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VOLUME
36
•
NUMBER
17
•
JUNE
10,
2018
JOURNAL OF CLINICAL ONCOLOGY
R A P I D
C O M M U N I C A T I O N
Durable Complete Response After Discontinuation of
Pembrolizumab in Patients With Metastatic Melanoma
Caroline Robert, Antoni Ribas, Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu,
Jeffrey S. Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana Dronca, Amita Patnaik, Hassane Zarour, Richard
Kefford, Peter Hersey, Jin Zhang, James Anderson, Scott J. Diede, Scot Ebbinghaus, and F. Stephen Hodi
Author affiliations and support information
(if applicable) appear at the end of this
article.
Published at jco.org on December 28,
2017.
Processed as a Rapid Communication
manuscript.
Clinical trial registration: NCT01295827.
Corresponding author: Caroline Robert,
MD, PhD, Institut Gustave Roussy,114
rue Edouard Vaillant, 94805, Villejuif Paris
Sud, France; e-mail: [email protected]
gustaveroussy.fr.
© 2017 by American Society of Clinical
Oncology
0732-183X/18/3617w-1668w/$20.00
A
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Purpose
Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete
response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient
disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and
long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001
study (ClinicalTrials.gov identifier: NCT01295827).
Patients and Methods
Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three
dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for $ 6 months
and at least two treatments beyond confirmed CR could discontinue therapy. Response was
assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For
this analysis, CR was defined per investigator assessment, immune-related response criteria, and
potential predictors of CR were evaluated using univariate and multivariate analyses.
Results
Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data
cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen
(13.3%) patients continued to receive treatment for a median of $ 40 months. Pembrolizumab was
discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without
additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in
all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for
observation. Tumor size and programmed death-ligand 1 status were among the baseline factors
independently associated with CR by univariate analysis.
Conclusion
Patients with metastatic melanoma can have durable complete remission after discontinuation of
pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years
from discontinuation provides hope for a cure for some patients. The mechanisms underlying
durable CR require further investigation.
J Clin Oncol 36:1668-1674. © 2017 by American Society of Clinical Oncology
INTRODUCTION
ASSOCIATED CONTENT
See accompanying Oncology
Grand Rounds on page 1649
Data Supplement
DOI: https://doi.org/10.1200/JCO.
2017.75.6270
DOI: https://doi.org/10.1200/JCO.2017.
75.6270
1668
Prognosis in patients with metastatic melanoma has
historically been poor, with a median overall survival
(OS) of , 1 year and a 10-year survival rate of approximately 10%.1,2 Melanoma treatment evolved
with the introduction of targeted therapy for BRAF
mutant disease and immune checkpoint inhibitors
for patients with advanced disease regardless of
BRAF mutation status. Ipilimumab, a monoclonal
antibody against cytotoxic T-lymphocyte antigen 4
(CTLA-4), was the first checkpoint inhibitor to
demonstrate activity in advanced melanoma, with an
objective response rate of 6% to 11% and median OS
of 9 months to 11 months.3-5 The anti–programmed
death 1 (PD-1) monoclonal antibodies pembrolizumab and nivolumab, which block binding of
PD-1 to its ligands PD-L1 and PD-L2, provided
response rates of 30% to 40% and median OS of
. 2 years in patients with metastatic melanoma.6-9
Pembrolizumab has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types, and is currently approved in . 60
countries for one or more advanced malignancies,
including unresectable or metastatic melanoma.
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Complete Responses in Melanoma After Pembrolizumab
In the multicohort, phase 1b KEYNOTE-001 study
(ClinicalTrials.gov identifier: NCT01295827), pembrolizumab monotherapy provided an objective response rate of 33% per Response
Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) by
independent central review in patients with advanced melanoma.6 The
two main goals of the current analysis were to (1) characterize
complete response (CR) in terms of time to response, duration of
response, and outcomes for patients from the time of CR and from
the time of discontinuation of treatment after CR; and (2) identify
potential predictors of these optimal treatment outcomes with use
of pembrolizumab in the KEYNOTE-001 study.
METHODS
Study Design and Patient Population
KEYNOTE-001 was an open-label, phase 1b clinical trial that included multiple cohorts of patients with advanced solid tumors, including
melanoma and non–small-cell lung cancer. Detailed eligibility criteria for
the patients with ipilimumab-naive or ipilimumab-treated advanced melanoma were published previously by Ribas et al.6 Briefly, eligible patients
were $ 18 years of age with confirmed metastatic melanoma, measurable
disease per immune-related response criteria (irRC),10 Eastern Cooperative
Oncology Group performance status (ECOG PS) 0 or 1, no history of
chemotherapy within 4 weeks of first pembrolizumab dose, and no history
of treatment targeting the PD-1/PD-L1 pathway. Patients were enrolled in
nonrandomized and randomized cohorts.
Treatment and Assessments
Patients received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg
every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient or investigator decision to withdraw. After
a protocol amendment, patients who experienced CR, confirmed by two
imaging scans $ 4 weeks apart, and who received pembrolizumab treatment
of $ 6 months could, at the discretion of the investigator and if the patient
desired, discontinue treatment after receiving at least two pembrolizumab
doses beyond the initial determination of CR. Patients were not considered
to have achieved CR if they had undergone surgery or radiation for residual
disease. Tumor response was assessed every 12 weeks by independent central
review using RECIST v1.1 (for determining efficacy) and by investigator
review using irRC (for patient management).
For the purpose of this analysis, CR was defined using investigator
response per irRC. Disease-free survival (DFS) was defined as the time
from declaration of CR to documented disease progression or death from
any cause; for patients who did not experience an event, CR duration was
censored at the time of their last disease evaluation. Duration of CR from
time of discontinuation of pembrolizumab was calculated similarly.
Statistical Analysis
All analyses were performed in the treated population, which was
defined as all patients who received at least one dose of pembrolizumab. CR
rates and associated 95% confidence intervals (CIs) were estimated using
the Clopper-Pearson method. DFS was estimated using the Kaplan-Meier
method. SAS software, version 9.4 (SAS Institute, Cary, NC), was used for
all analyses. Several potential prognostic baseline factors (Supplemental
Data) were studied in relation to response. PD-L1 expression was assessed
using a clinical trial immunohistochemistry assay (PD-L1 IHC 22C3
pharmDx; Agilent Technologies, Santa Clara, CA) and the 22C3 antibody
(Merck, Kenilworth, NJ), as previously described by Daud et al11; PD-L1
positivity was defined as $ 1% staining in tumor cells and mononuclear
inflammatory cells. Factors identified using a univariate analysis were
further examined in a multivariate analysis using a step-wise regression for
jco.org
variable selection. Analyses were performed using a data cutoff date of
September 1, 2016.
RESULTS
Patients
Of the 655 patients with advanced melanoma who received at
least one dose of pembrolizumab, 104 (15.9%) were still receiving
treatment as of the data cutoff date; median follow-up was 43 months
(range, 36 to 57 months). The most common reasons for treatment
discontinuation were progressive disease (41.7%) and adverse events
(AEs; 25.0%). Median duration of pembrolizumab exposure was
6 months (range, 1 day to 55 months).
Clinical Status
Median OS in all 655 treated patients was 23.8 months
(95% CI, 20.2-30.4), with 3-year and 4-year survival estimates of
42% and 37%, respectively. In the 152 treatment-naive patients, the
3-year and 4-year survival estimates were 51% and 48%, respectively.
In the 561 treated patients with an evaluable first clinical response
assessment, CR was the first radiologic response assessment in only
nine patients (1.6%) per irRC, as evaluated by investigator review. In
the 655 overall treated patients, across all assessments, 105 patients
had a best confirmed overall response of CR, as evaluated by investigator review, for a CR rate of 16.0% (95% CI, 13.3% to 19.1%;
Fig 1). Median time to first objective response was 3 months (range,
0.5 to 11 months); median time to CR was 12 months (range, 3 to
36 months). Notably, 84 of 105 patients (80.0%) with CR as their
best confirmed overall response had partial response (PR) or CR at
their first radiologic response assessment.
Of the 105 patients with confirmed CR as best overall response, 92 (87.6%) remained in CR after a median follow-up of
30 months from first declaration of CR; median time receiving
treatment was 24 months (range, 1 to 53 months). At the time of
data cutoff, 14 patients (13.3%) were still electively receiving
pembrolizumab, with a median time on treatment of $ 40 months
(range, $ 36 to $ 53 months; Fig 1). Pembrolizumab was discontinued by the other 91 patients (86.7%) who experienced CR,
which included 67 patients (63.8%) who elected to stop treatment
after CR and proceeded to observation without further anticancer
therapy (Fig 1). Among these 67 patients, median time to overall
response was 3 months (range, 0.5 to 11 months), median time to
CR was 13 months (range, 3 to 36 months), and median time
receiving pembrolizumab was 23 months (range, 8 to 44 months;
Fig 2). Median time receiving treatment after achieving CR (CR to
last pembrolizumab dose) was 7 months (range, 0.5 to 41 months).
Of the 67 patients who proceeded to observation without additional anticancer therapy, two (3.0%) died (of cardiac failure and
aspiration, considered unrelated to study treatment or progressive
disease), and four (6.0%) had progressive disease 5.6, 8.5, 22.8, and
37.3 months, respectively, after discontinuing pembrolizumab. Three
of these four patients subsequently started a second course of
pembrolizumab treatment. Of these patients, one remained on
pembrolizumab for 4 months before a second occurrence of
progressive disease and that patient is still alive; one is still
receiving pembrolizumab therapy and has been for approximately
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1669
Robert et al
Treated with pembrolizumab
(N = 655)
Had a best confirmed
overall response of CR
per irRC by investigator review*
(n = 105; 16%)
Remained on
pembrolizumab
(n = 14; 13%)
Discontinued
pembrolizumab
(n = 91; 87%)
Eligible for a second
course of pembrolizumab, proceeded
to observation without further
anticancer therapy
(n = 67)
Died
(n = 2)
Not eligible for a second
course of pembrolizumab,
discontinued pembrolizumab
(n = 24)
Remained
in CR
(n = 61)
Had PD
(n = 4)
AEs
(n = 12)
Physician
decision
(n = 7)
PD
(n = 2)
Remained
in CR
(n = 9)
Died
(n = 3)
Died
(n = 1)
Withdrew
consent
(n = 3)
Remained
in CR
(n = 6)
Fig 1. Patient disposition. (*) 92 patients (87.6%) remained in CR as of the data cutoff date. Of the 13 patients (12.4%) not in CR, seven experienced PD and six died. AE,
adverse event; CR, complete response; irRC, immune-related response criteria; PD, progressive disease.
15 months; and one was receiving pembrolizumab therapy for
approximately 9 months and subsequently died as a result of malignant neoplasm progression.
Most patients (n = 61; 91.0%) maintained CR after a median
time off pembrolizumab of 22 months (range, 4 to 46 months). For
the remaining 24 patients (22.9%) who experienced CR but were
Time to PD or last assessment
Last dose
Fig 2. Time to response and durability of
response from the start of therapy in complete
responders who discontinued pembrolizumab
and proceeded to observation (n = 67). Bar
length is equivalent to the time to the last
imaging assessment by investigator review.
CR, complete response; PD, progressive disease; PR, partial response.
CR
PR
PD
Time to death
0
6
12
18
24
30
36
42
48
54
60
Time Since the Start of Therapy (months)
1670
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JOURNAL OF CLINICAL ONCOLOGY
Complete Responses in Melanoma After Pembrolizumab
not eligible for a second course of pembrolizumab and who discontinued pembrolizumab because of AEs (n = 12), progressive
disease (n = 2), physician decision to withdraw (n = 7), or patient
withdrawal of consent (n = 3; Fig 1), median time receiving
treatment was 21 months (range, 1 to 44 months). Among the 12
patients who discontinued pembrolizumab because of an AE, three
(25.0%) deaths occurred, one each from respiratory failure, ventricular fibrillation, and cardiorespiratory arrest; all were considered
unrelated to study treatment. The remaining nine (75.0%) patients
remained in CR at data cutoff. Of the seven patients who discontinued per investigator decision to withdraw because of CR, one
(14.3%) died (of lymphoma) and six (85.7%) remained in CR.
Disease-Free Survival
As of the data cutoff date, only seven of 105 patients with CR
experienced confirmed progressive disease, two while receiving initial
pembrolizumab treatment, four after stopping pembrolizumab and
proceeding to observation, and one still reported as receiving pembrolizumab treatment. As of the cutoff date, all seven patients with
progressive disease were alive. For all 105 patients who experienced CR,
the estimated 24-month DFS rate from declaration of CR was 90.9%
(95% CI, 82.5% to 95.4%; Fig 3A). Four of 22 patients who discontinued pembrolizumab treatment for reasons other than progressive disease (AEs [n = 3], protocol violation [n = 1]) and who did
not proceed to observation had died as of the data cutoff date. For the
67 patients who discontinued pembrolizumab after CR for observation, the estimated 24-month DFS rate from treatment discontinuation was 89.9%. For all 89 patients who discontinued pembrolizumab
after CR for reasons other than progressive disease (regardless of
whether they proceeded to observation), the estimated 24-month DFS
rate from treatment discontinuation was 85.8% (Fig 3B).
Potential Predictors of Complete Response
Among the potential prognostic baseline factors explored and
per univariate analysis, age, ipilimumab status, lactate dehydrogenase (LDH) level, ECOG PS, BRAF mutation status, prior BRAF
inhibitor therapy, prior lines of therapy, tumor PD-L1 status, site of
metastasis, tumor size, and albumin level were statistically significantly associated with CR (Table 1).
Among the 655 patients treated, tumor PD-L1 status was
unknown in 146 patients because of missing samples or insufficient
tissue, and target lesion size per central review was unknown in 72
patients; tumor PD-L1 status and baseline tumor size both were
unknown in 22 patients. Among the 459 patients with assessment
data for baseline tumor PD-L1 status and tumor size, the highest
rates of CR (42.7%) occurred in patients with smaller (1 to 5 cm)
PD-L1–positive tumors at baseline (Table 2). Patients with larger
baseline tumors (5 to 90 cm) had a lower CR rate (, 10%), except
for those with baseline tumors 5 to 10 cm and with positive PD-L1
expression who had a CR rate of 20.5%, which was similar to the
CR rate of those patients with smaller tumors (1 to 5 cm) and
negative PD-L1 expression (20.7%).
After adjusting for the association of baseline tumor PD-L1
status and tumor size with CR in a multivariate analysis, only age
(P = .020) was associated with experiencing CR. CR rates were
higher in treatment-naive patients and in those $ 65 years of age
(Supplemental Data).
Because LDH level was a highly significant predictor of CR rate
in univariate analysis, is a known prognostic factor in melanoma
associated with baseline tumor size, and is easier to measure than
baseline tumor size, CR rates were also examined in subsets of
patients defined by LDH level (less than one times the upper level of
normal [ULN]; more than one times the ULN to no more than twice
the ULN; and more than twice the ULN) and tumor PD-L1 status. A
total of 155 patients could not be classified because of unknown LDH
level or unknown tumor PD-L1 status. Only one CR was observed in
a patient whose baseline LDH level was more than twice the ULN. In
patients with baseline LDH level no more than twice the ULN, CR
rates were lower in those with LDH level more than one times the
ULN to no more than twice the ULN than in those with normal
baseline LDH levels (no more than one times the ULN; Supplemental
Data). In patients with normal baseline LDH levels, CR rates were
higher in those with PD-L1–positive tumors (26.0%) than in those
with PD-L1–negative tumors (16.9%). However, after adjusting for
baseline tumor PD-L1 status and tumor size, the LDH level was no
B
100
Disease-Free Survival (%)
Disease-Free Survival (%)
A
90
80
70
60
50
40
30
20
10
0
6
12
18
24
30
36
42
48
100
90
80
70
60
50
40
30
20
10
54
0
Time Since Achieving CR (months)
No. at risk:
All patients 105
6
12
18
24
30
36
42
48
Time Since Stopping Therapy (months)
No. at risk:
97
90
70
63
38
18
9
3
0
All patients 89
75
56
42
26
12
5
1
0
Fig 3. Disease-free survival (A) from time of experiencing complete response (CR) in all patients who achieved CR (n = 105) and (B) from time of discontinuation of
pembrolizumab in patients who discontinued after CR for reasons other than progression (n = 89). The hash marks designate patients who were censored at that time point.
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Robert et al
Table 1. Statistically Significant (P , .05) Univariate Comparisons of CR Rates by Baseline Patient and Disease Characteristics
Characteristic
No. of Patients With CR/Total No. of Patients Per Group
CR Rate (95% CI), %
50/397
55/258
12.6 (9.5 to 16.3)
21.3 (16.5 to 26.8)
62/313
43/342
19.8 (15.5 to 24.7)
12.6 (9.3 to 16.6)
20/249
85/394
8.0 (5.0 to 12.1)
21.6 (17.6 to 26.0)
3/8
12/50
28/89
62/508
37.5
24.0
31.5
12.2
Age group, years
# 64
$ 65
Ipilimumab status
Naive
Exposed
LDH level
. ULN
# ULN
M stage
M0
M1a
M1b
M1c
ECOG PS
0
1
BRAF mutation status
Wild type
Mutant
Prior BRAF inhibitor therapy
Yes
No
Lines of prior therapy
0
1
2
3+
Tumor PD-L1 status
Negative
Positive
Unknown*
Site of metastasis
Lung only
Liver, with or without other sites
Other sites
No baseline metastasis per central review
Tumor burden†
$ 1 to , 5 cm
$ 5 to , 10 cm
$ 10 to , 20 cm
$ 20 to # 90 cm
Unknown*
Albumin level‡,
quartile (g/dL)
1 ($ 2.3 to , 3.7)
2 ($ 3.7 to , 4.1)
3 ($ 4.1 to , 4.4)
4 ($ 4.4 to # 5.6)
Unknown*
P
.003
.012
, .001
, .001
(8.5 to 75.5)
(13.1 to 38.2)
(22.0 to 42.2)
(9.5 to 15.4)
.002
85/444
20/210
19.1 (15.6 to 23.1)
9.5% (5.9 to 14.3)
87/493
17/156
17.6 (14.4 to 21.3)
10.3 (6.0 to 16.1)
7/111
98/544
6.3 (2.6 to 12.6)
18.0 (14.9 to 21.5)
36/157
40/207
16/178
13/113
22.9
19.3
9.0
11.5
13/123
75/386
17/146
10.6 (5.7 to 17.4)
19.4 (15.6 to 23.7)
11.6 (6.9 to 18.0)
29/84
16/201
46/298
14/72
34.5
8.0
15.4
19.4
(24.5 to 45.7)
(4.6 to 12.6)
(11.5 to 20.0)
(11.1 to 30.5)
57/161
21/128
13/155
0/139
14/72
35.4
16.4
8.4
0
19.4
(28.0 to 43.3)
(10.5 to 24.0)
(4.5 to 13.9)
(0 to 2.6)
(11.1 to 30.5)
.028
.002
.001
(16.6 to 30.3)
(14.2 to 25.4)
(5.2 to 14.2)
(6.3 to 18.9)
.024
, .001
, .001
.012
14/136
23/190
34/162
34/165
0/2
10.3
12.1
21.0
20.6
0
(5.7 to 16.7)
(7.8 to 17.6)
(15.0 to 28.1)
(14.7 to 27.6)
(0 to 84.2)
Abbreviations: CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; PD-L1, programmed death
ligand 1; ULN, upper limit of normal.
*Patients with unknown baseline characteristics were excluded from P value calculation.
†Defined as the sum of the longest dimension of all measurable target lesions assessed by Response Evaluation Criteria in Solid Tumor v1.1.
‡The difference in the number of patients per quartile is a result of many patients having an albumin value of exactly 3.7 g/dL.
longer significantly associated with CR, largely because tumor size
and LDH level were highly related.
DISCUSSION
Although data on antitumor activity and safety of immune
checkpoint inhibitors in oncology are abundant, to our knowledge,
1672
this report is the first in-depth analysis of CR in a large cohort of
patients with metastatic melanoma treated with a PD-1 inhibitor.
Similar results were recently published in a smaller retrospective
study in patients with melanoma.12 Among patients with advanced
melanoma enrolled in KEYNOTE-001, pembrolizumab provided
a confirmed best overall response based on investigator assessment
per irRC of CR in 16.2% of patients. Risk for disease progression or
death in patients who experienced CR was low; the 24-month DFS
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JOURNAL OF CLINICAL ONCOLOGY
Complete Responses in Melanoma After Pembrolizumab
Table 2. Response Rates by Baseline Tumor Size and Tumor PD-L1 Status for
the Patients With Available Data (n = 459)
Tumor Size, cm
Tumor PD-L1 Status
No.
PR, %
CR, %
ORR, %
$ 1 to , 5
Positive
Negative
Positive
Negative
Positive
Negative
96
29
78
23
179
54
24.0
6.9
37.2
8.7
24.0
16.7
42.7
20.7
20.5
8.7
5.6
1.9
66.7
27.6
57.7
17.4
29.6
18.5
$ 5 to , 10
$ 10 to # 90*
Abbreviations: CR, complete response; ORR, overall response rate; PD-L1,
programmed death ligand 1; PR, partial response.
*Patients with tumors measuring 10 to 20 cm or 20 to 90 cm at baseline were
pooled because these groups were not statistically different in univariate
analysis.
was estimated to be 90.9% after a median follow-up of 43 months
and a median follow-up of 30 months from the time of first
declaration of CR. The risk for disease progression or death after
CR and discontinuation of pembrolizumab was similarly low; 24month DFS was estimated to be 85.8% for all patients who stopped
treatment of any reason other than progressive disease and was
89.9% for those who discontinued treatment after CR for observation. In patients whose best confirmed overall response was CR,
the majority had PR at first evaluation several months before occurrence of CR (median duration of 11 months between PR and
CR), which is indicative of the delayed responses often seen with
immunotherapy.13
In line with results of previous analyses of the large, randomized, phase 3 KEYNOTE-006 study (ClinicalTrials.gov identifier: NCT01866319), which showed that pembrolizumab has
clinical activity in patients with advanced melanoma regardless of
tumor PD-L1 status, CR was achieved even in patients with PDL1–negative tumors as similarly observed for 10.6% of the patients
in this study.14,15 Analysis of baseline parameters potentially associated with objective response and CR showed that several
baseline factors were associated with CR, many of which are also
well-known prognostic factors like tumor burden, LDH level, and
ECOG PS. When combining tumor burden and PD-L1 expression,
we identified groups of patients with dramatically different objective response and CR rates (Fig 4). Indeed, patients (n = 96) with
target tumor size between 1 and 5 cm and PD-L1–positive tumors
had a CR rate of 42.7% versus 1.9% in patients (n = 54) with large
tumor size and PD-L1–negative tumors. Between these two extremes, CR rates progressively decreased. In multivariate analysis,
there was a similar, although less impressive, variation in CR rate
when combining LDH level and PD-L1 expression status. Difference in CR rates resulting from baseline LDH level, albumin
level, and ECOG PS probably reflect the relationship of these
variables with tumor size.
As of the data cutoff date in the current analysis, 61 of 67
patients (91.0%) who went on to observation after experiencing
CR maintained CR after a median of approximately 2 years after
pembrolizumab discontinuation. This prolongation of CR after
pembrolizumab discontinuation has not been observed with targeted agents for which treatment is typically continued indefinitely.2 Treatment discontinuation for CR was not initially
written into the protocol design for immune checkpoint inhibitors.
On the basis of the results observed during clinical studies, which
include the data presented herein from KEYNOTE-001, achievement of CR is now considered a possible reason for treatment
discontinuation of this class of drugs; however, there is no standard
recommendation for when to stop treatment after CR. Continued
remission after a median of approximately 2 years after discontinuing pembrolizumab treatment is a promising advance in
the field.
However, as with any new paradigm, many questions emerge.
The goal now is to understand the mechanisms underlying such
optimal responses to therapy and the reasons for primary or
secondary resistance in patients who do not experience CR. Additional studies are needed to evaluate the optimum duration of
treatment to achieve prolonged CR, determine when to stop
treatment after CR, and assess the interplay of the various factors
potentially associated with CR. Indeed, KEYNOTE-006 systematically addresses the optimal duration of pembrolizumab treatment by limiting patients to 2 years of treatment. After
approximately 10 months of median follow-up, more than 90% of
patients who had discontinued pembrolizumab after 2 years were
still experiencing CR or continued to have stable disease.16 In the
current study, the prolonged CRs experienced with pembrolizumab provide hope for a cure for advanced melanoma
without the need for additional treatment, a goal that seemed
previously unachievable.
Patients with known tumor size and PD-L1 expression status
CR rate: 76 of 459 patients (16.6%)
Small tumors 1-4.9 cm
CR rate: 47 of 125
patients (37.6%)
PD-L1+
CR rate:
41 of 96
patients
(42.7%)
jco.org
PD-L1−
CR rate:
6 of 29
patients
(20.7%)
Medium tumors 5-9.9 cm
CR rate: 18 of 101
patients (17.8%)
PD-L1+
CR rate:
16 of 78
patients
(20.5%)
PD-L1−
CR rate:
2 of 23
patients
(8.7%)
Large tumors 10-90 cm
CR rate: 11 of 233
patients (4.7%)
PD-L1+
CR rate:
10 of 179
patients
(5.6%)
Fig 4. Regression tree for baseline factors associated with objective response and CR. CR,
complete response; PD-L1, programmed death
ligand 1.
PD-L1−
CR rate:
1 of 54
patients
(1.9%)
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1673
Robert et al
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Caroline Robert, Adil Daud, Jedd D. Wolchok,
Wen-Jen Hwu, Jin Zhang, Scot Ebbinghaus, F. Stephen Hodi
Provision of study materials or patients: Caroline Robert, Antoni Ribas,
Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen
Hwu, Jeffrey S.Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana
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Dronca, Amita Patnaik, Hassane Zarour, Richard Kefford, Peter Hersey, F.
Stephen Hodi
Collection and assembly of data: Caroline Robert, Omid Hamid, Adil
Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffrey S.
Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana Dronca, Amita
Patnaik, Hassane Zarour, Richard Kefford, Peter Hersey, Jin Zhang, Scott J.
Diede, F. Stephen Hodi
Data analysis and interpretation: Caroline Robert, Antoni Ribas, Omid
Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu,
Jeffrey S. Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana Dronca,
Amita Patnaik, Hassane Zarour, Jin Zhang, James Anderson, Scott J. Diede,
Scot Ebbinghaus, F. Stephen Hodi
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
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pembrolizumab with tumor response and survival
among patients with advanced melanoma. JAMA
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8. Robert C, Long GV, Brady B, et al: Nivolumab
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(CheckMate 037): A randomised, controlled, open-label,
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10. Wolchok JD, Hoos A, O’Day S, et al: Guidelines for the evaluation of immune therapy activity in
solid tumors: Immune-related response criteria. Clin
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11. Daud AI, Wolchok JD, Robert C, et al: Programmed death-ligand 1 expression and response to
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12. Ladwa R, Atkinson V: The cessation of antiPD-1 antibodies of complete responders in metastatic melanoma. Melanoma Res 27:168-170, 2017
13. Hodi FS, Hwu WJ, Kefford R, et al: Evaluation of immune-related response criteria and
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14. Carlino MS, Ribas A, Gonzalez R, et al:
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vs ipilimumab (IPI) for advanced melanoma. Proc Am
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15. Daud A, Blank CU, Robert C, et al: KEYNOTE006 study of pembrolizumab (pembro) versus ipilimumab (ipi) for advanced melanoma: Efficacy by PDL1 expression and line of therapy. J Clin Oncol 34:
9513, 2016 (15_suppl)
16. Robert C, Long GV, Schachter J, et al: Longterm outcomes in patients (pts) with ipilimumab (ipi)naive advanced melanoma in the phase 3 KEYNOTE006 study who completed pembrolizumab (pembro)
treatment. J Clin Oncol 35:9504, 2017 (15_suppl)
Affiliations
Caroline Robert, Gustave Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France; Antoni Ribas, University of
California, Los Angeles; Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles; Adil Daud, University of California, San
Francisco, San Francisco, CA; Jedd D. Wolchok, Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY; Anthony M.
Joshua, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Wen-Jen Hwu, The University of Texas MD Anderson Cancer
Center, Houston; Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Jeffrey S. Weber, H Lee Moffitt
Cancer Center, Tampa; Richard W. Joseph, Mayo Clinic Cancer Center–Florida, Jacksonville, FL; Tara C. Gangadhar, Abramson Cancer
Center at the University of Pennsylvania, Philadelphia; Hassane Zarour, UPMC Hillman Cancer Center, Pittsburgh, PA; Roxana Dronca,
Mayo Clinic, Rochester, MN; Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead; Melanoma Institute
Australia, Wollstonecraft; and Macquarie University, MQ Health, Health Sciences Centre; Peter Hersey, University of Sydney, Sydney, New
South Wales, Australia; Jin Zhang, James Anderson, Scott J. Diede, and Scot Ebbinghaus, Merck & Co., Inc., Kenilworth, NJ; F. Stephen
Hodi, Dana-Farber Cancer Institute, Boston, MA.
Support
Supported by Merck & Co.
Prior Presentation
Presented in part at the 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2016. The current
data were presented in part at the 7th European Association of Dermato Oncology Post-Chicago Melanoma/Skin Cancer Meeting, Munich,
Germany, June 29-30, 2017.
nnn
1674
© 2017 by American Society of Clinical Oncology
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JOURNAL OF CLINICAL ONCOLOGY
Complete Responses in Melanoma After Pembrolizumab
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Caroline Robert
Consulting or Advisory Role: Amgen, Bristol-Myers Squibb, Roche,
Novartis, GlaxoSmithKline, Merck
Antoni Ribas
Stock or Other Ownership: Kite Pharma, Compugen, FLX Bio, CytomX
Therapeutics, Five Prime Therapeutics, Arcus Ventures
Consulting or Advisory Role: Merck, Amgen, Roche, Novartis
Omid Hamid
Consulting or Advisory Role: Amgen, Novartis, Roche, Bristol-Myers
Squibb, Merck
Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Novartis, Amgen
Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst),
Celldex (Inst), Genentech (Inst), Immunocore (Inst), Incyte (Inst), Merck
(Inst), Merck Serono (Inst), MedImmune (Inst), Novartis (Inst), Pfizer
(Inst), Rinat (Inst), Roche (Inst)
Adil Daud
Stock or Other Ownership: Oncosec
Honoraria: EMD Serono, Inovio Pharmaceuticals
Consulting or Advisory Role: Oncosec, Merck, GlaxoSmithKline,
Genoptix
Research Funding: Merck (Inst), GlaxoSmithKline (Inst), Pfizer (Inst),
Roche (Inst), Oncosec (Inst)
Patents, Royalties, Other Intellectual Property: Patent relating to test for
immunotherapy
Jedd D. Wolchok
Stock or Other Ownership: Potenza Therapeutics, Tizona Therapeutics,
Serametrix, Adaptive Biotechnologies, Trieza Therapeutics, Imvaq
Therapeutics
Consulting or Advisory Role: Bristol-Myers Squibb, Merck, MedImmune,
Polynoma, Polaris, Genentech, FStar, Beigene, Sellas Life Sciences, Lilly,
Potenza Therapeutics, Tizona Therapeutics, Amgen, Chugai Pharma,
Adaptive Biotechnologies, Janssen Pharmaceuticals
Research Funding: Bristol-Myers Squibb (Inst), Merck, Roche,
MedImmune
Patents, Royalties, Other Intellectual Property: Co-inventor on an issued
patent for DNA vaccines for treatment of cancer in companion animals,
and on a patent for use of oncolytic Newcastle Disease virus
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Chugai
Pharma, Roche, Janssen, Kadmon, Regeneron
Anthony M. Joshua
No relationship to disclose
Wen-Jen Hwu
Consulting or Advisory Role: Merck
Research Funding: Merck, Bristol-Myers Squibb, GlaxoSmithKline,
MedImmune
Jeffrey S. Weber
Stock or Other Ownership: Altor BioScience, Celldex, CytomX
Therapeutics
Honoraria: Bristol-Myers Squibb, Merck, Genentech, Abbvie,
AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience,
Lion Biotechnologies, Amgen, Roche, Ichor Medical Systems, Celldex,
cCam Biotherapeutics, Pieris , CytomX Therapeutics Pharmaceuticals,
Nektar, Novartis, Medivation, Sellas Life Sciences, WindMIL
Consulting or Advisory Role: Celldex, Ichor Medical Systems, cCam
Biotherapeutics, Lion Biotechnologies, Pieris Pharmaceuticals, Altor
BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen,
AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai,
GlaxoSmithKline CytomX Therapeutics, Nektar, Novartis, Medivation,
Sellas Life Sciences, WindMIL
Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst),
GlaxoSmithKline (Inst), Genentech (Inst), Astellas Pharma (Inst), Incyte
(Inst), Roche (Inst), Novartis (Inst)
Patents, Royalties, Other Intellectual Property: Named on a patent
submitted by Moffitt Cancer Center for an ipilimumab biomarker and on
a patent from Biodesix for an anti-programmed death 1 antibody
biomarker
Travel, Accommodations, Expenses: Bristol-Myers Squibb,
GlaxoSmithKline, Daiichi Sankyo, Pieris Pharmaceuticals, cCam
Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck,
AstraZeneca, Genentech, Novartis
Tara C. Gangadhar
Honoraria: Medscape, Novartis, Merck, Bristol-Myers Squibb, Incyte
Research Funding: Merck (Inst), Incyte (Inst), Bristol-Myers Squibb
(Inst), Roche (Inst)
Richard W. Joseph
Consulting or Advisory Role: Bristol-Myers Squibb, Nektar, Genoptix,
Eisai, Incyte, Novartis, Merck (Inst), Exelixis
Research Funding: Merck (Inst), Bristol-Myers Squibb (Inst), Roche
(Inst), X4P (Inst), Amgen (Inst)
Roxana Dronca
Research Funding: Merck (Inst)
Other Relationship: advisory board member for Elsevier’s Practice Update
Website
Amita Patnaik
Research Funding: Merck (Inst), Pfizer (Inst), AVEO (Inst), Lilly (Inst),
Plexxikon (Inst), Jiangsu Hengrui Medicine (Inst), Symphogen (Inst),
Corvus Pharmaceuticals (Inst), Tesaro (Inst), Bayer (Inst), Abbvie, Aeglea
Biotherapeutics, Alexion Pharmaceuticals, Amgen, Asana Biosciences,
Ascentage Pharma Group, Astex Pharmaceuticals, Calithera Biosciences,
Celgene (Inst), Daiichi Sankyo (Inst), Eisai (Inst), EMD Serono (Inst),
Endocyte (Inst), Forty Seven, Five Prime Therapeutics (Inst), Formation
Biologics (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst), Incyte
(Inst), Merck, Plexxikon, Upsher-Smith, Novartis, Bayer, OncoMed, Teva
(Inst), Zymeworks (Inst), Tesaro (Inst), TaiRx (Inst), Cerulean Pharma
(Inst), Regeneron (Inst), Jiangsu Hengrui Medicine, Macrogenics (Inst)
Hassane Zarour
Research Funding: Merck (Inst), Bristol-Myers Squibb (Inst), Tesaro
(Inst)
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Robert et al
Richard Kefford
Consulting or Advisory Role: Novartis, Merck, Bristol-Myers Squibb,
Teva, Amgen
Speakers’ Bureau: Merck
Travel, Accommodations, Expenses: Bristol-Myers Squibb
Peter Hersey
No relationship to disclose
Jin Zhang
Employment: Merck
Stock or Other Ownership: Merck
James Anderson
Employment: Merck
Scot Ebbinghaus
Employment: Merck
Stock or Other Ownership: Merck
F. Stephen Hodi
Consulting or Advisory Role: Merck, Novartis, Roche, Amgen, EMD
Serono, Bristol-Myers Squibb, Celldex
Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), Roche
(Inst), Novartis (Inst)
Patents, Royalties, Other Intellectual Property: Patent pending as per
institutional policy, and patent pending royalties received on MHC class I
chain-related gene A-related disorders application to institution per
institutional intellectual property policy
Scott J. Diede
Employment: Merck
Stock or Other Ownership: Merck
© 2017 by American Society of Clinical Oncology
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JOURNAL OF CLINICAL ONCOLOGY
Complete Responses in Melanoma After Pembrolizumab
Acknowledgment
We thank the patients and their families and all investigators and site personnel. We also thank Maxine Giannotti for data acquisition
and Roger Dansey for critical review of the manuscript, both from Merck. Medical writing and/or editorial assistance was provided by
Tricia Brown and Payal Gandhi of the ApotheCom pembrolizumab team (Yardley, PA). This assistance was funded by Merck.
Academic advisers, in conjunction with representatives of the company, designed the study. Data were collected by investigators and
site personnel and analyzed in collaboration with senior academic authors and representatives of the study sponsor.
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