
was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group
and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the
combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P = 0.005). The prespecified
interim stopping boundary was crossed, and the study was stopped for efficacy in
July 2014. Median progression-free survival was 11.4 months in the combination-
therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95%
CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-
therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse
events and study-drug discontinuations were similar in the two groups. Cutaneous
squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the
combination-therapy group and 18% of those in the vemurafenib group.
Conclusions
Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, signifi-
cantly improved overall survival in previously untreated patients with metastatic
melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.
(Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.)
The New England Journal of Medicine
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Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Combined Dabrafenib and Trametinib in Melanoma
n engl j med 372;1 nejm.org january 1, 2015
31
T
he treatment of metastatic mela-
noma is rapidly evolving. The potent and
specific BRAF inhibitors vemurafenib and
dabrafenib, as compared with chemotherapy, have
significantly improved response rates, along with
progression-free and overall survival, in patients
with metastatic melanoma with BRAF V600E or
V600K mutations.
1,2
However, acquired resistance
to BRAF inhibitors frequently develops through
reactivation of the mitogen-activated protein ki-
nase (MAPK) pathway, resulting in a median pro-
gression-free survival of 6 to 8 months.
2-5
In ad-
dition, the use of BRAF inhibitors may result in
the development of secondary skin tumors, orig-
inating from a paradoxical activation of the MAPK
pathway in cells without a BRAF mutation.
1,6-11
Combining a BRAF inhibitor with a MEK inhibi-
tor addresses the limitations of single-agent BRAF
inhibitors and results in a significant delay in the
emergence of resistance, with a longer median
progression-free survival than with dabrafenib
alone, as well as a decreased incidence of BRAF-
inhibitor–induced skin tumors.
12-14
In this open-label, randomized, phase 3 study,
we evaluated the effect of combination therapy
with dabrafenib plus trametinib versus vemu-
rafenib monotherapy on overall survival in previ-
ously untreated patients with unresectable stage
IIIC or IV melanoma with BRAF V600E or V600K
mutations.
Methods
Patients
From June 2012 through October 2013, a total of
1645 patients were screened at 193 centers world-
wide. The presence of BRAF V600E or V600K muta-
tions was centrally determined with the investiga-
tional use of the THxID BRAF assay (bioMérieux).
Additional key eligibility criteria were measureable
disease, according to the Response Evaluation Cri-
teria in Solid Tumors (RECIST), version 1.1,
15
and
an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1 (on a scale of 0 to 5,
with 0 indicating no symptoms and higher num-
bers reflecting greater disability).
16
Patients who
had undergone treatment for brain metastases with
no increase in lesion size for at least 12 weeks were
eligible for enrollment. Additional eligibility cri-
teria are provided in the Methods section in the
Supplementary Appendix, available with the full
text of this article at NEJM.org. Written informed
consent was obtained from all study participants.
Study Design and Treatment
Eligible patients were assigned in a 1:1 ratio to
receive either a combination of dabrafenib (150
mg orally twice daily) and trametinib (2 mg oral-
ly once daily) or vemurafenib (960 mg orally
twice daily). The primary end point was overall
survival. Secondary end points included progres-
sion-free survival, overall response rate, duration
of response, and safety. Crossover was prohibited
until the independent data and safety monitoring
committee recommended stopping the study
early for efficacy. After the recommendation, the
study protocol was amended to allow patients in
the vemurafenib group to cross over to the com-
bination-therapy group.
Assessment
We conducted tumor assessments according to
RECIST, version 1.1,
15
at baseline, every 8 weeks
until week 56, and then every 12 weeks until dis-
ease progression, death, or withdrawal from the
study (Table S1 in the Supplementary Appendix).
All responses were confirmed with a scan at least
4 weeks after the first RECIST response. Adverse
events were graded by the investigator, according
to the National Cancer Institute Common Termi-
nology Criteria for Adverse Events, version 4.0,
until day 30 after the discontinuation of study
treatment.
Study Oversight
The study was funded by the sponsor, Glaxo-
SmithKline, and conducted in accordance with
the provisions of the Declaration of Helsinki and
Good Clinical Practice guidelines. The protocol
was approved by the institutional review board or
human research ethics committee at each study
center. Data were collected at each study site and
monitored by the sponsor. The first author wrote
the first draft of the manuscript, with support
from the last author and representatives of the
sponsor. Representatives of the sponsor designed
the study, confirmed the accuracy of the data,
and compiled the data for analysis. All the au-
thors and sponsor representatives had full access
to the study data and were involved in their anal-
ysis. No one who was not an author contributed
to the writing of the manuscript. Editorial assis-
tance that did not involve writing was provided
by SciMentum and funded by the sponsor. All the
authors vouch for the accuracy and completeness
of the data reported and for the fidelity of the
study to the protocol (available at NEJM.org).
The New England Journal of Medicine
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Copyright © 2015 Massachusetts Medical Society. All rights reserved.
The
new england journal
of
medicine
n engl j med 372;1 nejm.org january 1, 2015
32
Statistical Analysis
We used the Kaplan–Meier method to estimate
overall and progression-free survival. We evalu-
ated between-group comparisons using a log-
rank test that was stratified for the BRAF muta-
tion status (V600E vs. V600K) and the baseline
level of lactate dehydrogenase (LDH) (above the
upper limit of the normal range vs. the upper
limit of the normal range or less). We estimated
that 288 events would be required to detect a
hazard ratio for death of 0.675 with an alpha
level of 0.05 (i.e., an increase in median overall
survival from 13.5 months in the vemurafenib
group to 20 months in the combination-therapy
group). Overall survival was defined as the time
from randomization until death from any cause.
A preplanned interim analysis for overall sur-
vival was to be conducted when 202 of 288
events that were required for the final analysis
(70%) had been observed. Owing to the inherent
lag in data entry, the actual number of deaths
was 222 at the time of the interim analysis. Per
protocol, efficacy boundaries were adjusted on
the basis of the actual number of deaths at the
time of the interim analysis. The data and safety
monitoring committee used the adjusted stop-
ping boundaries (two-sided P<0.0214 for the ef-
ficacy analysis and P>0.2210 for the futility
analysis) to review the interim data. The com-
mittee recommended stopping for efficacy. As
such, the interim summary is considered to be
the final analysis of overall survival.
Results
Patients
Of the 1645 patients who underwent screening at
193 centers, 704 underwent randomization, with
352 patients in each group. A total of 68 patients
(10%, 34 in each study group) had a BRAF V600K
mutation. Baseline characteristics of the patients
are provided in
Table 1
. Known prognostic mea-
sures were well balanced in the two groups ex-
cept for sex (59% men in the combination-thera-
py group vs. 51% in the vemurafenib group). At
the date of the analysis, the median follow-up
durations were 11 months and 10 months and
the median exposure durations were 10 months
and 6 months in the combination-therapy group
and the vemurafenib group, respectively.
A total of 80 patients in the combination-
therapy group and 81 in the vemurafenib group
(23% in each group) continued to receive study
treatment for at least 15 days after disease pro-
gression, according to the protocol, which al-
lowed for treatment after progression on the
basis of a request from an investigator for pa-
tients who seemed to benefit from the treatment
in spite of RECIST progression. The median
duration of study treatment after progression
was similar in the two study groups and was less
than 3 months for the majority of patients, with
more patients continuing to receive the combi-
nation therapy for 6 to 12 months (9%), as com-
pared with those who continued to receive ve-
murafenib (1%) (Table S2 in the Supplementary
Appendix).
Effic acy
The interim analysis for overall survival was per-
formed in the intention-to-treat population of
352 patients in each group. At the data-cutoff
date of April 17, 2014, the interim analysis was
performed after 222 events had occurred. For the
overall survival analysis, 100 patients (28%) in
the combination-therapy group and 122 (35%) in
the vemurafenib group had died (hazard ratio for
death in the combination-therapy group, 0.69;
95% confidence interval [CI], 0.53 to 0.89;
P = 0.005) (Fig. 1A). The prespecified stopping
boundary (P<0.0214) was crossed, and the study
was stopped for efficacy on July 14, 2014. A pro-
tocol amendment was issued to allow crossover
to the combination-therapy group for patients
assigned to the vemurafenib group, but no pa-
tient had crossed over as of the effective data-
freezing date of June 27, 2014.
The median overall survival was 17.2 months
for patients in the vemurafenib group and had
not been reached for patients in the combina-
tion-therapy group (Fig. 1A). The rate of overall
survival at 12 months was 72% (95% CI, 67 to
77) in the combination-therapy group and 65%
(95% CI, 59 to 70) in the vemurafenib group. The
hazard ratios for the variables of V600 mutation
type, sex, age (<65 years vs. ≥65 years), baseline
LDH level, and ECOG status have been calcu-
lated, although these subgroup analyses were
not powered to show a significant between-group
difference. They all favored the combination-thera-
py group except for the subgroup of patients with
an ECOG score of 1 (hazard ratio, 1.03) (Fig. 1B).
Median progression-free survival was longer
in the combination-therapy group than in the
vemurafenib group (11.4 months vs. 7.3 months;
The New England Journal of Medicine
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Copyright © 2015 Massachusetts Medical Society. All rights reserved.
