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Research Article
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Comparative efficacy of combination
immunotherapy and targeted therapy in the
treatment of BRAF-mutant advanced
melanoma: a matching-adjusted indirect
comparison
Michael B Atkins*,1, Ahmad Tarhini‡ ,2, Michael Rael§ ,3, Komal Gupte-Singh4, Elliott
O’Brien3, Corey Ritchings4, Sumati Rao4 & David F McDermott5
1Georgetown Lombardi Comprehensive Cancer Center, Washington, DC 20057, USA
2Center for Immuno-Oncology Research, Cleveland Clinic, Cleveland, OH 44106, USA
3Evidera, Inc., San Francisco, CA 94111, USA
4Bristol-Myers Squibb, Princeton, NJ 08540, USA
5Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
*Author for correspondence: mba41@georgetown.edu
‡Current affiliation: Winship Comprehensive Cancer Center of Emory University, Atlanta, GA 30322, USA
§M Rael was an employee of Evidera, Inc. at the time of study and manuscript development
Aim: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors
(dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma. Meth-
ods: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (Check-
Mate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall sur-
vival (OS), progression-free survival and objective response rates were assessed. Results: After adjusting,
nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64;
95% CI: 0.46–0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36–0.89); OS outcomes were sim-
ilar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response
rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6%
with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib. Conclusion: Nivolumab + ipil-
imumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increas-
ing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary
to prospectively validate these findings.
First draft submitted: 21 December 2018; Accepted for publication: 21 February 2019; Published online:
11 March 2019
Keywords: cobimetinib • comparative efficacy • dabrafenib • ipilimumab • matching-adjusted indirect comparison
• nivolumab • trametinib • vemurafenib
Melanoma is the most aggressive and the deadliest form of skin cancer [1]. Over 1.2 million people in the USA
were estimated to be living with melanoma of the skin in 2015, with an estimated 91,270 new cases and 9320
deaths estimated in 2018 [2]. About 50% of patients with cutaneous melanoma have tumors that are positive for
BRAF V600 mutations [3]. In recent years, the therapeutic armamentarium for advanced melanoma has expanded
to include immunotherapies and targeted therapies as two main classes of drugs.
With the emergence of immune checkpoint inhibitors, current treatment options include various immunother-
apies that inhibit cytotoxic T-lymphocyte antigen 4 (CTLA-4, ipilimumab) and programmed cell death protein-1
(PD-1, nivolumab). Long-lasting, durable antitumor immune responses are often observed in patients who re-
spond to immunotherapies [4]. Combination immunotherapy with checkpoint inhibitors, such as nivolumab + ip-
ilimumab, or nivolumab or pembrolizumab monotherapies resulted in superior long-term survival outcomes
compared with ipilimumab alone in patients with advanced melanoma. In CheckMate 067, 4-year overall survival
Immunotherapy (Epub ahead of print) ISSN 1750-743X10.2217/imt-2018-0208 C© 2019 Michael B Atkins
Research Article Atkins, Tarhini, Rael et al.
(OS) rates were 53% for the nivolumab + ipilimumab group, 46% in the nivolumab group and 30% in the
ipilimumab group [5]. OS was generally longer in the patients harboring BRAF mutations (4-year rates were 62%
for nivolumab + ipilimumab, 50% for nivolumab and 33% for ipilimumab) compared with those with BRAF
wild-type tumors (49, 45 and 28%, respectively) [5].
Molecularly targeted therapies specific to mitogen-associated protein kinase signaling pathways include BRAF
and MEK inhibitors [3]. Combined therapy with BRAF (dabrafenib and vemurafenib) and MEK (trametinib and
cobimetinib) inhibitors has significantly improved outcomes for patients with BRAF-mutated advanced melanoma;
the 3-year OS rate was 44% with dabrafenib + trametinib in COMBI-d [6] and 45% in COMBI-v [7] and
was 38.5% with vemurafenib + cobimetinib in coBRIM [8]. Despite the survival benefits, acquired resistance to
immunotherapies and targeted therapies continues to pose a challenge [3].
In the absence of data from head-to-head studies comparing combination CTLA-4/PD-1 inhibitors with
combination BRAF/MEK inhibitors, clinicians may consider cross-trial comparisons to assess the relative benefits
to patients treated with either immunotherapy or targeted therapy combinations. Although cross-trial comparisons
are inherently biased, some statistical tools can mitigate such bias and produce potentially more accurate findings.
In this regard, a matching-adjusted indirect comparison [9–11] is a widely accepted approach in health economic
settings that can derive indirect comparisons among treatments when head-to-head trial data are not available.
The method incorporates individual patient data from trials of one treatment to match baseline summary statistics
(aggregate data) reported from trials of another treatment [9]. Using several examples from different therapeutic
areas, Signorovitch et al. have demonstrated the benefits of this matching approach – in particular, how the use of
individual patient data and a matching-adjusted comparison can provide greater adjustment for observed cross-trial
differences compared with naive comparisons based only on published aggregate data. However, there can be
unobserved differences that may result in residual confounding, which is a limitation of this approach [9]. There
have been a number of studies that have utilized matching-adjusted indirect comparisons in oncology settings,
including health technology assessments [12–16].
In this study, we have conducted a matching-adjusted indirect comparison to assess the relative OS, progression-
free survival (PFS) and objective response rate (ORR) between combination CTLA-4/PD-1 inhibitors and com-
bination BRAF/MEK inhibitors in treatment-naive patients with BRAF-mutant advanced melanoma. Safety was
also compared between immunotherapy and targeted therapies.
Methods
Study populations
Two matching-adjusted indirect comparisons were conducted: a comparison of nivolumab + ipilimumab with
dabrafenib+ trametinib; and a comparison of nivolumab+ ipilimumab with vemurafenib+ cobimetinib. Patient-
level data for nivolumab+ ipilimumab were obtained from the Phase III CheckMate 067 (NCT01844505) [17] and
Phase II CheckMate 069 (NCT01927419) [18] studies, whereas aggregate data for comparators were obtained from
the published COMBI-d [19,20], COMBI-v [7,21], and coBRIM [8,22] Phase III studies. The comparator aggregate
data included published summary-level baseline characteristics, OS, PFS, and ORR outcomes.
To provide a larger sample size in these analyses, the nivolumab + ipilimumab arms of CheckMate 067 and
069 were pooled, as well as the dabrafenib + trametinib arms of the COMBI-d and COMBI-v trials. Each pair of
treatment arms within the CheckMate and COMBI studies used identical dosages and treatment schedules, had
similar inclusion/exclusion criteria, and had identical tumor assessment schedules. The most significant difference
in the nivolumab + ipilimumab treatment arm, compared with targeted therapies, was the exclusion of patients
with autoimmune diseases, which occur in 5% to 8% of patients withmetastatic melanoma [23].A notable difference
between the dabrafenib + trametinib studies is that COMBI-d was double-blind, whereas COMBI-v was open-
label. Because the reference arms of the studies were not used in this analysis and the outcomes were assessed
according to Response Evaluation Criteria In Solid Tumors version 1.1 in both studies, this difference was not
expected to create bias in the comparison.
All studies were similar in study design, with minor differences in tumor assessment schedules (Table 1). The
most significant difference among the CheckMate, COMBI, and coBRIM studies was related to the population of
patients with BRAF wild-type tumors; whereas CheckMate 067 and 069 included patients with both BRAF-mutant
and wild-type tumors, the COMBI and coBRIM studies comprised only patients with BRAF-mutant tumors.
To adjust for this difference, only patients with BRAF-mutant tumors enrolled in CheckMate 067 and 069 were
included in these analyses.
10.2217/imt-2018-0208 Immunotherapy (Epub ahead of print) future science group
Indirect comparison of immunotherapy & targeted therapy Research Article
Table 1. Comparison of key design features of CheckMate, COMBI, and coBRIM trials.
CheckMate 067† (N = 945) CheckMate 069† (N = 142) COMBI-d (N = 423) COMBI-v (N = 704) coBRIM (N = 495)
Treatments NIVO + IPI: NIVO
1 mg/kg + IPI 3 mg/kg iv.
Q3W for 4 doses, then
NIVO 3 mg/kg iv. Q2W
NIVO: 3 mg/kg iv. Q2W
IPI: 3 mg/kg iv. Q3W for 4
doses
NIVO + IPI: NIVO
1 mg/kg + IPI 3 mg/kg iv.
Q3W for 4 doses, then
NIVO 3 mg/kg iv. Q2W
IPI: 3 mg/kg iv. Q3W for 4
doses
DAB + TRAM: DAB
150 mg PO BID + TRAM
2 mg PO QD
DAB: 150 mg PO BID
DAB + TRAM: DAB
150 mg PO BID + TRAM
2 mg PO QD
VEM: 960 mg PO BID
VEM + COBI: VEM 960 mg
PO BID + COBI 60 mg PO
QD
VEM: 960 mg PO BID
Tumor assessment
schedule
At 12 weeks, then every 6 weeks for 48 weeks, then
every 12 weeks thereafter
Every 8 weeks to 56 weeks, then every 12 weeks
thereafter
Every 8 weeks
Mean follow-up
(estimated)
25.7 months 16.7 months 23.0 months 23.8 months 20.3 months
Melanoma diagnosis Unresectable stage III or stage IV Unresectable stage IIIC or stage IV
Treatment history No prior systemic treatment for advanced disease
BRAF status Wild-type and mutant Mutant
†Patient-level data were restricted to BRAF-mutant populations.
BID: Twice daily; COBI: Cobimetinib; DAB: Dabrafenib; IPI: Ipilimumab; iv.: Intravenous; NIVO: Nivolumab; PO: Per os (by mouth); Q2W: Every 2 weeks; Q3W: Every 3 weeks; QD: Once
daily; TRAM: Trametinib; VEM: Vemurafenib.
Overview of matching-adjusted indirect comparison approach
Weights for this analysis derived from a propensity-score-type equation (a method of moments logistic regression)
predicted the odds of each index patient being from either the index (i.e., nivolumab + ipilimumab) or the
comparator (i.e., BRAF + MEK inhibitor) population as a function of selected matching baseline characteristics.
Mean values were used to estimate the coefficients of the equation because patient-level data were not available for
BRAF + MEK inhibitors. These weights were then applied to the index patients, ensuring that the reweighted
index baseline characteristics would match the comparator baseline characteristics. The adjustment approach is
summarized in Figure 1.
The effective sample size1 of the index population was calculated from the weights. To ensure that the increase
in uncertainty is reflected in the final relative effectiveness estimates, the index cohort weights were renormalized
so they sum to the effective sample size.
Selection of matching variables
When conducting a matching-adjusted indirect comparison in the absence of a common reference arm in the index
and comparator studies, adjustments should be made for all prognostic factors and treatment effect modifiers [9].
Accordingly, in this analysis, matching was done on all reported patient characteristics that were determined to be
of clinical relevance and predictive of outcomes.
The nivolumab + ipilimumab versus dabrafenib + trametinib comparison was matched based on patient
characteristics including median age, sex, metastasis stage (M0 vs M1a vs M1b vs M1c), Eastern Cooperative
Oncology Group (ECOG) performance status (0 vs ≥1), lactate dehydrogenase (LDH) (>upper limit of normal
[ULN] vs≤ULN) level, number of disease sites (>3 vs≤3) and prior immunotherapy (cytokines and investigational
vaccines). BRAF mutation subtype (V600E or V600K) was not adjusted for, as it was not considered predictive of
clinical outcomes. Visceral disease definitions in CheckMate and COMBI did not align, so visceral disease was not
adjusted for; however, adjustment for M stage also involves an adjustment for visceral metastasis (M1a vs M1b and
M1c).
The nivolumab + ipilimumab versus vemurafenib + cobimetinib comparison was matched based on patient
characteristics including median age (<65 vs ≥65), sex, race (white vs other), geographic region (North America vs
Europe vs rest of world), metastasis stage (M0 vs M1a vs M1b vs M1c), LDH (>ULN vs ≤ULN), ECOG status
(0 vs ≥1) and history of brain metastases. BRAF mutation subtype and prior adjuvant therapy were not adjusted
for, as they were not considered to be predictive of clinical outcomes.
1 The effective sample size is given by (�wi)2/(�wi2), where wi are the individual weights derived for patients in the index trial.
future science group 10.2217/imt-2018-0208
Research Article Atkins, Tarhini, Rael et al.
NIVO + IPI
n = 409
(CheckMate 067 and 069 patient-level data)
DAB + TRAM
n = 563
VEM + COBI
n = 247
COMBI-v and COMBI-d/coBRIM published data
DAB + TRAM
n = 563
VEM + COBI
n = 247
(patient populations are unchanged)
NIVO + IPI
n = 124
NIVO + IPI
matched OS, PFS and ORR
Compare efficacy
weighted Cox models for OS and PFS,
weighted logistic regression for ORR
BRAF + MEKi
published OS*, PFS* and ORR
NIPO + IPI vs BRAF + MEKi
Relative efficacy
OS HRs, PFS HRs, ORR ORs
NIVO + IPI ESS = 106.3 vs DAB + TRAM
NIVO + IPI ESS = 59.2 vs VEM + COBI
BRAF MT BRAF WT Baseline meansdo no: match
Weighted NIVO + IPI
baseline means
match BRAF + MEKi
means
Exclude BRAF WT patients
Apply MAIC weights
Apply MAIC weights to outcomes
Weight adjust relative impact
of each NIVO + IPI patient
Figure 1. Matching-adjusted indirect comparison approach.
*Virtual patient-level data were generated from digitized curves using the Guyot et al. approach.
BRAF + MEKi: BRAF and MEK inhibitors; ESS: Effective sample size (used to quantify the information lost during matching); HR: Hazard
ratio; MT: Mutant; OR: Odds ratio; WT: Wild type.
Comparisons of efficacy outcomes
To compare OS and PFS, the Kaplan–Meier curves for the comparators were digitized using ENGAUGE [24]
and used to generate virtual patient-level data [25]. Virtual patient-level data consisted of event and censor times,
equal in number to the initial N at risk, which closely reproduced the digitized Kaplan–Meier curve. The virtual
patient-level data were assigned weights of 1 and combined with the nivolumab + ipilimumab weighted outcomes.
Weighted Kaplan–Meier curves were computed and weighted Cox models fitted to estimate hazard ratios (HRs)
with 95% CIs.
To compare ORRs, published responder counts for the comparator population were combined with the weighted
nivolumab + ipilimumab outcomes and analyzed using weighted logistic regression to derive ORs with 95% CIs.
Comparisons of safety outcomes
Safety endpoints are primarily associated with treatment exposure and generally are not predictable from baseline
characteristics; therefore, an unadjusted comparison of adverse event rates is more reliable than a matching-adjusted
indirect comparison. For nivolumab + ipilimumab, adverse event counts were extracted from the CheckMate
studies using the full safety populations and not just thosewith BRAF mutations, as BRAF mutation status is not
10.2217/imt-2018-0208 Immunotherapy (Epub ahead of print) future science group
Indirect comparison of immunotherapy & targeted therapy Research Article
Table 2. Baseline characteristics before and after matching for nivolumab + ipilimumab versus dabrafenib + trametinib.
Characteristic, % Before matching After matching
NIVO + IPI (n = 124) DAB + TRAM (n = 563) NIVO + IPI (ESS = 106.3) DAB + TRAM (n = 563)
Age ≤55 years (DAB + TRAM
median)
43.5 50.0 50.0 50.0
Sex
– Male 62.1 56.7 56.7 56.7
– Female 37.9 43.3 43.3 43.3
M stage
– M0 5.6 3.4 3.4 3.4
– M1a 23.4 13.2 13.2 13.2
– M1b 15.3 18.9 18.9 18.9
– M1c 55.6 64.6 64.6 64.6
LDH level
– ≤ULN 65.9 65.2 65.2 65.2
– �ULN 34.1 34.8 34.8 34.8
ECOG performance status
– 0 76.6 72.0 72.0 72.0
– ≥1 23.4 28.0 28.0 28.0
Number of disease sites
– ≥3 50.0 49.0 49.0 49.0
– �3 50.0 51.0 51.0 51.0
Prior therapy in non-metastatic
setting
16.9 21.0 21.0 21.0
Not used in matching: BRAF mutation status and visceral disease (study definitions may differ and are redundant with metastasis stage).
DAB: Dabrafenib; ECOG: Eastern Cooperative Oncology Group; IPI: Ipilimumab; LDH: Lactate dehydrogenase; NIVO: Nivolumab; TRAM: Trametinib; ULN: Upper limit of normal.
thought to be predictive of adverse event rates. Adverse events that had been extracted for any of the BRAF + MEK
inhibitors or had incidence rates ≥10% were included. Adverse event counts for the BRAF + MEK inhibitors
were extracted from the primary publications of COMBI-d, COMBI-v and coBRIM studies with incidence rates
≥10% or otherwise noted as an adverse event of interest. Adverse event counts were used to compute the adverse
event rates along with 95% Clopper–Pearson CIs. Where possible, ORs with 95% CI were computed via logistic
regression comparing adverse events from nivolumab + ipilimumab with BRAF + MEK inhibitors.
Results
Baseline characteristics
Before matching in the first comparison, the baseline characteristics of both index (nivolumab + ipilimumab) and
comparator (dabrafenib + trametinib) populations were generally similar (Table 2). The nivolumab + ipilimumab
population was slightly older (43.5 vs 50.0% were ≤55 years), with a male preponderance (62.1 vs 56.7%) and
more patients were likely to have stage M1a cancer (23.4 vs 13.2%) and less likely to have stage M1c cancer (55.6
vs 64.6%) compared with the dabrafenib + trametinib population. After matching, the effective sample size was
106.3, which was relatively large (86.4% of the original sample size), indicating that the populations were similar
before adjustment.
Before matching in the second comparison, there were differences in baseline characteristics between the index
(nivolumab + ipilimumab) and comparator (vemurafenib + cobimetinib) populations (Table 3). These included
differences in age, sex, race and geographic region. Notably, nivolumab + ipilimumab patients were more likely
to have stage M1a cancer (23.4 vs 16.2%) and less likely to have elevated LDH (34.1 vs 46.3%) compared with
vemurafenib + cobimetinib. After matching, the effective sample size was 59.2, which was 48.1% of the original
sample size; sample size losses of approximately 50% have been reported [12] in matching-adjusted comparisons.
Overall survival
In both comparisons, the OS of nivolumab + ipilimumab decreased after matching adjustment relative to an
unadjusted comparison (Table 4). The Cox HR (95% CI) for nivolumab + ipilimumab versus dabrafenib + tram-
future science group 10.2217/imt-2018-0208
Research Article Atkins, Tarhini, Rael et al.
Table 3. Baseline characteristics before and after matching for nivolumab + ipilimumab versus vemurafenib +
cobimetinib.
Characteristic, % Before matching After matching
NIVO + IPI (n = 124) VEM + COBI (n = 247) NIVO + IPI (ESS = 59.2) VEM + COBI (n = 247)
Age
– ≤56 years (VEM + COBI
median)
45.2 50.0 50.0 50.0
– �65 years 74.2 74.1 74.1 74.1
– ≥65 years 25.8 25.9 25.9 25.9
Sex
– Male 62.1 59.1 59.1 59.1
– Female 37.9 40.9 40.9 40.9
Race
– White 98.4 91.9 91.9 91.9
– Non-white 1.6 8.1 8.1 8.1
Geographic region
– North America 33.9 10.1 10.1 10.1
– Europe 48.4 73.7 73.7 73.7
– Rest of world 17.7 16.2 16.2 16.2
M stage
– M0 5.6 8.5 8.5 8.5
– M1a 23.4 16.2 16.2 16.2
– M1b 15.3 16.2 16.2 16.2
– M1c 55.6 59.1 59.1 59.1
LDH level
– ≤ULN 65.9 53.7 53.7 53.7
– �ULN 34.1 46.3 46.3 46.3
ECOG performance status
– 0 76.6 75.7 75.7 75.7
– ≥1 23.4 24.3 24.3 24.3
History of brain metastases 1.6 0.4 0.4 0.4
Not used in matching: BRAF mutation status and prior adjuvant therapy.
COBI: Cobimetinib; ECOG: Eastern Cooperative Oncology Group; ESS: Effective sample size; IPI: Ipilimumab; LDH: Lactate dehydrogenase; NIVO: Nivolumab; ULN: Upper limit of normal;
VEM: Vemurafenib.
etinib was 0.58 (0.42, 0.80) before matching and 0.64 (0.46, 0.89) after matching. The Cox HR (95% CI)
for nivolumab + ipilimumab versus vemurafenib + cobimetinib was 0.53 (0.38, 0.75) before matching and 0.56
(0.36, 0.89) after matching. This change after matching suggests that the comparator populations contained slightly
higher-risk patients before the adjustment. Nevertheless, the HRs after matching showed a strong and statistically
significant benefit for nivolumab + ipilimumab over both BRAF + MEK inhibitor regimens.
The overall Cox HRs did not reflect the nonproportionality in the OS comparisons between nivolumab + ip-
ilimumab and comparators. In both comparisons, the nivolumab + ipilimumab curves closely followed the
comparator curves for the first 12 months, after which they started to plateau while the comparator curves contin-
ued to drop. To illustrate, the 1-year OS rate was 73.0% for nivolumab + ipilimumab (matched) versus 72.6% for
dabrafenib + trametinib. Starting at 12 months, the survival curves separate in favor of nivolumab + ipilimumab
with a 2-year OS rate of 64.7%, whereas the dabrafenib + trametinib survival curves continue to fall to 51.3%
(Figure 2A). Similar trends were noted in the comparison against vemurafenib + cobimetinib (Figure 2B). Pro-
portionality tests confirmed a statistically significant violation of the proportional hazards hypothesis. Accordingly,
interval Cox models fitted with a single boundary point at 12 months showed insignificant differences in HRs in
the first 12 months, but statistically significant benefit for nivolumab + ipilimumab over the comparators in the
12+ month analyses (Table 4).
10.2217/imt-2018-0208 Immunotherapy (Epub ahead of print) future science group
Indirect comparison of immunotherapy & targeted therapy Research Article
Table 4. Comparative effectiveness estimates before and after matching.
NIVO + IPI versus DAB + TRAM before matching NIVO + IPI versus DAB + TRAM after matching
Estimate (95% CI) p-value Estimate (95% CI) p-value
Overall survival
Overall HR 0.58 (0.42, 0.80) 0.001 0.64 (0.46, 0.89) 0.009
0–12 months HR 0.85 (0.57, 1.26) 0.411 1.00 (0.67, 1.49) 0.997
12+ months HR 0.35 (0.20, 0.60) �0.001 0.33 (0.18, 0.60) �0.001
Progression-free survival
Overall HR 0.81 (0.62, 1.05) 0.108 0.83 (0.63, 1.10) 0.189
0–12 months HR 1.07 (0.81, 1.43) 0.636 1.11 (0.82, 1.50) 0.502
12+ months HR 0.28 (0.14, 0.58) 0.001 0.29 (0.14, 0.62) 0.001
Objective response rate
Odds ratio 0.98 (0.65, 1.47) 0.913 0.93 (0.60, 1.44) 0.744
NIVO + IPI versus VEM + COBI before matching NIVO + IPI versus VEM + COBI after matching
Estimate (95% CI) p-value Estimate (95% CI) p-value
Overall survival
Overall HR 0.53 (0.38, 0.75) �0.001 0.56 (0.36, 0.89) 0.014
0–12 months HR 0.94 (0.60, 1.48) 0.799 1.01 (0.57, 1.80) 0.974
12+ months HR 0.27 (0.15, 0.48) �0.0001 0.29 (0.14, 0.63) 0.002
Progression-free survival
Overall HR 0.85 (0.62, 1.16) 0.311 0.94 (0.64, 1.39) 0.759
0–12 months HR 1.17 (0.85, 1.62) 0.3251.33 (0.89, 1.99) 0.165
12+ months HR 0.08 (0.03, 0.27) �0.0001 0.15 (0.04, 0.54) 0.003
Objective response rate
Odds ratio 0.82 (0.52, 1.30) 0.400 0.72 (0.40, 1.29) 0.267
COBI: Cobimetinib; DAB: Dabrafenib; HR: Hazard ratio; IPI: Ipilimumab; NIVO: Nivolumab; TRAM: Trametinib; VEM: Vemurafenib.
MonthsMonths
O
S
 (
%
)
DAB + TRAM
NIVO + IPI unmatched NIVO + IPI matched DAB + TRAM NIVO + IPI unmatched NIVO + IPI matched VEM + COBI
VEM + COBI
100
75
50
25
0
O
S
 (
%
)
100
75
50
25
0
0 6 12 18 24 30 36 0 6 12 18 24 30 3642
A B
Figure 2. Overall survival comparisons. Comparison of OS before and after matching for nivolumab + ipilimumab versus dabrafenib +
trametinib (A) and nivolumab + ipilimumab versus vemurafenib + cobimetinib (B).
Shaded area represents 95% CI.
COBI: Cobimetinib; DAB: Dabrafenib; IPI: Ipilimumab; NIVO: Nivolumab; OS: Overall survival; TRAM: Trametinib; VEM: Vemurafenib.
future science group 10.2217/imt-2018-0208
Research Article Atkins, Tarhini, Rael et al.
MonthsMonths
P
F
S
 (
%
)
DAB + TRAM
NIVO + IPI unmatched NIVO + IPI matched DAB + TRAM NIVO + IPI unmatched NIVO + IPI matched VEM + COBI
VEM + COBI
100
75
50
25
0
P
F
S
 (
%
)
100
75
50
25
0
0 6 12 18 24 30 36 0 6 12 18 20 24 30 3642
A B
Figure 3. Progression-free survival comparisons. Comparison of PFS before and after matching for nivolumab + ipilimumab versus
dabrafenib + trametinib (A) and nivolumab + ipilimumab versus vemurafenib + cobimetinib (B).
Shaded area represents 95% CI.
COBI: Cobimetinib; DAB: Dabrafenib; IPI: Ipilimumab; NIVO: Nivolumab; PFS: Progression-free survival; TRAM: Trametinib; VEM:
Vemurafenib.
Progression-free survival
In both comparisons, the PFS benefit of nivolumab + ipilimumab decreased after the matching adjustment relative
to unadjusted comparison, indicating that the BRAF + MEK inhibitor groups included patients with higher
risk for progression. The Cox HR (95% CI) for nivolumab + ipilimumab versus dabrafenib + trametinib was
0.81 (0.62, 1.05) before matching and 0.83 (0.63, 1.10) after matching (Table 4). The Cox HR (95% CI) for
nivolumab+ ipilimumab versus vemurafenib+ cobimetinib was 0.85 (0.62, 1.16) before matching and 0.94 (0.64,
1.39) after matching. None of the overall PFS comparisons, before or after matching, were statistically significant.
As with OS, nonproportionality was also apparent in the PFS comparisons. Starting at 12 months, the
nivolumab + ipilimumab curves separate and start to plateau while the comparator curves continue to decline. At
12months, the PFS rates were 49.5% for nivolumab+ ipilimumab (matched) versus 48.2% for dabrafenib+ tram-
etinib; at 24 months, rates were 43.2 versus 30.6%, respectively (Figure 3A). Similar patterns were observed for
vemurafenib + cobimetinib comparisons (Figure 3B). Cox models did not show statistically significant differences
in the HRs in the first 12 months. However, a significant benefit for nivolumab + ipilimumab over comparators
was evident in the 12+ month analyses (Table 4).
All studies reported investigator-assessed PFS per RECIST v1.1. Except for COMBI-v, all studies were double-
blind.
Objective response rate
In both comparisons, the ORR for nivolumab + ipilimumab decreased slightly after matching. In the comparison
versus dabrafenib + trametinib, the response rate (95% CI) for nivolumab + ipilimumab was 65.3% (56.3%,
73.6%) before matching and 64.2% (54.3%, 73.3%) after matching; the observed dabrafenib + trametinib rate
was 65.8% (61.8%, 69.8%). In the comparison versus vemurafenib + cobimetinib, the response rate (95% CI) for
nivolumab+ ipilimumab was 65.3% (56.3%, 73.6%) before matching and 62.1% (48.6%, 74.4%) after matching;
the observed vemurafenib + cobimetinib rate was 69.6% (63.5%, 75.3%). ORs were statistically insignificant in
all ORR comparisons (Table 4).
All studies reported investigator-assessed best overall response per RECIST v1.1. Except for COMBI-v, all studies
were double-blind.
10.2217/imt-2018-0208 Immunotherapy (Epub ahead of print) future science group
Indirect comparison of immunotherapy & targeted therapy Research Article
Table 5. Treatment-related adverse events† in nivolumab + ipilimumab versus dabrafenib + trametinib or vemurafenib +
cobimetinib.
Any grade AEs‡
≥ 10%
NIVO + IPI % (95% CI) DAB + TRAM % (95% CI) NIVO + IPI versus DAB + TRAM Odds ratio§
(95% CI)
Any grade Grade 3/4 Any grade Grade 3/4 Any grade Grade 3/4
Any AE 94.6 (91.9, 96.6) 54.1 (49.1, 59.0) 89.5 (86.6, 91.9) 31.6 (25.3, 38.4) 2.1 (1.2, 3.4) 2.6 (1.8, 3.6)
Diarrhea 43.0 (38.1, 48.0) 8.9 (6.3, 12.0) 18.2 (13.2, 24.1) 0.5 (0.0, 2.6) 3.4 (2.3, 5.1) 20.2 (2.8, 148.3)
Fatigue 35.4 (30.7, 40.2) 4.4 (2.6, 6.9) 26.8 (20.9, 33.3) 1.9 (0.5, 4.8) 1.5 (1.0, 2.2) 2.4 (0.8, 7.1)
Pruritus 33.4 (28.9, 38.2) 1.7 (0.7, 3.5) 7.2 (4.1, 11.6) 0 (0, 1.8) 6.5 (3.7, 11.4) NC
Rash 30.2 (25.8, 34.9) 3.0 (1.5, 5.1) 23.9 (18.3, 30.3) 0 (0, 1.8) 1.4 (0.9, 2.0) NC
Nausea 24.8 (20.7, 29.3) 2.0 (0.9, 3.8) 19.6 (14.5, 25.7) 0 (0, 1.8) 1.4 (0.9, 2.0) NC
Pyrexia 18.7 (15.0, 22.8) 1.2 (0.4, 2.8) 51.7 (44.7, 58.6) 7.2 (4.1, 11.6) 0.2 (0.2, 0.3) 0.2 (0.1, 0.5)
Increased ALT 18.2 (14.6, 22.3) 8.4 (5.9, 11.5) 9.6 (5.9, 14.4) 1.9 (0.5, 4.8) 2.1 (1.2, 3.6) 4.7 (1.6, 13.4)
Increased AST 16.7 (13.2, 20.7) 5.9 (3.8, 8.7) 10.5 (6.7, 15.5) 2.9 (1.1, 6.1) 1.7 (1.0, 2.9) 2.1 (0.9, 5.3)
Decreased appetite 16.2 (12.8, 20.2) 1.0 (0.3, 2.5) �10 �10 NC NC
Hypothyroidism 14.7 (11.4, 18.6) 0.3 (0.0, 1.4) �10 �10 NC NC
Vomiting 14.3 (11.0, 18.0) 2.2 (1.0, 4.2) 14.4 (9.9, 19.9) 0.5 (0.0, 2.6) 1.0 (0.6, 1.6) 4.7 (0.6, 37.4)
Colitis 14.0 (10.8, 17.8) 9.6 (6.9, 12.9) �10 �10 NC NC
Hypophysitis 12.8 (6.8, 21.2) 2.1 (0.3, 7.5) �10 �10 NC NC
Maculopapular rash 12.8 (9.7, 16.4) 2.2 (1.0, 4.2) �10 �10 NC NC
Increased lipase 11.1 (8.2, 14.5) 8.4 (5.9, 11.5) �10 �10 NC NC
Arthralgia 10.6 (7.8, 14.0) 0.3 (0.0, 1.4) 16.3 (11.5, 22.0) 0.5 (0.0, 2.6) 0.6 (0.4, 1.0) 0.5 (0.0, 8.2)
Headache 10.6 (7.8, 14.0) 0.7 (0.2, 2.1) 18.7 (13.6, 24.6) 0 (0, 1.8) 0.5 (0.3, 0.8) NC
Vitiligo 10.6 (5.2, 18.7) 0 (0, 3.9) �10 �10 NC NC
Dyspnea 10.2 (7.1, 14.1) 0.6 (0.1, 2.3) �10 �10 NC NC
Chills 7.4 (5.0, 10.4) 0 (0.0, 0.9) 27.8 (21.8, 34.4) 0 (0.0, 1.8) 0.2 (0.1, 0.3) NC
Peripheral edema 1.7 (0.7, 3.5) 0 (0.0, 0.9) 10.5 (6.7, 15.5) 1.0 (0.1, 3.4) 0.2 (0.1, 0.4) NC
NIVO + IPI % (95% CI) VEM + COBI¶ % (95% CI) NIVO + IPI versus VEM + COBI Odds ratio§
(95% CI)
Any grade Grade 3/4 Any grade Grade 3/4 Any grade Grade 3/4
Any AE 94.6 (91.9, 96.6) 54.1 (49.1, 59.0) 97.6 (94.8, 99.1) 59.5 (53.1, 65.7) 0.4 (0.2, 1.1) 0.8 (0.6, 1.1)
†The AEs for immunotherapies and BRAF + MEK inhibitors may be different even though the same AE terms were used.
‡The reporting thresholds were 10% for DAB + TRAM and VEM + COBI and 2% for NIVO + IPI treatment-related AEs.
§Odds ratios were not calculable when either of the AE counts could not be extracted and when either of the AE counts were zero.
¶ Individual treatment-related AE rates were not reported for VEM + COBI.
AE: Adverse event; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; COBI: Cobimetinib; DAB: Dabrafenib; IPI: Ipilimumab; NC: Not calculable; NIVO: Nivolumab; TRAM:
Trametinib; VEM: Vemurafenib.
Safety
Unadjusted adverse events that were considered to be related to treatment were reported in 94.6% of the patients
treated with nivolumab + ipilimumab, 89.5% of those treated with dabrafenib + trametinib and 97.6% of
those treated with vemurafenib + cobimetinib; grade 3/4 adverse events occurred in 54.1, 31.6 and 59.5%,
respectively. The ORs (95% CI) for any grade and grade 3/4 adverse events for nivolumab + ipilimumab versus
dabrafenib + trametinib were 2.1 (1.2, 3.4) and 2.6 (1.8, 3.6), respectively. For nivolumab + ipilimumab versus
vemurafenib + cobimetinib,ORs were 0.4 (0.2, 1.1) and 0.8 (0.6, 1.1) for any grade and grade 3/4, respectively
(Table 5).
Discussion
Treatment strategies in melanoma have undergone a paradigm shift as immuno- and targeted therapies have
made their way into clinical practice. Despite extensive clinical experience, the choice of initial treatment between
combination immunotherapy and combination targeted therapy in patients with BRAF-mutant melanoma remains
complex. In clinical studies, BRAF + MEK inhibitor combinations administered orally to patients with BRAF-
mutant melanoma had the advantage of rapid, predictable and high tumor responses (as high as 67%) [6,7];
however, patients often acquired resistance [3]. The side effects of these targeted inhibitors can be rapidly reversed
future science group 10.2217/imt-2018-0208
Research Article Atkins, Tarhini, Rael et al.
with dose interruptions and reductions [22]. Combination immunotherapy, on the other hand, has been shown
to produce less rapid and slightly lower tumor responses (52% in patients with BRAF-mutant melanoma) in
clinical studies [18], with more frequent and prolonged grade 3/4 adverse events [26] leading to treatment cessation.
However, responses with combination immunotherapy are viewed as more durable [5,18] and can frequently be
sustained even with treatment cessation. In this regard, our recent work has shown that initiating first-line treatment
with immunotherapy (anti-PD-1 + anti-CTLA-4 or anti-PD-1) yields a longer survival benefit compared with
combination BRAF + MEK inhibitors, driven by a long treatment-free interval [27]. Based on this durability of
response, many providers favor immunotherapy for patients with BRAF-mutant melanoma; however, others may
have safety concerns, particularly for those with comorbidities. Consequently, the debate persists regarding the best
initial treatment or optimal sequence of therapies in patients overall and for specific patients identified based on
clinical and tumor-related properties. Although many of these questions are being prospectively investigated with
the Phase III DREAMseq study of dabrafenib + trametinib versus nivolumab + ipilimumab (NCT02224781) [28],
currently there are few data available to guide clinicians and patients in choosing between these options.
In the present study, amatching-adjusted indirect comparison of combination checkpoint inhibitor immunother-
apy and BRAF/MEK targeted therapy was performed to assess the relative benefits of patients treated with either
treatment approach. After adjusting for differences in the baseline characteristics, combination immunotherapy
with nivolumab + ipilimumab had significant survival benefits over BRAF + MEK inhibitors for the treatment of
patients with BRAF-mutant advanced melanoma. Our findings showed that the adjusted outcomes were slightly
lower for nivolumab + ipilimumab on all endpoints compared with the unadjusted outcomes, suggesting that
the BRAF + MEK inhibitor groups included patients with higher baseline risk. It is likely that differences in
cancer stages and LDH levels may have contributed toward the higher baseline risk in patients included in the
BRAF + MEK studies. Yet, the degree of change due to matching in the nivolumab + ipilimumab group was rela-
tively minor compared with the outcome differences between the trials. For instance, the 2-year OS for nivolumab
+ ipilimumab decreased by 2.2% due to matching, but the matched OS was 13.4% greater than dabrafenib +
trametinib. Given the magnitude of these differences, it is highly unlikely that any residual patient differences can
explain the disparate outcomes.
Although short-termmatchedOS andPFSwere similar between nivolumab+ ipilimumab and theBRAF+MEK
inhibitors, significant benefits emerged after 12 months of treatment. Notably, landmark OS and PFS (matched)
at 24 months were 13.4 and 12.6% higher, respectively, for nivolumab + ipilimumab compared with dabrafenib
+ trametinib. These findings provide evidence that long-term outcomes are needed to assess the benefits of
immunotherapy. A comparison of safety outcomes before matching showed a higher occurrence of adverse events
with nivolumab + ipilimumab compared with dabrafenib + trametinib. Although the results were not statistically
significant, patients treated with nivolumab + ipilimumab were less likely to have an adverse event compared
with vemurafenib + cobimetinib. No safety comparison was conducted after matching because adverse events are
primarily exposure related and generally not explainable by baseline characteristics. The specific type of adverse
events associated with nivolumab + ipilimumab is also different from those of BRAF + MEK inhibitors, and
these differences should also be considered when weighing the relative benefit-risk of combination immunotherapy
and targeted therapy. It should also be noted that adverse events from BRAF + MEK inhibitors can be managed
by reducing dose or withholding therapy [22], whereas most grade 3/4 treatment-related adverse events from
immunotherapy would require immune-modulating medication and can take weeks to resolve [26].
Some degree of confounding is inevitable in any indirect comparison. Given the general compatibility and
similarity of study designs and that all baseline characteristics considered clinically relevant were adjusted for, it
is expected that these results are reliable, despite the specific limitations. Limitations of the matching-adjusted
indirect comparison include that the approach cannot adjust for structural differences between studies. The minor
differences in tumor assessment schedules may also introduce some confounding for PFS and ORR but should
not affect OS (the BRAF + MEK inhibitor trials had earlier and more frequent response assessments during the
first 32 weeks of treatment [20–22], which may create a slight bias toward detecting earlier PFS with the targeted
therapies; however, this bias was limited to a period of 4 weeks). As BRAF + MEK inhibitor trials were initiated
before the CheckMate trials, there may be differences in subsequent systemic therapies used in the trials, which may
confound OS outcomes. The studies reported that of all patients who received subsequent therapy, the majority of
nivolumab + ipilimumab patients received subsequent BRAF inhibitor (31%) or MEK inhibitor (24%) therapy [8]
and the majority (41%) of BRAF + MEK patients received subsequent ipilimumab [5]. However, few patients in
the BRAF + MEK inhibitor trials received subsequent anti-PD-1 treatment. Another limitation of the matching
10.2217/imt-2018-0208 Immunotherapy (Epub ahead of print) future science group
Indirect comparison of immunotherapy & targeted therapy Research Article
approach is that the method cannot adjust for unmeasured/unmatched baseline characteristics (BRAF mutation
status was not tested for all patients in CheckMate studies, PD-L1 expression was not measured for BRAF + MEK
inhibitor studies, visceral disease definitions did not align between studies) or for the effect of subsequent therapies.
In addition, including patients and data from Phase II and Phase III clinical trials excludes the broader melanoma
population, as patients with active brain metastases, ECOG performance status 2, autoimmune disease and ocular
melanoma typically are excluded from these controlled trials.
Conclusion
After adjusting for patient population differences, nivolumab+ ipilimumab had a statistically significant OS benefit
over BRAF + MEK inhibitors. For both OS and PFS, nivolumab + ipilimumab demonstrated a significant benefit
in analyses starting at 12 months, indicating that immunotherapy has a more durable benefit than the comparator
targeted therapies. Ongoing randomized studies (NCT02224781; NCT02631447) comparing the outcomes of
patients initiating treatment with nivolumab + ipilimumab or BRAF + MEK inhibitors will address the issue of
confounding by subsequenttreatment and are needed to validate these results.
Summary points
• Head-to-head studies comparing combination CTLA-4/PD-1 inhibitors with combination BRAF/MEK inhibitors for
the treatment of patients with BRAF-mutant advanced melanoma are unavailable. In their absence, two
matching-adjusted indirect comparisons were conducted: a comparison of nivolumab + ipilimumab with
dabrafenib + trametinib and a comparison of nivolumab + ipilimumab with vemurafenib + cobimetinib.
• The analysis was based on patient-level data for nivolumab + ipilimumab (CheckMate 067/069 studies) and
summary-level data for the Phase III BRAF + MEK inhibitor trials (COMBI-d, COMBI-v and coBRIM studies), and
adjusted for differences in baseline patient and clinical characteristics.
• After adjusting for differences in the baseline characteristics, combination immunotherapy with nivolumab +
ipilimumab had a significant survival benefit over BRAF + MEK inhibitors for the treatment of patients with
BRAF-mutant advanced melanoma.
• For both overall survival and progression-free survival, nivolumab + ipilimumab demonstrated a significant
benefit in analyses starting at 12 months, indicating that the benefit observed with combination immunotherapy
emerges later and may be more durable compared with targeted therapies.
Financial & competing interests disclosure
This study was supported by Bristol-Myers Squibb (Princeton, NJ, USA). MB Atkins has disclosed a consulting role with Bristol-Myers
Squibb, Merck, Novartis, Roche, Exelixis, Eisai, Pfizer, Agenus, NewLink Genetics and Array BioPharma, and advisory role with
Merck, Novartis, and Bristol-Myers Squibb, and has received research funding from Bristol-Myers Squibb. A Tarhini has disclosed a
consulting or advisory role with Bristol-Myers Squibb and has received research funding from Bristol-Myers Squibb, Merck Sharp &
Dohme, Amgen, Novartis, Incyte and Prometheus Laboratories. A Tarhini has also disclosed a consulting or advisory role with No-
vartis, Genentech-Roche, Array Biopharma, NewLink Genetics, Incyte, HUYA, EMD Serono, Pfizer, Sanofi-Aventis and Regeneron.
DF McDermott has disclosed a consulting or advisory role with Bristol-Myers Squibb, Merck, Pfizer, Novartis, Eisai, Exelixis, Array
BioPharma, Alkermes, Inc., Jounce Therapeutics, X4 Pharmaceuticals, Peloton Therapeutics, EMD Serono and Genentech BioOn-
cology, and has received research support from Bristol-Myers Squibb, Prometheus Laboratories, Merck, Genentech, Pfizer, Exelixis,
Novartis, X4 Pharmaceuticals, Alkermes, Inc. and Peloton. M Rael and E O’Brien serve as paid consultants for Bristol-Myers Squibb.
K Gupte-Singh, C Ritchings and S Rao are employees of Bristol-Myers Squibb. MB Atkins and DF McDermott are NIH-funded in-
vestigators. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. In de-
velopment of the manuscript, medical writing support was provided by Evidera, with the financial support of Bristol-Myers Squibb.
Editorial assistance was provided by K Parai and C Hunsberger at StemScientific, an Ashfield Company, funded by Bristol-Myers
Squibb.
Acknowledgments
The authors thank the patients and families who made the trials possible and the clinical study teams who participated in the trials.
Study design, data analysis and interpretation, and review of the manuscript occurred in collaboration with Bristol-Myers Squibb
and non-Bristol-Myers Squibb authors.
future science group 10.2217/imt-2018-0208
Research Article Atkins, Tarhini, Rael et al.
Author contributions
All authors participated in the development of this manuscript and in the decision to submit this manuscript for publication. This
analysis was designed and conducted by M Rael, K Gupte-Singh, and E O’Brien. MB Atkins, DF McDermott, A Tarhini, K Gupte-
Singh, C Ritchings and S Rao had a role in formulating the concept of the review, and editing and reviewing the manuscript.
Data sharing
The BMS policy on data sharing may be found at www.bms.com/researchers-and-partners/independent-research/data-sharing-r
equest-process.html.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license,
visit http://creativecommons.org/licenses/by-nc-nd/4.0/
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