rapid communications

Pembrolizumab or Placebo Plus Etoposide

and Platinum as First-Line Therapy for
Extensive-Stage Small-Cell Lung Cancer:
Randomized, Double-Blind, Phase III
KEYNOTE-604 Study
Charles M. Rudin, MD, PhD1; Mark M. Awad, MD, PhD2; Alejandro Navarro, MD3; Maya Gottfried, MD4; Solange Peters, MD, PhD5;
Tibor Cs}oszi, MD6; Parneet K. Cheema, MD7; Delvys Rodriguez-Abreu, MD8; Mirjana Wollner, MD9; James Chih-Hsin Yang, MD, PhD10;
Julien Mazieres, MD, PhD11; Francisco J. Orlandi, MD12; Alexander Luft, PhD, MD13; Mahmut Gümüş, MD14; Terufumi Kato, MD15;
Gregory P. Kalemkerian, MD16; Yiwen Luo, PhD17; Victoria Ebiana, MD17; M. Catherine Pietanza, MD17; and Hye Ryun Kim, MD18 on
behalf of the KEYNOTE-604 Investigators
abstract

PURPOSE Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer
(SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus eto-
poside and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC.
METHODS Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline
placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST
version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective
response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries
were one-sided P 5 .0048 for PFS and .0128 for OS.
RESULTS Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo
plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91;
P 5 .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus
EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI,
0.64 to 0.98; P 5 .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was
70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion
of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab
plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and
74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%.
ASSOCIATED CONCLUSION Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line
CONTENT therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data
Appendix support the benefit of pembrolizumab in ES-SCLC.
Data Supplement J Clin Oncol 38. © 2020 by American Society of Clinical Oncology
Protocol
Author affiliations
and support
information (if INTRODUCTION has remained chemotherapy with etoposide and
applicable) appear Small-cell lung cancer (SCLC) is an aggressive neu- platinum (EP) for the past 30 years. Although EP is
at the end of this associated with high response rates, responses are not
roendocrine malignancy strongly associated with to-
article.
bacco use that accounts for approximately 15% of all durable, and median overall survival (OS) is approxi-
Accepted on April 30,
lung cancers. 1 SCLC is characterized by a rapid mately 10 months.5,6
2020 and published at
ascopubs.org/journal/ doubling time and high growth fraction, and approx- Monoclonal antibodies against programmed death 1
jco on May 29, 2020: imately two thirds of patients present with metastases (PD-1) and its ligand PD-L1 have shown efficacy in
DOI https://doi.org/10.
at diagnosis.2 The 5-year survival rate for patients with patients with ES-SCLC in the monotherapy7,8 and
1200/JCO.20.00793
Written on behalf of
SCLC is only approximately 6%-7%.3,4 Despite ex- combination therapy9,10 settings. In a pooled analysis
the KEYNOTE-604 tensive study of different combinations, standard-of- of the 83 participants who received $ 2 prior therapies
Investigators. care first-line therapy for extensive-stage (ES) SCLC for recurrent or metastatic SCLC before enrolling in the

1
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 Rudin et al

CONTEXT
Key Objective
Small-cell lung cancer (SCLC) is an aggressive cancer associated with a 5-year survival rate of , 10%. Availability of more
efficacious first-line therapy would improve this prognosis. The phase III KEYNOTE-604 study of 453 patients with
previously untreated extensive-stage (ES) SCLC assessed whether the addition of pembrolizumab to standard-of-care
etoposide and platinum (EP) improved progression-free and overall survival.
Knowledge Generated
Although the addition of pembrolizumab to EP did not significantly prolong overall survival, it did significantly prolong the
time that patients lived without disease progression. The adverse event profile of pembrolizumab plus EP was as expected
and generally manageable.
Relevance
Pembrolizumab has clinical activity in ES-SCLC as well as an adverse event profile that allows it to be combined with other
therapies. There is value in exploring pembrolizumab in combination with other therapies in patients with SCLC to identify
a regimen that significantly prolongs overall survival.

KEYNOTE-028 and KEYNOTE-158 studies, monotherapy corticosteroids for $ 7 days before starting study treatment.
with pembrolizumab (anti–PD-1) was associated with Full eligibility criteria are summarized in the protocol (Data
a confirmed objective response rate (ORR) of 19.3% and Supplement).
a grade 3-5 treatment-related adverse event (AE) rate of
9.6%.7 Responses were durable, with an estimated 67.7% Treatment
of responses lasting $ 12 months. On the basis of these Participants were randomly allocated in a 1:1 ratio to re-
data, pembrolizumab was approved as third-line or later ceive pembrolizumab 200 mg or matching saline placebo
therapy for patients with metastatic SCLC in several once every 3 weeks for 35 cycles or until disease pro-
countries, including the United States. In KEYNOTE-604, gression, intolerable toxicity, or physician or participant
we assessed the efficacy and safety of adding pembrolizumab decision. For the first 4 cycles, participants also received
to EP as first-line therapy for ES-SCLC. etoposide 100 mg/m2 on days 1, 2, and 3 and the in-
vestigator’s choice of carboplatin area under the plasma
METHODS drug concentration-time curve 5 or cisplatin 75 mg/m2 on
day 1 of each 3-week cycle. All treatment was administered
Study Design and Participants
intravenously. Participants who achieved complete re-
This randomized, double-blind, placebo-controlled phase sponse (CR) or partial response (PR) after cycle 4 could
III trial was conducted at 140 sites in 18 countries (Data receive up to 25 Gy of prophylactic cranial irradiation (PCI)
Supplement, online only) in accordance with Good Clinical in 10 fractions at the discretion of the investigator. Random
Practice and the protocol and its amendments, which were allocation was performed using an interactive voice re-
approved by the ethics body at each study site. All par- sponse/integrated web-response system and stratified by
ticipants provided written informed consent. An indepen- choice of platinum (carboplatin or cisplatin), baseline
dent data and safety monitoring committee periodically ECOG performance status (0 or 1), and baseline lactate
assessed safety and assessed efficacy at prespecified in- dehydrogenase (LDH) concentration (# or . upper limit of
terim analyses. normal [ULN]).
Key eligibility criteria were age $ 18 years; histologically or
cytologically confirmed SCLC not previously treated with Assessments
systemic therapy; stage IV disease per American Joint Tumor imaging was performed at baseline, every 6 weeks
Committee on Cancer, seventh edition, criteria11; mea- for the first 48 weeks, and every 9 weeks thereafter. AEs
surable disease per RECIST version 1.112; Eastern Co- were collected throughout treatment and for 30 days
operative Oncology Group (ECOG) performance status of thereafter (90 days for serious AEs) and graded according
0 or 1; provision of a tumor sample for biomarker as- to the National Cancer Institute Common Terminology
sessment; life expectancy $ 3 months; and adequate or- Criteria for Adverse Events (version 4.0). Survival was
gan function. Patients with brain metastases were eligible if assessed every 8 weeks during follow-up. PD-L1 expression
they completed treatment (eg, whole-brain radiation, ste- was assessed retrospectively using the PD-L1 IHC 22C3
reotactic radiosurgery) $ 14 days before starting study pharmDx assay (Agilent Technologies, Carpinteria, CA) and
treatment, had no evidence of new or enlarging brain measured using the combined positive score (CPS), de-
metastases, and were neurologically stable without fined as the number of PD-L1–staining cells (tumor cells,

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 Pembrolizumab Plus EP for Extensive-Stage SCLC

lymphocytes, macrophages) divided by the total number of 22 months after study start when the estimated number of
viable tumor cells, multiplied by 100.13 PFS events and deaths was 387 and 224, respectively. IA2
End Points was based on a data cutoff of March 29, 2019, at which
time 396 PFS events and 274 deaths accrued; the su-
The dual primary end points were progression-free survival periority boundary for PFS was one-sided P 5 .0048. The
(PFS; ie, the time from random assignment to disease final analysis was planned to occur when 294 deaths ac-
progression or death, whichever occurred first) and OS (ie, crued or approximately 31 months from study start,
the time from random assignment to death). Secondary end whichever occurred later. The final analysis was based on
points were ORR (ie, the proportion of participants with CR a data cutoff of December 2, 2019, at which time 357
or PR), duration of response (DOR; ie, the time from first deaths accrued; the superiority boundary for OS was one-
evidence of CR or PR to disease progression or death, sided P 5 .0128. All superiority boundaries were calculated
whichever occurred first), and safety. PFS, ORR, and DOR using the Lan-DeMets O’Brien-Fleming spending function.
were assessed per RECIST version 1.1 by blinded, in-
dependent central review (BICR).
RESULTS
Statistical Analysis
Participants
Efficacy was assessed in the intention-to-treat (ITT) pop-
Between May 15, 2017, and July 30, 2018, 453 partici-
ulation, defined as all participants randomly allocated to
pants from 133 sites in 18 countries met eligibility criteria
treatment. Safety was assessed in the as-treated pop-
and were randomly allocated to receive pembrolizumab
ulation, defined as all participants who received $ 1 dose of
plus EP (n 5 228) or placebo plus EP (n 5 225; Fig 1).
study treatment. A post hoc analysis of OS in the as-treated
Baseline demographics and disease characteristics were
population was also performed. PFS, OS, and DOR were
generally balanced between groups (Table 1). Median age
assessed using the Kaplan-Meier method; censoring rules
was 65 years, 74.4% of participants had an ECOG per-
are summarized in the Data Supplement. Between-group
formance status of 1, 56.5% had an LDH concentration .
differences in PFS and OS were assessed using the
ULN, and 40.8% had PD-L1 CPS $ 1; more participants in
stratified log-rank test; all resultant P values are one-sided.
the pembrolizumab plus EP group had baseline brain
A stratified Cox proportional hazards model with Efron’s
metastases (14.5% v 9.8%).
method of tie handling was used to estimate the hazard
ratios (HRs) and 95% CIs for PFS and OS. To account for At least 1 dose of study treatment was received by 224
possible nonproportional hazards of PFS and OS, explor- participants in the pembrolizumab plus EP group and 222
atory analyses using the restricted mean survival time participants in the placebo plus EP group. One participant
(RMST) method14 were performed. Stratified Miettinen and in the pembrolizumab plus EP group was cross-treated with
Nurminen’s method was used to assess the treatment placebo plus EP for the duration of treatment; the as-treated
difference in ORR. All stratified analyses were performed population, therefore, included 223 participants for each
using the randomization stratification factors. group. Among the 446 treated participants, 317 (71.1%)
received carboplatin, and 129 (28.9%) received cisplatin.
The protocol specified two interim analyses and a final
At final analysis, median time from random assignment to
analysis. The second interim analysis (IA2) was the pre-
data cutoff was 21.6 months (range, 16.1-30.6 months), 20
specified final PFS analysis. The graphical method of Maurer
participants in the pembrolizumab plus EP group (8.9%)
and Bretz15 was used to control the familywise type I error
and 3 (1.4%) in the placebo plus EP group remained on
rate at one-sided a 5 .025 across all hypotheses and interim
treatment, and 2 (0.9%) and 1 (0.5%), respectively,
analyses (Appendix Fig A1, online only). With the as-
completed 35 cycles. The remainder of participants dis-
sumption of 453 participants enrolled over 14.5 months,
continued treatment, most commonly for disease pro-
median PFS of 4.3 months and median OS of 10 months in
gression (Fig 1). PCI was received by 27 participants in the
the placebo plus EP group, and an exponential dropout rate
pembrolizumab plus EP group (11.8%) and by 32 (14.2%)
of 1% per month, the study had 96% power to demonstrate
participants in the placebo plus EP group. In the as-treated
a PFS HR of 0.65 at a 5 .006 with 387 PFS events at the
population, $ 1 subsequent anticancer therapy was re-
final PFS analysis and 94% power to demonstrate an OS HR
ceived by 118 participants in the pembrolizumab plus EP
of 0.65 at a 5 .019 with 294 deaths at the final OS analysis.
group (52.9%) and 146 (65.5%) in the placebo plus EP
The study was positive if pembrolizumab plus EP signifi-
group, including 9 (4.0%) and 31 (13.9%), respectively,
cantly prolonged at least one of the primary end points.
who received immunotherapy (Data Supplement).
The first interim analysis was planned to occur approxi-
mately 18 months after study start when the estimated Efficacy
number of PFS events and deaths was 332 and 175, re- At IA2, 188 participants in the pembrolizumab plus EP
spectively. The analysis was based on a data cutoff of group (82.5%) and 208 (92.4%) in the placebo plus EP
November 6, 2018, at which time 345 PFS events and 182 group experienced disease progression or death. Median
deaths accrued. IA2 was planned to occur approximately PFS was 4.5 months (95% CI, 4.3 to 5.4 months) in the

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 Rudin et al

Patients screened
(N = 663)

Not allocated (n = 210)

Did not meet eligibility criteria (n = 210)

Randomly allocated
(n = 453)

Allocated to pembrolizumab plus EP (n = 228) Allocated to placebo plus EP (n = 225)

Did not receive treatment (n = 4) Did not receive treatment (n = 3)
Died (n = 3) Died (n = 1)
Withdrew consent (n = 1) Withdrew consent (n = 2)

Discontinued treatment (n = 218)

Discontinued treatment (n = 202)
Adverse event (n = 13)
Adverse event (n = 31)
Clinical progression (n = 10)
Clinical progression (n = 8)
Physician decision (n = 3)
Physician decision (n = 1)
Protocol violation (n = 1)
Radiographic progression (n = 154)
Radiographic progression (n = 184)
Withdrawal of consent (n = 8)
Withdrawal of consent (n = 7)

Completed pembrolizumab plus EP (n = 2) Completed placebo plus EP (n = 1)

Still receiving pembrolizumab Still receiving placebo
at data cutoff (n = 20) at data cutoff (n = 3)

Pembrolizumab plus EP ITT population (n = 228) Placebo plus EP ITT population (n = 225)
Pembrolizumab plus EP Placebo plus EP as-treated
as-treated population (n = 223)a population (n = 223)a

FIG 1. CONSORT diagram. (a) The participant allocated to the pembrolizumab plus etoposide and platinum (EP) group who received placebo plus EP in
error was included in the placebo plus EP as-treated population. ITT, intention to treat.

pembrolizumab plus EP group and 4.3 months (95% CI, significance boundary was not reached in the ITT pop-
4.2 to 4.4 months) in the placebo plus EP group, and ulation (HR, 0.80; 95% CI, 0.64 to 0.98; P 5 .0164). In
12-month PFS estimates were 13.6% and 3.1%, re- a post hoc analysis of OS in the as-treated population,
spectively (Fig 2A). Pembrolizumab plus EP significantly nominal P 5 .0124 (HR, 0.78; 95% CI, 0.63 to 0.97;
prolonged PFS at IA2 (HR, 0.75; 95% CI, 0.61 to 0.91; Appendix Fig A3, online only). RMST for OS at 24 months
P 5 .0023). RMST for PFS at 12 months also favored was 12.77 months for pembrolizumab plus EP and
pembrolizumab plus EP (5.86 v 5.14 months; difference, 11.56 months for placebo plus EP (difference, 1.21
0.72 months; 95% CI, 0.14 to 1.29). The PFS benefit was months; 95% CI, 0.18 to 2.60). In subgroup analysis, all
observed in most subgroups (Fig 2B) and was maintained HRs favored pembrolizumab plus EP except for the sub-
at final analysis (HR, 0.73; 95% CI, 0.60 to 0.88; Appendix groups of participants with brain metastases and those with
Fig A2, online only). Although the point estimate for par- , 3 metastases (Fig 3B); in both subgroups, the CIs were
ticipants with brain metastases was . 1, the CI was wide wide and crossed those of the total population.
and overlapped that of the total population and the pop-
At final analysis, ORR was 70.6% (95% CI, 64.2% to
ulation without brain metastases.
76.4%) in the pembrolizumab plus EP group and
At final analysis, 169 participants in the pembrolizumab 61.8% (95% CI, 55.1% to 68.2%) in the placebo plus EP
plus EP group (74.1%) and 188 (83.6%) in the placebo group (Table 2). Among responders, median DOR was
plus EP group had died. Median OS was 10.8 months 4.2 months (range, 1.01 to 26.01 months) in the pem-
(95% CI, 9.2 to 12.9 months) in the pembrolizumab plus brolizumab plus EP group and 3.7 months (range, 1.41 to
EP group and 9.7 months (95% CI, 8.6 to 10.7 months) in 25.81 months) in the placebo plus EP group (Fig 4; 1
the placebo plus EP group, and estimated OS rates indicates no PD at last assessment); at 1 year, the estimated
were 45.1% and 39.6%, respectively, at 12 months and proportion of ongoing responses was 19.3% and 3.3%,
22.5% and 11.2%, respectively, at 24 months (Fig 3A). The respectively.

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 Pembrolizumab Plus EP for Extensive-Stage SCLC

TABLE 1. Participant Demographics and Disease Characteristics at Baseline

Pembrolizumab Plus EP Placebo Plus EP
Characteristic (n 5 228) (n 5 225)
Median age, years (range) 64 (24-81) 65 (37-83)
Age $ 65 years 113 (49.6) 124 (55.1)
Male sex 152 (66.7) 142 (63.1)
Region of enrollment
East Asia 52 (22.8) 32 (14.2)
Not East Asia 176 (77.2) 193 (85.8)
ECOG performance status
0 60 (26.3) 56 (24.9)
1 168 (73.7) 169 (75.1)
Smoking status
Current 148 (64.9) 133 (59.1)
Former 72 (31.6) 84 (37.3)
Never 8 (3.5) 8 (3.6)
LDH concentration
# ULN 100 (43.9) 95 (42.2)
. ULN 127 (55.7) 129 (57.3)
Unknown 1 (0.4) 1 (0.4)
Median sum of largest diameters of target lesions, mm (range) 134.8 (24.4-431.7) 126.6 (20.8-408.8)
No. of metastatic sites
,3 88 (38.6) 73 (32.4)
$3 140 (61.4) 152 (67.6)
Brain metastases 33 (14.5) 22 (9.8)
Liver metastases 95 (41.7) 92 (40.9)
PD-L1 CPS
,1 97 (42.5) 78 (34.7)
$1 88 (38.6) 97 (43.1)
Unknown 43 (18.9) 50 (22.2)

Abbreviations: CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; EP, etoposide and platinum; LDH, lactate
dehydrogenase; PD-L1, programmed death ligand 1; ULN, upper limit of normal.

Safety In both groups, neutropenia, anemia, nausea, and alopecia

Median number of cycles was 7 (range, 1-35 cycles) in the were the most common any-grade AEs, and neutropenia,
pembrolizumab plus EP group and 6 (range, 1-35 cycles) anemia, thrombocytopenia, and leukopenia were the most
in the placebo plus EP group. AEs of any cause occurred in common grade 3-4 AEs (Table 3). Among AEs with in-
all 223 participants in the pembrolizumab plus EP group cidence $ 10%, pyrexia, hypothyroidism, dizziness, and
(100%) and 222 (99.6%) participants in the placebo plus rash were more frequent in the pembrolizumab plus EP
EP group, including 171 (76.7%) and 167 (74.9%), re- group (Appendix Fig A4A, online only). There were no
spectively, who experienced grade 3-4 AEs. Discontinuation grade 3-5 AEs that occurred more frequently in the
of any study treatment because of AEs occurred in 33 of pembrolizumab plus EP group (Appendix Fig A4B). A
participants in the pembrolizumab plus EP group (14.8%) summary of treatment-related AEs is available in the Data
and 14 (6.3%) in the placebo plus EP group; discontinuation Supplement. Immune-mediated AEs, which were defined
of all treatment occurred in 9 (4.0%) and 8 (3.6%), re- on the basis of a list of terms specified by the sponsor,
spectively. AEs were generally similar in participants treated occurred in 55 participants in the pembrolizumab plus EP
with carboplatin (Data Supplement) and with cisplatin (Data group (24.7%) and 23 (10.3%) in the placebo plus EP
Supplement). AEs led to death in 14 participants in the group (Data Supplement). The most common immune-
pembrolizumab plus EP group (6.3%) and 12 (5.4%) in the mediated AEs were hypothyroidism (10.3% in the pem-
placebo plus EP group (Data Supplement). brolizumab plus EP group and 2.2% in the placebo plus EP

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 Rudin et al

A 100
Events,
No. (%)
Median, months
(95% CI)
HR
(95% CI)
P

90 Pembrolizumab plus EP 188 (82.5) 4.5 (4.3 to 5.4) 0.75 (0.61 to 0.91) .0023
Placebo plus EP 208 (92.4) 4.3 (4.2 to 4.4)
80
34.1%
70
23.8%
60
PFS (%)

50
13.6%
40 3.1%

30

20

10

0 3 6 9 12 15 18 21
Time (months)
No. at risk:
Pembrolizumab plus EP 228 181 71 31 15 5 1 0 FIG 2. Progression-free survival (PFS)
Placebo plus EP 225 187 50 14 3 1 1 0 assessed per RECIST version 1.1 by
blinded, independent central review in
B Events/ the intention-to-treat population at the
Participants HR 95% CI second interim analysis. (A) Kaplan-
Meier estimates of PFS. (B) Forest plot
Overall 396/453 0.75 0.61 to 0.91
Age, years
of PFS in subgroups. The protocol-
< 65 186/216 0.76 0.57 to 1.01 specified final analysis of PFS oc-
65 210/237 0.70 0.53 to 0.92 curred at the second interim analysis. In
Sex (B), analysis for the overall population is
Male 261/294 0.68 0.53 to 0.87
based on a Cox regression model with
Female 135/159 0.78 0.56 to 1.10
ECOG performance status
treatment as a covariate stratified by
0 97/116 0.60 0.40 to 0.91 platinum chemotherapy, Eastern Co-
1 299/337 0.79 0.63 to 0.99 operative Oncology Group (ECOG)
Region of enrollment performance status, and lactate de-
East Asia 73/84 0.58 0.36 to 0.94
hydrogenase (LDH) concentration; for
Not East Asia 323/369 0.74 0.59 to 0.92
Smoking status subgroups, analyses are based on an
Current 246/281 0.73 0.57 to 0.94 unstratified Cox regression model with
Former 136/156 0.72 0.51 to 1.02 treatment as a covariate. 1, no PD at the
LDH concentration last disease assessment; CPS, combined
ULN 155/195 0.66 0.48 to 0.91
positive score; EP, etoposide and plati-
> ULN 240/256 0.76 0.58 to 0.98
No. of metastatic sites num; HR, hazard ratio; PD-L1, pro-
<3 138/162 0.70 0.50 to 0.97 grammed death ligand 1; ULN, upper
3 258/291 0.76 0.59 to 0.97 limit of normal.
Baseline brain metastasis
Yes 48/54 1.07 0.60 to 1.91
No 348/399 0.69 0.55 to 0.85
Baseline liver metastasis
Yes 176/190 0.90 0.67 to 1.21
No 220/263 0.64 0.49 to 0.83
PD-L1 CPS
<1 159/174 0.73 0.54 to 1.01
1 154/184 0.68 0.49 to 0.94
Platinum administered
Cisplatin 113/129 0.60 0.41 to 0.88
Carboplatin 277/317 0.77 0.60 to 0.97

0.25 0.5 1 2 4

Favors Favors
pembrolizumab plus placebo plus
EP EP

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 Pembrolizumab Plus EP for Extensive-Stage SCLC

A 100 Events, Median, months HR P

No. (%) (95% CI) (95% CI)
90
Pembrolizumab plus EP 169 (74.1) 10.8 (9.2 to 12.9) 0.80 (0.64 to 0.98) .0164
80 Placebo plus EP 188 (83.6) 9.7 (8.6 to 10.7)

70
45.1%
60 39.6%
OS (%)

50
22.5%
40 11.2%

30

20

10

0 3 6 9 12 15 18 21 24 27 30 33
Time (months)
No. at risk:
Pembrolizumab plus EP 228 201 175 132 102 87 60 31 15 3 1 0
Placebo plus EP 225 212 170 123 89 63 44 19 8 3 0 0

B Events/
Participants HR 95% CI FIG 3. Overall survival (OS) in the in-
tention-to-treat population at final analysis.
Overall 357/453 0.80 0.64 to 0.98
(A) Kaplan-Meier estimates of OS. (B)
Age, years
< 65 168/216 0.83 0.61 to 1.12 Forest plot of OS in subgroups. In (B),
65 189/237 0.78 0.59 to 1.05 analysis for the overall population is based
Sex on a Cox regression model with treatment
Male 237/294 0.76 0.59 to 0.98 as a covariate stratified by platinum che-
Female 120/159 0.88 0.61 to 1.26 motherapy, Eastern Cooperative Oncology
ECOG performance status
0 84/116 0.68 0.44 to 1.05
Group (ECOG) performance status, and
1 273/337 0.86 0.68 to 1.09 lactate dehydrogenase (LDH) concentra-
Region of enrollment tion; for subgroups, analyses are based on
East Asia 64/84 0.72 0.44 to 1.19 an unstratified Cox regression model with
Not East Asia 293/369 0.84 0.67 to 1.06
treatment as a covariate. CPS, combined
Smoking status
Current 227/281 0.86 0.66 to 1.11
positive score; EP, etoposide and plati-
Former 118/156 0.71 0.49 to 1.02 num; HR, hazard ratio; PD-L1, pro-
LDH concentration grammed death ligand 1; ULN, upper
ULN 137/195 0.72 0.52 to 1.01 limit of normal.
> ULN 219/256 0.84 0.65 to 1.10
No. of metastatic sites
<3 115/161 1.04 0.72 to 1.50
3 242/292 0.71 0.55 to 0.92
Baseline brain metastasis
Yes 44/55 1.32 0.72 to 2.42
No 313/398 0.75 0.60 to 0.94
Baseline liver metastasis
Yes 163/187 0.75 0.55 to 1.02
No 194/266 0.82 0.62 to 1.08
PD-L1 CPS
<1 146/175 0.80 0.58 to 1.11
1 134/185 0.84 0.60 to 1.18
Platinum administered
Cisplatin 100/129 0.73 0.49 to 1.08
Carboplatin 251/317 0.83 0.65 to 1.07

0.25 0.5 1 2 4

Favors Favors
pembrolizumab plus placebo plus
EP EP

Journal of Clinical Oncology 7

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Rudin et al

TABLE 2. Summary of Confirmed Response Assessed Per RECIST Version 1.1 by Blinded, Independent Central Review at Final Analysis
Pembrolizumab Plus EP Placebo Plus EP
Confirmed Response (n 5 228), No. (%) (n 5 225), No (%)
ORR, % (95% CI) 70.6 (64.2 to 76.4) 61.8 (55.1 to 68.2)
Treatment difference,a percentage points (95% CI) 8.9 (0.2 to 17.4)
Best response
Complete response 4 (1.8) 2 (0.9)
Partial response 157 (68.9) 137 (60.9)
Stable disease 40 (17.5) 56 (24.9)
Progressive disease 8 (3.5) 12 (5.3)
Not evaluableb 6 (2.6) 5 (2.2)
Not assessedc 13 (5.7) 13 (5.8)

Abbreviations: EP, etoposide and platinum; ORR, objective response rate.

a
Calculated using stratified Miettinen and Nurminen’s method, with strata weighting by sample size.
b
Participants who had $ 1 postbaseline imaging assessment, none of which were evaluable for response.
c
Participants who did not have $ 1 postbaseline imaging assessment.

group), hyperthyroidism (6.7% and 2.7%, respectively), (HR, 0.80; P 5 .0164). ORR was numerically higher in the
and pneumonitis (4.0% and 2.2%, respectively). Grade pembrolizumab plus EP group. The proportion of partici-
3 immune-mediated AEs occurred in 16 participants pants who experienced grade 3-4 AEs and who died as
(7.2%) and 2 participants (0.9%), respectively. There were a result of AEs was similar in the treatment groups; more
no grade 4 or 5 immune-mediated AEs in the pem- participants in the pembrolizumab plus EP group dis-
brolizumab plus EP group. Infusion-related reactions oc- continued treatment because of AEs.
curred in 8 participants in the pembrolizumab plus EP
A generally consistent treatment effect for pembrolizumab
group (3.6%) and in 4 (1.8%) in the placebo plus EP group.
plus EP was observed across key subgroups. The only
subgroup that did not seem to benefit from pembrolizumab
DISCUSSION plus EP was participants with baseline brain metastases.
In this randomized, double-blind, phase III study of patients Given the small population size for this subgroup and wide
with previously untreated ES-SCLC, the addition of pem- CIs, it is difficult to make conclusions. The PFS and OS
brolizumab to EP significantly improved PFS assessed per HRs were similar in participants with PD-L1–positive and
RECIST version 1.1 by BICR (HR, 0.75; P 5 .0023). Al- PD-L1–negative tumors and regardless of the choice of
though the OS HR favored pembrolizumab plus EP, the platinum. These findings are consistent with those of
prespecified significance threshold was narrowly missed pembrolizumab plus chemotherapy in NSCLC.16,17

100 Median, months

(range)
90
Pembrolizumab plus EP 4.2 (1.0+ to 26.0+)
80 Placebo plus EP 3.7 (1.4+ to 25.8+)
Ongoing Reponse (%)

70
19.3%
3.3%
60

50
16.3%
40 1.3%
FIG 4. Kaplan-Meier estimates of duration of re-
30 sponse assessed per RECIST version 1.1 by blinded,
20
independent central review at final analysis in par-
ticipants who experienced complete or partial re-
10
sponse. EP, etoposide and platinum.

0 3 6 9 12 15 18 21 24 27 30 33
Time (months)
No. at risk:
Pembrolizumab plus EP 161 107 49 32 25 18 8 3 1 0 0 0
Placebo plus EP 139 82 17 8 4 3 1 1 1 0 0 0

8 © 2020 by American Society of Clinical Oncology

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Pembrolizumab Plus EP for Extensive-Stage SCLC

TABLE 3. All-Cause Adverse Events With Incidence $ 10% in Either Group in the As-Treated Population at Final Analysis
Pembrolizumab Plus EP (n 5 223), Placebo plus EP (n 5 223),
No. (%) No. (%)

Adverse Event Any Grade Grade 3-4 Any Grade Grade 3-4
Neutropenia 127 (57.0) 97 (43.5) 119 (53.4) 91 (40.8)
Anemia 108 (48.4) 35 (15.7) 104 (46.6) 34 (15.2)
Nausea 86 (38.6) 2 (0.9) 96 (43.0) 3 (1.3)
Alopecia 75 (33.6) 0 (0.0) 84 (37.7) 1 (0.4)
Decreased appetite 69 (30.9) 1 (0.4) 55 (24.7) 4 (1.8)
Constipation 66 (29.6) 1 (0.4) 59 (26.5) 2 (0.9)
Fatigue 61 (27.4) 6 (2.7) 61 (27.4) 4 (1.8)
Thrombocytopenia 59 (26.5) 31 (13.9) 49 (22.0) 25 (11.2)
Leukopenia 50 (22.4) 26 (11.7) 46 (20.6) 21 (9.4)
Diarrhea 47 (21.1) 6 (2.7) 42 (18.8) 6 (2.7)
Cough 44 (19.7) 1 (0.4) 45 (20.2) 2 (0.9)
Asthenia 41 (18.4) 8 (3.6) 43 (19.3) 11 (4.9)
Dyspnea 40 (17.9) 3 (1.3) 38 (17.0) 4 (1.8)
Vomiting 36 (16.1) 2 (0.9) 40 (17.9) 4 (1.8)
Pyrexia 34 (15.2) 1 (0.4) 15 (6.7) 1 (0.4)
Dizziness 32 (14.3) 0 (0.0) 15 (6.7) 0 (0.0)
Headache 30 (13.5) 0 (0.0) 34 (15.2) 1 (0.4)
Rash 30 (13.5) 3 (1.3) 13 (5.8) 0 (0.0)
Back pain 26 (11.7) 1 (0.4) 26 (11.7) 0 (0.0)
Pneumonia 26 (11.7) 15 (6.7) 25 (11.2) 10 (4.5)
Hyponatremia 25 (11.2) 0 (0.0) 20 (9.0) 0 (0.0)
Insomnia 25 (11.2) 0 (0.0) 28 (12.6) 0 (0.0)
Pruritus 25 (11.2) 0 (0.0) 18 (8.1) 0 (0.0)
Hypothyroidism 23 (10.3) 0 (0.0) 5 (2.2) 0 (0.0)
Peripheral edema 17 (7.6) 0 (0.0) 27 (12.1) 0 (0.0)

Data are presented in order of descending incidence in the pembrolizumab plus etoposide and platinum (EP) group.

With results of the phase III IMpower133 and CASPIAN CASPIAN, which suggests that KEYNOTE-604 may have
studies, immune checkpoint inhibitors became the first enrolled sicker patients. KEYNOTE-604 enrolled more
class of agents to improve first-line outcomes in ES-SCLC in participants with brain metastases and a performance
approximately 3 decades. The lack of a statistically sig- status of 1 than IMpower133 and CASPIAN, as well as high
nificant survival benefit in KEYNOTE-604 was unex- proportions of participants with large tumor dimensions,
pected on the basis of the findings of these studies. In elevated LDH concentration, and $ 3 metastases at
IMpower133, adding atezolizumab (anti–PD-L1) to 4 cycles baseline; these factors are associated with poor prognosis
of etoposide and carboplatin significantly improved the in SCLC.18 The findings of KEYNOTE-604 are generally
dual primary end points of investigator-assessed PFS (HR, consistent with those of IMpower133 and CASPIAN and
0.77; 95% CI, 0.62 to 0.96) and OS (HR, 0.70; 95% CI, together with data from studies of monotherapy in later lines
0.54 to 0.91) compared with placebo plus 4 cycles of of therapy,7,8 support the value of checkpoint inhibitors in
etoposide and carboplatin.9 In CASPIAN, the addition of treating ES-SCLC.
durvalumab (anti–PD-L1) to 4 cycles of EP significantly There is increasing recognition that medians do not fully
improved the primary end point of OS compared with 6 capture the PFS and OS benefits of immunotherapy and
cycles of EP (HR, 0.73; 95% CI, 0.59 to 0.91).10 Although that there is a need for therapies that raise the survival
cross-study comparisons should be made with caution, OS curve.19 The KEYNOTE-604 Kaplan-Meier curves support
in KEYNOTE-604 was shorter than in IMpower133 and a long-term benefit of pembrolizumab plus EP for a subset

Journal of Clinical Oncology 9

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Rudin et al

of participants with ES-SCLC. The PFS curves overlap for No unexpected toxicities were observed in KEYNOTE-604.
the first 4-5 months, which likely reflects the effect of EP, The most frequently observed AEs in both treatment groups
then separate after the medians are reached (approxi- were hematologic events, rates of which did not seem to
mately the time of the third postbaseline imaging as- be increased by pembrolizumab. AE profiles were similar
sessment) with an evident plateau for pembrolizumab plus in carboplatin- and cisplatin-treated participants. The in-
EP. The OS curves diverged in favor of pembrolizumab plus cidence and types of immune-mediated AEs observed in
EP starting at approximately 5 months. Separation was the pembrolizumab plus EP group were consistent with
those observed for pembrolizumab monotherapy in SCLC.7
maintained over time, as evidenced by 12-month OS rates
Although more participants treated with pembrolizumab
of 45.1% in the pembrolizumab plus EP group and
plus EP discontinued any study therapy, the proportion of
39.6% in the placebo plus EP group and 24-month OS
participants who discontinued all study therapy and who
rates of 22.5% and 11.2%, respectively. RMST analysis of
died as a result of AEs was similar in the treatment groups,
PFS and OS supports divergence of outcomes in favor of which suggests that AEs associated with pembrolizumab
pembrolizumab plus EP over long-term follow-up. Similar to plus EP can be successfully managed.
the PFS curves, the DOR curves diverged around the time
In conclusion, results of KEYNOTE-604 show that adding
the medians were reached and remained separated in favor
pembrolizumab to standard first-line EP significantly im-
of pembrolizumab plus EP over long-term follow-up. These
proves PFS in patients with ES-SCLC and is associated with
findings are consistent with those observed in IMpower1339
durable responses in a subset of patients. The statistical
and CASPIAN,10 which likely underscores the inherent threshold for declaring significant prolongation of OS was
heterogeneity of this disease. Additional correlative ana- narrowly missed. Pembrolizumab monotherapy remains
lyses, including exploration of molecular biomarkers such as approved as third-line or later therapy for metastatic SCLC
tumor mutational burden and gene expression signatures20,21 in several countries. Overall, these data support the benefit
and the recently described SCLC molecular subtypes,22 of pembrolizumab in SCLC and add to the growing body of
may help to identify patients who derive long-term benefit evidence that supports the value of immune checkpoint
from checkpoint inhibitors. inhibitors in this historically difficult-to-treat cancer.

AFFILIATIONS PRIOR PRESENTATION

1
Memorial Sloan Kettering Cancer Center, New York, NY Presented at the ASCO20 Virtual Scientific Program, Chicago, IL, May
2
Dana-Farber Cancer Institute, Boston, MA 29-31, 2020.
3
Vall d’Hebron University Hospital and Vall d’Hebron Institute of
Oncology, Barcelona, Spain
4
SUPPORT
Meir Medical Center, Kfar-Saba, Israel
5 Supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co.
Lausanne University Hospital, Lausanne, Switzerland
6
Hetényi Géza Kórház Onkológiai Központ, Szolnok, Hungary
7
William Osler Health System, University of Toronto, Brampton, Ontario, CLINICAL TRIAL INFORMATION
Canada NCT03066778
8
Complejo Hospitalario Universitario Insular Materno-Infantil de Gran
Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran
DATA AVAILABILITY
Canaria, Spain
9 Data will be available according to Merck Sharp & Dohme’s data
Rambam Medical Center, Haifa, Israel
10 sharing policy, which, including restrictions, is available at http://
National Taiwan University Hospital and National Taiwan University
engagezone.msd.com/ds_documentation.php. Requests for access to
Cancer Center, Taipei, Taiwan
11 the clinical study data can be submitted through the EngageZone site
Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier,
or by e-mail to [email protected].
Toulouse, France
12
Oncologı́a-Health and Care, Santiago, Chile
13
Leningrad Regional Clinical Hospital, St Petersburg, Russia AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF
14
Istanbul Medeniyet University Hospital, Istanbul, Turkey INTEREST AND DATA AVAILABILITY STATEMENT
15
Kanagawa Cancer Center, Yokohama, Japan Disclosures provided by the authors and data availability statement (if
16
University of Michigan, Ann Arbor, MI applicable) are available with this article at DOI https://doi.org/10.1200/
17
Merck & Co, Kenilworth, NJ JCO.20.00793.
18
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul,
South Korea
AUTHOR CONTRIBUTIONS
Conception and design: Charles M. Rudin, Solange Peters, Yiwen Luo,
CORRESPONDING AUTHOR M. Catherine Pietanza
Charles M. Rudin, MD, PhD, Memorial Sloan Kettering Cancer Center, Provision of study material or patients: Charles M. Rudin, Mark M. Awad,
1275 York Ave, New York, NY 10065; e-mail: [email protected]. Alejandro Navarro, Maya Gottfried, Solange Peters, Tibor Cs}oszi, Parneet
K. Cheema, Delvys Rodriguez-Abreu, Mirjana Wollner, James Chih-Hsin

10 © 2020 by American Society of Clinical Oncology

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Pembrolizumab Plus EP for Extensive-Stage SCLC

Yang, Julien Mazieres, Francisco J. Orlandi, Alexander Luft, Terufumi ACKNOWLEDGMENT

Kato, Gregory P. Kalemkerian, Hye Ryun Kim We thank the patients and their families and caregivers for participating
Collection and assembly of data: All authors in this trial; all investigators and site personnel; and all employees of
Data analysis and interpretation: All authors Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Kenilworth, NJ
Manuscript writing: All authors (MSD), who made contributions to this study, particularly Ananya Roy for
Final approval of manuscript: All authors previous service as the lead study statistician, Xiaodong Li and Yue
Accountable for all aspects of the work: All authors Shentu for statistical support, Diana Francisco for support of data
collection, and Gregory Lubiniecki for contributions to study design and
oversight of the research. Medical writing and editorial assistance were
provided by Melanie Leiby, an employee of MSD.

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n n n

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 Rudin et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase
III KEYNOTE-604 Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 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/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Charles M. Rudin Mirjana Wollner

Consulting or Advisory Role: AbbVie, Harpoon Therapeutics, Genentech, Honoraria: MSD, AstraZeneca
Roche, AstraZeneca, Ascentage Pharma, Bicycle Therapeutics, Celgene, Consulting or Advisory Role: Roche Israel (Inst), Takeda Pharmaceuticals,
Daiichi Sankyo, Ipsen, Loxo Oncology, PharmaMar, Bridge Medicines, Amgen Bristol-Myers Squibb, AstraZeneca, MSD, Pfizer
Research Funding: AbbVie (Inst), Stemcentrx (Inst), Viralytics (Inst), Daiichi Speakers’ Bureau: Roche Israel, Boehringer Ingelheim, Novartis, Bristol-Myers
Sankyo (Inst), Merck Sharp & Dohme Corp (Inst) Squibb
Research Funding: Merck Sharp & Dohme Corp (Inst)
Mark M. Awad
Travel, Accommodations, Expenses: Pfizer, Bristol-Myers Squibb
Consulting or Advisory Role: Genentech, Merck & Co, Pfizer, Boehringer
Ingelheim, AbbVie, AstraZeneca, MedImmune, Clovis Oncology, Nektar, Bristol- James Chih-Hsin Yang
Myers Squibb, ARIAD Pharmaceuticals, Foundation Medicine, Syndax, Honoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol-
Novartis, Blueprint Medicines, Maverick Therapeutics, Achilles Therapeutics, Myers Squibb, Ono Pharmaceutical, Takeda Pharmaceuticals, Eli Lilly, Pfizer
Neon Therapeutics, Hengrui Therapeutics, Gritstone Oncology Consulting or Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca,
Research Funding: Genentech (Inst), Roche (Inst), Eli Lilly (Inst), AstraZeneca Roche, Genentech, Clovis Oncology, Eli Lilly, MSD, Merck Serono, Celgene,
(Inst), Bristol-Myers Squibb (Inst), Merck Sharp & Dohme Corp (Inst) Astellas Pharma, Bayer AG, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb,
Boehringer Ingelheim (Inst), AstraZeneca (Inst), Yuhan, Hansoh, Blueprint
Alejandro Navarro
Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Amgen, Takeda Oncology,
Honoraria: Pfizer, Roche, AstraZeneca
Incyte
Consulting or Advisory Role: Boehringer Ingelheim
Research Funding: Merck Sharp & Dohme Corp (Inst)
Expert Testimony: Oryzon Genomics
Travel, Accommodations, Expenses: Pfizer
Research Funding: Merck Sharp & Dohme Corp (Inst)
Travel, Accommodations, Expenses: Boehringer Ingelheim, Pfizer Julien Mazieres
Consulting or Advisory Role: Novartis, Roche, Genentech, Pfizer, Bristol-Myers
Maya Gottfried
Squibb, Eli Lilly, ImClone, MSD, AstraZeneca, Pierre Fabre
Consulting or Advisory Role: Pfizer, Boehringer Ingelheim, Roche
Research Funding: Roche (Inst), Bristol-Myers Squibb (Inst), AstraZeneca (Inst),
Research Funding: Merck Sharp & Dohme Corp (Inst)
Merck Sharp & Dohme Corp (Inst)
Travel, Accommodations, Expenses: Pfizer, Roche, Boehringer Ingelheim
Travel, Accommodations, Expenses: Pfizer, Roche, Bristol-Myers Squibb
Solange Peters
Francisco J. Orlandi
Honoraria: Roche (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst),
Honoraria: Roche, Genentech
MSD (Inst), AstraZeneca (Inst), Takeda Pharmaceuticals (Inst), Illumina (Inst)
Consulting or Advisory Role: AstraZeneca, Roche, Genentech, Bristol-Myers
Consulting or Advisory Role: Roche (Inst), Genentech (Inst), Novartis (Inst),
Squibb, MSD, Eli Lilly, Pfizer, Novartis, Sanofi
Bristol-Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca
Speakers’ Bureau: AstraZeneca, MedImmune, Roche
(Inst), Janssen Pharmaceuticals (Inst), Regeneron Pharmaceuticals (Inst),
Research Funding: AstraZeneca, MedImmune, Amgen, Genentech, Roche,
Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda Pharmaceuticals
Boehringer Ingelheim, Astellas Pharma, Medivation, Merck Sharp & Dohme
(Inst), Eli Lilly (Inst), AbbVie (Inst), Bayer AG (Inst), Biocartis (Inst), Debiopharm
Corp (Inst), Bristol-Myers Squibb, Celltrion, Pfizer, mAbxience, Nektar, Sanofi
Group (Inst), Illumina (Inst), PharmaMar (Inst), Sanofi (Inst), Seattle Genetics
Travel, Accommodations, Expenses: Pfizer, MSD, AstraZeneca, MedImmune,
(Inst), Blueprint Medicines, Daiichi Sankyo, Incyte, Bioinvent (Inst), Clovis
Roche, Bristol-Myers Squibb, Genentech, Roche,
Oncology (Inst), Vaccibody (Inst)
Research Funding: Roche (Inst), Bristol-Myers Squibb (Inst), Merck Sharp & Mahmut Gümüş
Dohme Corp (Inst), Amgen (Inst), Eli Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Consulting or Advisory Role: Roche, Eli Lilly (Inst), Amgen (Inst)
Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Speakers’ Bureau: Roche (Inst), MSD (Inst)
Ingelheim (Inst), Iovance (Inst) Research Funding: Merck Sharp & Dohme Corp (Inst)
Travel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, MSD, Travel, Accommodations, Expenses: Pfizer
Sanofi, Incyte
Terufumi Kato
Uncompensated Relationships: Journal of Thoracic Oncology Deputy Editor,
Employment: Eli Lilly (I)
European Society for Medical Oncology President 2020/2021, European
Honoraria: Chugai Pharma, Roche, Boehringer Ingelheim, Ono Pharmaceutical,
Thoracic Oncology Platform Scientific Coordinator
Eli Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Bristol-Myers Squibb Japan,
Tibor Cs}oszi MSD, Novartis, Sumitomo Dainippon, Takeda Pharmaceuticals, AbbVie, Merck
Consulting or Advisory Role: Novartis KGaA, Nitto Denko, Daiichi Sankyo, Shionogi, Nippon Kayaku
Speakers’ Bureau: Ipsen, Janssen-Cilag Consulting or Advisory Role: AstraZeneca, MSD, Eli Lilly, Chugai Pharma, Nitto
Research Funding: Merck Sharp & Dohme Corp (Inst) Denko, AbbVie, Merck Serono, Pfizer
Travel, Accommodations, Expenses: Sanofi, Pfizer Research Funding: Chugai Pharma (Inst), Merck Sharp & Dohme Corp (Inst),
Kyowa Hakko Kirin (Inst), Pfizer (Inst), Taiho Pharmaceutical (Inst), AstraZeneca
Parneet K. Cheema
(Inst), Eli Lilly (Inst), AbbVie (Inst), Ono Pharmaceutical (Inst), Merck Serono
Honoraria: Merck, F. Hoffmann-La Roche, AstraZeneca, Pfizer, Takeda
(Inst), Kyorin, Regeneron Pharmaceuticals, Bristol-Myers Squibb, Novartis,
Pharmaceuticals, Novartis
Kyowa Hakko Kirin
Consulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, Pfizer, Amgen,
F. Hoffmann-La Roche, EMD Serono, Novartis, Genomic Health, Takeda Gregory P. Kalemkerian
Pharmaceuticals, Merck & Co Consulting or Advisory Role: BioMed Valley Discoveries (I), Takeda (I), Unum
Research Funding: Merck Sharp & Dohme Corp (Inst) Therapeutics (I), Molecular Templates (I), Boston Biomedical (I), Skyline
Biosciences (I), Synlogic (I)
Delvys Rodriguez-Abreu
Research Funding: Takeda Pharmaceuticals (Inst), AbbVie (Inst), Merck Sharp
Consulting or Advisory Role: Roche, Bristol-Myers Squibb, MSD
& Dohme Corp (Inst)
Speakers’ Bureau: Roche, Bristol-Myers Squibb, MSD
Research Funding: Merck Sharp & Dohme Corp (Inst) Yiwen Luo
Travel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, MSD Employment: Merck & Co
Stock and Other Ownership Interests: Merck & Co

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 Pembrolizumab Plus EP for Extensive-Stage SCLC

Victoria Ebiana Hye Ryun Kim

Employment: Merck & Co Honoraria: AstraZeneca, Bristol-Myers Squibb, Ono Pharmaceutical, Roche
Stock and Other Ownership Interests: Merck & Co Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb
Research Funding: Merck Sharp & Dohme Corp (Inst)
M. Catherine Pietanza
Employment: Merck & Co No other potential conflicts of interest were reported.
Stock and Other Ownership Interests: Merck & Co

Journal of Clinical Oncology

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Rudin et al

APPENDIX

0.999
PFS OS
D = .006 D = .019
0.999

0.001 0.001

ORR
α=0

FIG A1. Multiplicity diagram for type I error control. The initial a
allocated to each hypothesis is represented in the ovals; the weights
for reallocation from each hypothesis to the others are represented in
the boxes on the lines that connect the hypotheses. If the
progression-free survival (PFS) test is significant, the overall survival
(OS) hypothesis may be tested at a 5 .025. If the OS test is sig-
nificant, the PFS hypothesis may be tested at a 5 .025. If both PFS
and OS are significant, objective response rate (ORR) may be tested
at a 5 .025. The actual boundaries were updated on the basis of the
number of events observed and the a spent at previous analyses
using the Lan-DeMets O’Brien-Fleming spending function.

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 Pembrolizumab Plus EP for Extensive-Stage SCLC

A
100 Events, Median, months HR
No. (%) (95% CI) (95% CI)
90
Pembrolizumab plus EP 196 (86.0) 4.8 (4.3 to 5.4) 0.73 (0.60 to 0.88)
80
Placebo plus EP 220 (97.8) 4.3 (4.2 to 4.5)
70

60

PFS (%)
50
15.9%
40 5.0%

30 10.8%
2.1%
20

10

0 3 6 9 12 15 18 21 24 27 30 33
Time (months)
No. at risk:
Pembrolizumab plus EP 228 182 76 42 32 26 15 10 1 1 0 0
Placebo plus EP 225 189 56 23 11 4 3 1 1 1 0 0

B
Events/
Participants HR 95% CI

Overall 416/453 0.73 0.60 to 0.88

Age, years
< 65 197/216 0.71 0.54 to 0.95
65 219/237 0.72 0.55 to 0.94
Sex
Male 272/294 0.66 0.52 to 0.84
Female 144/159 0.76 0.54 to 1.06
ECOG performance status
0 102/116 0.63 0.43 to 0.94
1 314/337 0.75 0.60 to 0.94
Region of enrollment
East Asia 77/84 0.60 0.37 to 0.95
Not East Asia 339/369 0.72 0.58 to 0.90
Smoking status
Current 260/281 0.70 0.55 to 0.90
Former 141/156 0.71 0.50 to 0.99
LDH concentration
ULN 168/195 0.67 0.49 to 0.90
> ULN 246/256 0.73 0.56 to 0.94
No. of metastatic sites
<3 146/161 0.67 0.48 to 0.93
3 270/292 0.75 0.59 to 0.95
Baseline brain metastasis
Yes 50/55 1.06 0.60 to 1.86
No 366/398 0.67 0.54 to 0.83
Baseline liver metastasis
Yes 179/187 0.88 0.65 to 1.18
No 237/266 0.62 0.48 to 0.81
PD-L1 CPS
<1 163/175 0.72 0.53 to 0.98
1 167/185 0.67 0.49 to 0.92
Platinum administered
Cisplatin 120/129 0.60 0.42 to 0.87
Carboplatin 290/317 0.75 0.59 to 0.95

0.25 0.5 1 2 4

Favors Favors
pembrolizumab plus placebo plus
EP EP

FIG A2. Progression-free survival (PFS) assessed per RECIST version 1.1 by blinded, independent
central review in the intention-to-treat population at the final analysis. (A) Kaplan-Meier estimates
of PFS. (B) Forest plot of PFS in subgroups. In (B), analysis for the overall population is based on
a Cox regression model with treatment as a covariate stratified by platinum chemotherapy, Eastern
Cooperative Oncology Group (ECOG) performance status, and lactate dehydrogenase (LDH)
concentration; for subgroups, analyses are based on an unstratified Cox regression model with
treatment as a covariate. CPS, combined positive score; EP, etoposide and platinum; HR, hazard
ratio; PD-L1, programmed death ligand 1; ULN, upper limit of normal.

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 Rudin et al

100 Events, Median, months HR

No. (%) (95% CI) (95% CI)
90
Pembrolizumab plus EP 165 (74.0) 10.8 (9.7 to 12.9) 0.78 (0.63 to 0.97)
80 Placebo plus EP 186 (83.4) 9.7 (8.6 to 10.7)

70
46.0%
39.9%
60

OS (%)
50
23.0%
40 11.3%

30

20

10

0 3 6 9 12 15 18 21 24 27 30 33
Time (months)
No. at risk:
Pembrolizumab plus EP 223 198 174 132 102 87 60 31 15 3 1 0
Placebo plus EP 223 211 169 122 89 63 44 19 8 3 0 0

FIG A3. Kaplan-Meier estimates of overall survival (OS) in a post hoc analysis of the as-treated
population at final analysis. EP, etoposide and platinum; HR, hazard ratio.

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 Pembrolizumab Plus EP for Extensive-Stage SCLC

A
Incidence, No. (%)
Pembro plus Placebo plus
Risk Difference (95% CI), EP EP
Percentage Points (n = 223) (n = 223)

Pyrexia 34 (15.2) 15 (6.7)

Hypothyroidism 23 (10.3) 5 (2.2)
Dizziness 32 (14.3) 15 (6.7)
Rash 30 (13.5) 13 (5.8)
Decreased appetite 69 (30.9) 55 (24.7)
Thrombocytopenia 59 (26.5) 49 (22.0)
Neutropenia 127 (57.0) 119 (53.4)
Pruritus 25 (11.2) 18 (8.1)
Constipation 66 (29.6) 59 (26.5)
Diarrhea 47 (21.1) 42 (18.8)
Hyponatremia 25 (11.2) 20 (9.0)
Anemia 108 (48.4) 104 (46.6)
Leukopenia 50 (22.4) 46 (20.6)
Dyspnea 40 (17.9) 38 (17.0)
Pneumonia 26 (11.7) 25 (11.2)
Back pain 26 (11.7) 26 (11.7)
Fatigue 61 (27.4) 61 (27.4)
Cough 44 (19.7) 45 (20.2)
Asthenia 41 (18.4) 43 (19.3)
Insomnia 25 (11.2) 28 (12.6)
Headache 30 (13.5) 34 (15.2)
Vomiting 36 (16.1) 40 (17.9)
Alopecia 75 (33.6) 84 (37.7)
Nausea 86 (38.6) 96 (43.0)
Peripheral edema 17 (7.6) 27 (12.1)

–15 –12 –9 –6 –3 0 3 6 9 12 15

Favors Favors
pembro plus placebo plus
EP EP

B
Incidence, No. (%)
Pembro plus Placebo plus
Risk Difference (95% CI), EP EP
Percentage Points (n = 223) (n = 223)

Neutropenia 97 (43.5) 91 (40.8)

Thrombocytopenia 31 (13.9) 25 (11.2)
Leukopenia 26 (11.7) 21 (9.4)
Pneumonia 16 (7.2) 11 (4.9)
Hypophosphatemia 5 (2.2) 2 (0.9)
Fatigue 6 (2.7) 4 (1.8)
Pulmonary embolism 6 (2.7) 4 (1.8)
Anemia 35 (15.7) 34 (15.2)
Febrile neutropenia 17 (7.6) 16 (7.2)
Diarrhea 6 (2.7) 6 (2.7)
Hypotension 3 (1.3) 5 (2.2)
Asthenia 8 (3.6) 11 (4.9)
Hyponatremia 14 (6.3) 17 (7.6)
–15 –12 –9 –6 –3 0 3 6 9 12 15

Favors Favors
pembro plus placebo plus
EP EP

FIG A4. Risk difference between treatment groups for adverse events of any cause in the as-treated population. (A)
Adverse events of any grade with incidence $ 10%. (B) Adverse events of grade 3-5 with incidence $ 2%. EP,
etoposide and platinum; pembro, pembrolizumab.

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