Received: 1 April 2021 | Accepted: 11 May 2021

DOI: 10.1111/cas.14980

ORIGINAL ARTICLE

Pembrolizumab plus pemetrexed-­platinum for metastatic

nonsquamous non–­small-­cell lung cancer: KEYNOTE-­189 Japan
Study

Hidehito Horinouchi1 | Naoyuki Nogami2 | Hideo Saka3 | Makoto Nishio4 |

5 6 7 8
Takaaki Tokito | Toshiaki Takahashi | Kazuo Kasahara | Yoshihiro Hattori |
Eiki Ichihara9 | Noriaki Adachi10 | Kazuo Noguchi10 | Fabricio Souza11 |
Takayasu Kurata12
1
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
2
Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
3
Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
4
Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
5
Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan
6
Division of Thoracic Oncology, Shizuoka Cancer Center, Sunto-­gun, Japan
7
Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan
8
Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan
9
Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
10
MSD K.K, Tokyo, Japan
11
Merck & Co., Inc., Kenilworth, NJ, USA
12
Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan

Correspondence
Hidehito Horinouchi, Department of Abstract
Thoracic Oncology, National Cancer Center Pembrolizumab plus pemetrexed-­platinum significantly improved overall survival
Hospital, 5-­1-­1 Tsukiji, Chuo-­ku, Tokyo, 104-­
0045 Japan. (OS) and progression-­free survival (PFS) with manageable safety compared with pla-
Email: [email protected] cebo plus pemetrexed-­platinum in patients with previously untreated metastatic non-
Funding information squamous non–­small-­cell lung cancer (NSCLC) without EGFR/ALK alterations in the
Merck Sharp & Dohme Corp., a subsidiary of global, randomized, double-­blind, phase 3 KEYNOTE-­189 study. We present results
Merck & Co., Inc., Kenilworth, NJ, USA
of Japanese patients enrolled in the KEYNOTE-­189 global and Japan extension stud-
ies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo
every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/
m2 plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, fol-
lowed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co–­primary
endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab,
n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomiza-
tion to data cutoff, 18.5 [range, 14.7‒­38.2] months), the median OS was not reached
in the pembrolizumab plus pemetrexed-­platinum arm; the median OS was 25.9 (95%

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© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Cancer Science. 2021;00:1–11.  wileyonlinelibrary.com/journal/cas | 1

2 | HORINOUCHI et al.

confidence interval [CI], 11.9‒­29.0) months in the placebo plus pemetrexed-­platinum

arm (hazard ratio [HR] .29; 95% CI, .07‒­1.15). The median (95% CI) PFS was 16.5 (8.8‒­
21.1) compared with 7.1 (4.7‒­21.4) months (HR, .62; 95% CI, .27‒­1.42), respectively.
There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of
patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-­mediated
AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar
to those from the global study and support first-­line therapy with pembrolizumab
plus pemetrexed-­platinum in Japanese patients with nonsquamous NSCLC without
EGFR/ALK alterations.

KEYWORDS

PD-­L1 protein, Japan, non–­small-­cell lung carcinoma, pembrolizumab, treatment outcome

1 | I NTRO D U C TI O N alone.13 The randomized, double-­blind, placebo-­controlled phase 3

KEYNOTE-­189 study of pembrolizumab plus pemetrexed and plati-
Cancer of the trachea and lung is the leading cause of cancer-­related num in 616 patients with previously untreated metastatic nonsqua-
death globally as well as in Japan, where it accounts for approxi- mous NSCLC without sensitizing EGFR or ALK alterations confirmed
mately 20% of all cancer-­related deaths.1,2 Non–­small-­cell lung can- these findings and led to full FDA approval in these patients.14
cer (NSCLC) is the most common type of lung cancer, accounting Compared with placebo plus pemetrexed-­platinum, pembrolizumab
for approximately 85% of cases.3 Historically, first-­line treatment plus pemetrexed-­platinum significantly improved overall survival
for advanced NSCLC without sensitizing EGFR/ALK alterations (OS; HR, .49; 95% CI, .38-­.64; P < .001) and PFS (HR, .52; 95% CI,
consisted primarily of platinum-­based chemotherapy.4-­6 However, .43-­.64; P < .001) after a median time from randomization to the
the introduction of programmed death 1 (PD-­1) and programmed date of death or data cutoff of 10.5 months. These findings were
death ligand 1 (PD-­L1) inhibitors has dramatically altered the treat- extended in an updated analysis with 10 additional calendar months
ment paradigm for patients with NSCLC. Accordingly, the current of follow up (HR for OS, .56 [95% CI, .45-­.70]; HR for PFS, .48 [95%
Japanese Lung Cancer Society guidelines recommend anti–­PD-­(L)1 CI, .40-­.58]).15 Pembrolizumab plus pemetrexed-­platinum demon-
immunotherapy in combination with platinum-­based chemotherapy strated a manageable safety profile, with no apparent increase in the
as first-­line treatment in patients with metastatic NSCLC without frequency of adverse events (AE) commonly associated with peme-
targetable gene alterations. In addition, pembrolizumab monother- trexed plus platinum-­based chemotherapy.14,15
apy is recommended as first-­line treatment in patients with meta- Given that Asian patients are generally underrepresented in
static NSCLC without targetable gene alterations and with PD-­L1 global randomized trials with anti‒­PD-­(L)1 therapies16 and be-
4
tumor proportion score (TPS) ≥50%. cause of documented ethnic differences in response to treatment
Pembrolizumab is a humanized monoclonal antibody that se- for NSCLC,17,18 it is of interest to evaluate these treatments spe-
lectively binds to the inhibitory immune checkpoint receptor, PD-­ cifically in Asian populations. Accordingly, after enrollment in the
1, and blocks its interactions with its ligands, PD-­L1 and PD-­L 2, KEYNOTE-­189 global study ended, additional patients were enrolled
thus reactivating T-­cell–­mediated tumor destruction.7-­9 As first-­line in an extension study to further assess clinical outcomes in Japanese
therapy, pembrolizumab in combination with platinum-­based che- patients.
motherapy is approved (including in Japan10,11) for the treatment of The current study reports on the efficacy and safety of pem-
12 13,14
patients with metastatic squamous and nonsquamous NSCLC brolizumab plus pemetrexed and platinum as first-­line therapy in
without EGFR or ALK alterations and regardless of PD-­L1 TPS after Japanese patients with metastatic nonsquamous NSCLC enrolled in
demonstrating significant survival benefit compared with che- the KEYNOTE-­189 global and Japan extension studies.
motherapy alone in these patients. The benefits associated with
first-­line pembrolizumab plus platinum-­based chemotherapy in pa-
tients with metastatic nonsquamous NSCLC without EGFR or ALK 2 | M ATE R I A L S A N D M E TH O DS
alterations were first demonstrated in the randomized, open-­label,
phase 2 cohort G of the multicohort KEYNOTE-­021 study, where 2.1 | Study design and patients
the combination was associated with a significantly higher objective
response rate (ORR; 55% vs 29%; P = .0016) and significantly longer The study design of the phase 3, global, randomized, double-­
progression-­free survival (PFS; hazard ratio [HR], .53; 95% confi- blind, placebo-­controlled KEYNOTE-­189 trial (NCT02578680) has
dence interval [CI], .31-­.91; P = .010) compared with chemotherapy been published previously.14,15 The design of the KEYNOTE-­189
HORINOUCHI et al. | 3

Japan extension study (NCT03950674) was identical to the global Common Terminology Criteria for Adverse Events version 4.0.
KEYNOTE-­189 study, with the exception that it only enrolled pa- Immune-­mediated AE and infusion reactions were assessed based
tients in Japan. Briefly, eligible patients had untreated stage IV non- on a list of preferred terms identified by the sponsor as having an
squamous NSCLC without sensitizing EGFR or ALK alterations, an immune etiology, regardless of attribution to study treatment.
Eastern Cooperative Oncology Group performance status (ECOG
PS) of 0 or 1, no symptomatic brain metastases, and no history of
noninfectious pneumonitis requiring systemic steroids. Patients 2.3 | Endpoints
with active autoimmune disease and those receiving systemic im-
munosuppressive therapy were not eligible for enrollment. Eligible The dual primary endpoints were OS and PFS. Secondary endpoints
patients were required to provide a tumor sample from either archi- included ORR, duration of response (DOR), and safety. PFS2, de-
val or recently obtained tissue for PD-­L1 assessment. All patients fined as the time from randomization to objective tumor progres-
provided written informed consent before participation in the study. sion on next-­line treatment (including subsequent anti‒­PD-­[L]1
The study protocols and all amendments were approved by an in- therapy) or death from any cause, whichever occurred first, was a
stitutional review board or independent ethics committee at each protocol-­specified exploratory endpoint. PFS2 events were charac-
study site, and the studies were conducted in accordance with Good terized as time of investigator-­assessed disease progression leading
Clinical Practice guidelines and the Declaration of Helsinki. to cessation of second-­line therapy, initiation of third-­line therapy
Eligible patients were randomized (2:1) to receive intravenous for patients who discontinued second-­line therapy without disease
pembrolizumab 200 mg or saline placebo every 3 weeks (Q3W) for progression, and time of death for those who either did not receive
up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus second-­line therapy or stopped second-­line therapy without dis-
the investigator’s choice of cisplatin 75 mg/m2 or carboplatin area ease progression and did not begin third-­line therapy.15,19 Patients
under the concentration–­time curve 5 mg/mL/min Q3W for four were censored for PFS2 at the time of last known survival if they
cycles, followed by maintenance therapy with pemetrexed 500 mg/ were alive and either had not received second-­line therapy or had
m2 Q3W (all administered intravenously). Treatment continued for stopped it without disease progression and had not initiated third-­
the prespecified number of cycles or until documented disease pro- line therapy.
gression, unacceptable AE, intercurrent illness, investigator’s deci-
sion, withdrawal of consent, pregnancy, or noncompliance, or due
to administrative reasons. Randomization was stratified by PD-­L1 2.4 | Statistical analysis
TPS (<1% vs ≥1%), choice of platinum (cisplatin vs carboplatin), and
smoking history (never vs former/current). Patients randomized to Overall, approximately 40 Japanese patients were planned for enroll-
placebo could cross over to pembrolizumab monotherapy at the time ment, including 10 in the global study and 30 in the Japan extension
of disease progression (as verified by a blinded, independent central study. Efficacy was analyzed by assigned treatment in the intent-­to-­
radiologic review [BICR]) if they met all eligibility criteria. treat population, which included all randomized patients. Safety was
analyzed in all patients who received at least one dose of treatment
(as-­treated population). OS, PFS, and PFS2 were estimated using the
2.2 | Assessments Kaplan-­Meier method. HR and 95% CI were determined using a Cox
proportional hazards model. The relatively small patient population
Tumor tissue samples obtained by biopsy at the time of diagnosis precluded further analyses by PD-­L1 status. ORR were summarized
were fixed in formalin and assessed for PD-­L1 expression at a cen- by treatment group. DOR was summarized descriptively using the
tral laboratory using the PD-­L1 IHC 22C3 pharmDx assay (Agilent Kaplan-­Meier method. Inferential testing for statistical significance
Technologies, Carpinteria, CA, USA), and PD-­L1 expression was was not preplanned, and the results were descriptively presented.
characterized by TPS (the percentage of tumor cells with membra-
nous PD-­L1 staining). Tumor imaging was performed at weeks 6 and
12, followed by every 9 weeks through to week 48, and then every 3 | R E S U LT S
12 weeks for patients remaining on treatment beyond week 48.
Tumor response was assessed using Response Evaluation Criteria in 3.1 | Patients and treatment
Solid Tumors (RECIST) version 1.1 by BICR. Following discontinua-
tion of study treatment, survival was assessed every 12 weeks until Of 62 patients screened at 11 Japanese sites between 15 March
death, withdrawal of consent, or the end of the study. 2016 to 1 March 2018, 40 were enrolled (10 in the global study;
Safety and tolerability were assessed by clinical review of all 30 in the extension study), including 25 randomly assigned to
relevant parameters, including AE, laboratory tests, and vital signs. pembrolizumab plus pemetrexed-­platinum and 15 to placebo plus
AE, including those of special interest, occurring through 30 days pemetrexed-­platinum (Figure 1). Baseline demographics and clini-
(90 days for serious AE) after the last treatment dose or until start cal characteristics were generally similar in the pembrolizumab plus
of new therapy were graded using the National Cancer Institute pemetrexed-­platinum arm and the placebo plus pemetrexed-­platinum
4 | HORINOUCHI et al.

• 62 patients screened in Japan

• 22 excluded
• 6 activating EGFR/ALK/KRAS alteration
• 4 inadequate tumor tissue specimen
• 3 investigator opinion
• 2 consent withdrawal
• 7 other (eligibility criteria not met)

40 patients randomized
(10 in global study, 30 in Japan extension study)

• 25 allocated to pembrolizumab combination • 15 allocated to placebo combination

(4 global study, 21 Japan extension study) (6 global study, 9 Japan extension study)
• 25 received assigned treatment • 15 received assigned treatment

• 5 ongoing (remaining on ≥1 component of allocated • 1 ongoing (remaining on ≥1 component of allocated

study therapy) study therapy)
• 4 ongoing on pembrolizumab plus pemetrexed • 1 ongoing on placebo plus pemetrexed
• 1 ongoing on pembrolizumab • 14 discontinued all components of allocated study therapy
• 20 discontinued all components of allocated study therapy • 11 progressive diseasea
• 11 progressive disease • 3 adverse event
• 6 adverse event
• 3 patient withdrawal

• 6 (24%) alive with no subsequent antineoplastic therapy • 2 (13%) alive with no subsequent antineoplastic therapy
• 0 died without subsequent antineoplastic therapy • 2 (13%) died without subsequent antineoplastic therapy
• 14 (56%) received subsequent antineoplastic therapyb • 10 (67%) received subsequent antineoplastic therapy
• 4 (16%) ≥1 subsequent PD-1 or PD-L1 inhibitor • 6 (40%) ≥1 subsequent PD-1 or PD-L1 inhibitor

F I G U R E 1 Disposition of patients in the study. PD-­1, programmed death 1; PD-­L1, programmed death ligand 1. aIncludes patients with
clinical progression or progressive disease. bIncludes patients who received subsequent antineoplastic therapy. It excludes 1 patient in the
pembrolizumab combination arm who received radiation (see Table S1 for further details)

arm, with the exception of fewer patients with brain metastases placebo plus pemetrexed-­platinum arm crossed over on study to
(16% vs 33%), previous adjuvant therapy (12% vs 20%) and PD-­L1 pembrolizumab monotherapy, and 4 patients (16%) in the pembroli-
TPS not evaluable (4% vs 20%), and a larger proportion of patients zumab plus pemetrexed-­platinum arm and 6 (40%) in the placebo
with PD-­L1 TPS <1% (56% vs 40%) (Table 1). plus pemetrexed-­platinum arm received subsequent PD-­(L)1 inhib-
At data cutoff (20 May 2019), the median time from random- itor therapy (Table S1).
ization to the date of database cutoff was 18.5 (range, 14.7-­38.2)
months. The median treatment duration was 9 (range, 0‒­21.2)
months with pembrolizumab plus pemetrexed-­platinum and 6 (range, 3.2 | Efficacy outcomes
1.2 ‒­17.2) months in the placebo plus pemetrexed-­platinum arm. At
data cutoff, 5 patients (20%) in the pembrolizumab plus pemetrexed-­ At the time of data cutoff, 3 patients (12%) in the pembrolizumab
platinum arm compared with 1 (7%) in the placebo plus pemetrexed-­ plus pemetrexed-­p latinum arm and 7 (47%) in the placebo plus
platinum arm remained on ≥1 component of study therapy (Figure 1). pemetrexed-­p latinum arm had died. Median OS was not reached
A total of 6 patients (24%) in the pembrolizumab plus pemetrexed-­ (NR; 95% CI, NE–­N E) among patients receiving pembrolizumab
platinum arm and 2 (13%) in the placebo plus pemetrexed-­platinum plus pemetrexed-­p latinum and was 25.9 (95% CI, 11.9-­29.0)
arm were alive without subsequent treatment, including 4 (16%) and months among those receiving placebo plus pemetrexed-­p latinum
1 (7%), respectively, who did not have disease progression. A total of (HR [95% CI], .29 [.07-­1 .15]; Figure 2A). Estimated 12-­m onth OS
14 patients (56%) in the pembrolizumab plus pemetrexed-­platinum rates were 92% and 80% in the pembrolizumab plus pemetrexed-­
arm and 10 (67%) in the placebo plus pemetrexed-­platinum arm re- platinum and placebo plus pemetrexed-­p latinum arms,
ceived subsequent antineoplastic therapy; 4 patients (27%) in the respectively.
HORINOUCHI et al. | 5

TA B L E 1 Patient demographic and

Pembrolizumab + pemetrexed-­ Placebo + pemetrexed-­
disease characteristics at baseline
Characteristic platinum (n = 25) platinum (n = 15)

Age, median (range), y 64.0 (34-­77) 66.0 (34-­74)

Male 19 (76) 12 (80)
ECOG PS
0 15 (60) 9 (60)

1 10 (40) 6 (40)
Histology
Adenocarcinoma 23 (92) 14 (93)
NSCLC NOS 1 (4) 0 (0)
Other 1 (4) 1 (7)
Smoking status
Former/current smoker 18 (72) 12 (80)
Never 7 (28) 3 (20)
Brain metastases 4 (16) 5 (33)
PD-­L1 TPS
<1% 14 (56) 6 (40)
≥1% 10 (40) 6 (40)
Not evaluable 1 (4) 3 (20)
Prior therapy
Neoadjuvant therapy 0 0
Adjuvant therapy 3 (12) 3 (20)
Prior radiationa 8 (32) 4 (27)

Note: Data are n (%) unless otherwise noted.

ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC NOS, non–­small-­cell
lung cancer not otherwise specified; PD-­L1, programmed death ligand 1; TPS, tumor proportion
score.
a
No patient had prior thoracic radiation.

At data cutoff, disease progression or death had occurred in 13 Median PFS2 was not reached (95% CI, 16.4 months–­NE) in the
patients (52%) in the pembrolizumab plus pemetrexed-­platinum pembrolizumab plus pemetrexed-­platinum arm and was 12.4 (95%
arm and 11 (73%) in the placebo plus pemetrexed-­platinum arm. CI, 7.6-­20.5) months in the placebo plus pemetrexed-­platinum arm
Median (95% CI) PFS was 16.5 (8.8-­21.1) months in the pembroli- (HR [95% CI], .34 [.14-­.86]). The estimated 12-­month PFS2 rate was
zumab plus pemetrexed-­platinum arm and 7.1 (4.7-­21.4) months in 80% in the pembrolizumab plus pemetrexed-­platinum arm and 53%
the placebo plus pemetrexed-­platinum arm (HR [95% CI], .62 [.27-­ in the placebo plus pemetrexed-­platinum arm (Figure 4).
1.42]; Figure 2B). Estimated 12-­month PFS rates were 64% and 29%,
respectively.
Confirmed ORR was 56% (1 with complete response; 13 with par- 3.3 | Safety
tial response [PR]) in the pembrolizumab plus pemetrexed-­platinum
arm and 33% (all 5 with PR) in the placebo plus pemetrexed-­platinum All patients in both treatment arms experienced at least one AE
arm (Table 2). At data cutoff, no patient had progressive disease in (Table 3; Table S2). The most commonly reported AE were nausea,
the pembrolizumab plus pemetrexed-­platinum arm compared with constipation, decreased appetite, and anemia. Grade 3/4 AE occurred
13% (n = 2) in the placebo plus pemetrexed-­platinum arm (Table 2). in 18 patients (72%) in the pembrolizumab plus pemetrexed-­platinum
Median (range) DOR was 13.6 (3.3+ to 19.6) months in the pembroli- arm and in 9 patients (60%) in the placebo plus pemetrexed-­platinum
zumab plus pemetrexed-­platinum arm and 9.7 (3.4 to 26.4+) months arm; there were no grade 5 AE in either treatment arm. There were
in the placebo plus pemetrexed-­platinum arm (+ indicates no pro- three AE associated with renal toxicity in the pembrolizumab plus
gressive disease by the time of last assessment; Figure 3). Overall, pemetrexed-­platinum arm (blood creatinine increased, n = 2 [8%]; cre-
62% of patients in the pembrolizumab plus pemetrexed-­platinum atinine renal clearance decreased, n = 1 [4%]) and four in the placebo
arm compared with 40% in the placebo plus pemetrexed-­platinum plus pemetrexed-­platinum arm (acute kidney injury, renal impairment,
arm had estimated DOR ≥12 months. blood creatinine increased and creatinine renal clearance decreased,
 6 | HORINOUCHI et al.

(A) n Events, n (%) HR (95% CI) F I G U R E 2 Kaplan-­Meier analysis

Pembrolizumab combination 25 3 (12) of (A) OS and (B) PFS in the intent-­to-­
.29 (0.07–1.15) treat population. HR, hazard ratio; NR,
Placebo combination 15 7 (47)
not reached; OS, overall survival; PFS,
92% progression-­free survival
80%
100
90
80
Overall Survival, %

70
Median (95% CI)
60 NR (NR–NR)
25.9 mo (11.9–29.0 mo)
50
40
30
20
10
0
0 6 12 18 24 30 36

No. at risk
Time, months
25 23 23 11 3 1 0
15 15 12 6 3 0 0

(B) n Events, n (%) HR (95% CI)

Pembrolizumab combination 25 13 (52)
.62 (0.27–1.42)
Placebo combination 15 11 (73)

64%
29%
100
Progression-Free Survival, %

90
80
70
Median (95% CI)
60 16.5 mo (8.8–21.1 mo)
7.1 mo (4.7–21.4 mo)
50
40
30
20
10
0
0 6 12 18 24 30

No. at risk
Time, months
25 19 12 3 0 0
15 9 4 2 1 0

n = 1 each [7%]). In the pembrolizumab plus pemetrexed-­platinum arm, clearance, only pemetrexed was discontinued. In the placebo plus
in 1 patient with increased blood creatinine both pembrolizumab and pemetrexed-­platinum arm, only treatment with pemetrexed was inter-
pemetrexed were discontinued; in the second patient with increased rupted in the patient with decreased creatinine renal clearance.
blood creatinine treatment with both pembrolizumab and pemetrexed Immune-­mediated AE occurred in 10 patients (40%) in the pem-
was interrupted; and in the patient with decreased creatinine renal brolizumab plus pemetrexed-­platinum arm and 3 (20%) in the placebo
HORINOUCHI et al. | 7

TA B L E 2 Summary of tumor response

Pembrolizumab +pemetrexed-­ Placebo + pemetrexed-­
per RECIST Version 1.1 by BICR
platinum (n = 25) platinum (n = 15)

Objective response rate, % 56 (34.9 to 75.6) 33 (11.8 to 61.6)

(95% CI)
Complete response 1 (4) 0 (0)
Partial response 13 (52) 5 (33)
Stable diseasea 9 (36) 8 (53)
Progressive disease 0 (0) 2 (13)
Not evaluableb 2 (8) 0 (0)
Time to response, median 1.4 (1.2 to 3.0) 1.4 (1.2 to 4.9)
(range), monthsc
Duration of response, median 13.6 (3.3+ to 19.6) 9.7 (3.4 to 26.4+)
(range), monthsc,d
Kaplan-­Meier estimate of patients with extended duration of response, %c,d
≥12 mo 61.9 40.0

Note: Data are n (%) unless otherwise noted.

+, no progressive disease at time of last assessment.
BICR, blinded, independent central radiologic review; RECIST, Response Evaluation Criteria in Solid
Tumors.
a
Includes stable disease and noncomplete response/nonprogressive disease.
b
Postbaseline assessments were not evaluable or complete response/partial response/stable
disease was <6 wk from randomization.
c
Assessed in patients with a best objective response of confirmed complete or partial response.
d
Estimated using product-­limit (Kaplan-­Meier) method for censored data.

plus pemetrexed-­platinum arm, and infusion reactions occurred in 1 patients with PD-­L1 TPS <1% (40%–­56% vs 31%), and patients with
patient (4%) in the pembrolizumab plus pemetrexed-­platinum arm previous thoracic radiotherapy (27%–­32% vs 7%–­9%).15 At the time
and none in the placebo plus pemetrexed-­platinum arm (Table 3). No of data cutoff, median OS was not reached in the Japan study, but,
patient experienced a grade 5 immune-­mediated AE or infusion re- the HR (95% CI) for OS (.29 [.07 − 1.15]) and PFS (.62 [.27 − 1.42]) in
action. Grade 3/4 immune-­mediated AE occurred in 4 patients (16%) the Japan study suggest prolonged survival with pembrolizumab plus
in the pembrolizumab plus pemetrexed-­platinum arm (severe skin pemetrexed-­platinum compared with the placebo plus pemetrexed-­
reaction, n = 2; colitis, n = 1; pneumonitis, n = 1) and 2 (13%) in the platinum arm, consistent with the global patient population (HR for OS,
placebo plus pemetrexed-­platinum arm (pneumonitis, n = 2). .56 [.45 − .70]; PFS, .48 [.40 − .58]). The 12-­month OS and PFS rates
were higher in the Japan study for pembrolizumab plus pemetrexed-­
platinum compared with placebo plus pemetrexed-­platinum (12-­
4 | D I S CU S S I O N month OS, 92% vs 80%; PFS, 64% vs 29%), similar to the global
population (12-­month OS, 70% vs 48%; PFS, 39% vs 17%),15 despite
These results from the KEYNOTE-­189 Japan study are, to our knowl- a higher proportion of patients with PD-­L1 TPS <1% in the pembroli-
edge, the first published findings from a phase 3 placebo-­controlled zumab plus pemetrexed-­platinum arm. These trends were also in line
trial evaluating clinical outcomes with first-­line anti–­PD-­(L)1 therapy with the prespecified final analysis from the global KEYNOTE-­189
in combination with platinum-­based chemotherapy in Japanese pa- study, which reported HR (95% CI) for OS of .56 (.46-­.69) and for PFS
tients with advanced nonsquamous NSCLC. Treatment with pem- of .49 (.41-­.59).20 The small patient population in the Japan study,
brolizumab plus pemetrexed and platinum was associated with however, precludes further analyses by PD-­L1 status. Similar to the
prolonged OS, PFS, and PFS-­2 compared with placebo plus peme- global KEYNOTE-­189 study, the HR (95% CI) for PFS2 in the Japan
trexed and platinum, with manageable toxicity. These data were gen- study, defined as the time from randomization to objective tumor pro-
erally consistent with those of the global population from this study gression on next line of therapy or death from any cause, whichever
and support the use of pembrolizumab plus pemetrexed-­platinum as occurred first, also favored pembrolizumab plus pemetrexed-­platinum
first-­line treatment for Japanese patients with metastatic nonsqua- compared with placebo plus pemetrexed-­platinum. This PFS2 out-
mous NSCLC without sensitizing EGFR or ALK alterations. come indicates that treatment effects observed in the first-­line setting
Baseline characteristics in the Japan study were largely consistent in Japanese patients with metastatic NSCLC were maintained into the
with the global population, with the exceptions of a greater percent- second line of therapy and thereby supports the use of pembrolizumab
age of male patients (76%–­80% vs 53%–­62% in the global study), in the first-­line setting.
8 | HORINOUCHI et al.

TPS, %
1–49 CR
1–49 PR
≥50
PD
<1
<1 Treatment discontinued
1–49 Discontinued due to an AE
<1 Start of second line treatment
<1 Second line PD
<1 Ongoing on pembrolizumab
1–49
Alive
<1
Time to death
≥50
1–49 Duration of pembrolizumab
≥50 Duration of pemetrexed
NE
<1
<1
<1
<1
<1
≥50
<1
<1
<1
1–49

0 3 6 9 12 15 18 21 24 27 30 33
Time, months

F I G U R E 3 Treatment duration and time to response among patients in the pembrolizumab plus pemetrexed-­platinum group. Light green
bars indicate the months of follow up. AE, adverse event; CR, complete response; PD, progressive disease; PR, partial response

No new safety signals were identified in this population of enrolled in KEYNOTE-­011 received pembrolizumab in combination
Japanese patients and, overall, pembrolizumab plus pemetrexed-­ with platinum-­based chemotherapy for four cycles, followed by
platinum was associated with a manageable toxicity profile, with no pembrolizumab for up to 2 years as monotherapy (squamous NSCLC)
apparent increase in the frequency of AE commonly associated with or in combination with pemetrexed (nonsquamous NSCLC). At the
pemetrexed-­platinum. A similar proportion of patients experienced time of data cutoff, the ORR was 50% in patients with squamous
grade 3 or 4 AE in the two treatment arms, and there were no deaths NSCLC and 67% and 80% in patients in the cisplatin and carboplatin
due to AE in either treatment arm. While a higher proportion of pa- cohorts, respectively, with nonsquamous NSCLC. Treatment-­related
tients in the pembrolizumab plus pemetrexed-­platinum arm in the pri- deaths due to pneumonitis were reported for 2 patients in part B of
mary analysis from the global KEYNOTE-­189 study experienced acute KEYNOTE-­011 (none were reported in part C of the study); how-
kidney injury compared to the placebo plus pemetrexed-­platinum arm ever, similar AE were not observed in the current analysis (1 patient
(5.2% vs .5%),14 there was no evidence of increased renal toxicity in in the pembrolizumab plus pemetrexed-­platinum arm and 2 patients
either treatment arm in the current analysis of Japanese patients from in the placebo plus pemetrexed-­platinum arm experienced grade
the KEYNOTE-­189 global and extension studies. Overall, the safety 3 or 4 pneumonitis). Separately, a subset analysis of data from 50
profile of pembrolizumab plus pemetrexed-­platinum was similar in the Japanese patients enrolled in the global, phase 3, placebo-­controlled
Japan and the KEYNOTE-­189 global studies. KEYNOTE-­4 07 study demonstrated efficacy and safety of pem-
The findings from this study add to the growing body of evidence brolizumab plus chemotherapy as first-­line therapy in patients with
demonstrating the efficacy and safety of pembrolizumab in combi- metastatic squamous NSCLC. 22 Median OS was 17.3 months in the
nation with platinum-­based chemotherapy in Japanese patients pembrolizumab plus chemotherapy arm compared with 11.0 months
with NSCLC. The phase 1 KEYNOTE-­011 study parts B and C sug- in the placebo plus chemotherapy arm (HR, .56; 95% CI, .27-­1.15),
gested clinical benefit of first-­line therapy with pembrolizumab plus and median PFS was 8.3 compared with 7.2 months (HR, .65; 95%
platinum-­based chemotherapy in Japanese patients with advanced CI, .35-­1.23), respectively. The safety profile of pembrolizumab plus
nonsquamous (n = 12) or squamous (n = 14) NSCLC. 21 Patients chemotherapy was manageable in both of the above analyses.
HORINOUCHI et al. | 9

F I G U R E 4 Kaplan-­Meier analysis n Events, n (%) HR (95% CI)

of progression-­free survival-­2 (PFS2) in Pembrolizumab combination 25 8 (32)
the intent-­to-­treat population. PFS2 was .34 (0.14–0.86)
Placebo combination 15 11 (73)
defined as the time from randomization
to objective tumor progression on next-­ 80%
line treatment (including subsequent 53%

Progression-Free Survival-2, %
anti–­PD-­[L]1 therapy) or death from any 100
cause, whichever occurred first.19 HR, 90
hazard ratio; NR, not reached; PD-­(L)1,
programmed death 1 or programmed 80
death ligand 1
70
60
50
Median (95% CI)
40 NR (16.4 mo–NR)
30 12.4 mo (7.6–20.5 mo)

20
10
0
0 6 12 18 24 30
Time, months
No. at risk
25 23 20 9 3 1
15 14 8 3 1 0

The current study had certain limitations. Given the relatively In conclusion, consistent with the global KEYNOTE-­189 study,
small number of patients (N = 40), the KEYNOTE-­189 Japan study pembrolizumab in combination with pemetrexed and platinum
was not powered for formal statistical analysis and, as discussed improved OS, PFS, ORR, and PFS2 compared with placebo plus
above, did not allow for comparison of outcomes among key patient pemetrexed-­platinum and demonstrated a manageable safety profile
subgroups. In addition, it is unclear whether or how potential differ- in Japanese patients with previously untreated metastatic nonsqua-
ences between treatment groups in clinical characteristics, includ- mous NSCLC. The results from this study confirm the role of pem-
ing the smaller proportion of patients with brain metastases and the brolizumab plus pemetrexed-­platinum as a first-­line standard-­of-­care
smaller proportion with previous adjuvant therapy in the pembroli- therapy for Japanese patients with metastatic nonsquamous NSCLC.
zumab plus pemetrexed-­platinum arm compared with the placebo
plus pemetrexed-­platinum arm, might have contributed to observed AC K N OW L E D G M E N T S
outcomes. Nonetheless, the trends for HR in the Japan study were Funding for this research was provided by Merck Sharp & Dohme
consistent with those in the global study, which demonstrated survival Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical
benefits with pembrolizumab plus pemetrexed-­platinum compared writing assistance was provided by Adrienne Drinkwater, PhD, and
with placebo plus pemetrexed-­platinum among patients with and Shilpa Kamboj, PhD, of ICON plc (North Wales, PA, USA). This as-
without liver or brain metastases, suggesting that there is substantial sistance was funded by Merck Sharp & Dohme Corp., a subsidiary of
benefit with pembrolizumab plus pemetrexed-­platinum compared Merck & Co., Inc., Kenilworth, NJ, USA. A portion of the results from
with pemetrexed-­platinum alone as first-­line treatment in Japanese this study were presented at the 60th Annual Meeting of the Japan
patients with advanced nonsquamous NSCLC. Notably, based on Lung Cancer Society; 6−8 December 2019; Osaka, Japan.
the results from KEYNOTE-­189, pembrolizumab in combination with
pemetrexed and platinum-­based chemotherapy was approved in D I S C LO S U R E
Japan in 2018 for first-­line treatment of unresectable, advanced or Hidehito Horinouchi: Lecture fees, honoraria, or other fees from
recurrent nonsquamous NSCLC regardless of PD-­L1 expression,10 Eli Lilly, AstraZeneca, Kyowa Kirin, MSD, Ono Pharmaceutical, and
and the Pan Asian adapted clinical practice guidelines recommended Bristol-­Myers Squibb; Research funds from Chugai Pharmaceutical,
consideration of pembrolizumab plus pemetrexed-­platinum as first-­ Daiichi Sankyo, AstraZeneca, MSD, Ono Pharmaceutical, Bristol-­
23
line treatment for this indication. Finally, the addition of a PD-­(L)1 Myers Squibb, and Genomic Health. Naoyuki Nogami: Honoraria from
inhibitor to platinum-­based chemotherapy is “strongly recommended” AstraZeneca, Chugai Pharmaceutical, Pfizer Japan Inc, Eli Lilly Japan
in the Japanese Lung Cancer Society guidelines for patients with driver KK, Ono Pharmaceutical, Taiho Pharmaceutical, MSD KK, Kyowa Kirin,
oncogene-­negative stage IV NSCLC with ECOG PS 0-­1.4 Bristol-­Myers Squibb KK, and Nippon Boehringer Ingelheim. Hideo
10 | HORINOUCHI et al.

TA B L E 3 Summary of all-­cause AE in the as-­treated populationa TA B L E 3 (Continued)

Pembrolizumab + ​ Placebo + ​ Pembrolizumab + ​ Placebo + ​

pemetrexed-­platinum pemetrexed-­ pemetrexed-­platinum pemetrexed-­
(n = 25) platinum (n = 15) (n = 25) platinum (n = 15)

Grade Grade
AE, n (%) Any grade Grade 3-­5b Any grade 3-­5b AE, n (%) Any grade Grade 3-­5b Any grade 3-­5b

Experienced ≥1 AEc 25 (100) 18 (72) 15 (100) 9 (60) Immune-­mediated 10 (40) 4 (16) 3 (20) 2 (13)
AE and infusion
Led to 9 (36) 4 (16) 3 (20) 2 (13)
reactionsd
discontinuation
of any treatment Adrenal insufficiency 2 (8) 0 (0) 0 (0) 0 (0)
component Colitis 1 (4) 1 (4) 0 (0) 0 (0)
Led to death 0 (0) 0 (0) 0 (0) 0 (0) Hyperthyroidism 2 (8) 0 (0) 0 (0) 0 (0)
Occurring in ≥15% of patients in either treatment arm Hypothyroidism 0 (0) 0 (0) 1 (7) 0 (0)
Nausea 18 (72) 0 (0) 8 (53) 1 (7) Infusion reactions 1 (4) 0 (0) 0 (0) 0 (0)
Constipation 16 (64) 0 (0) 11 (73) 0 (0) Pneumonitis 2 (8) 1 (4) 2 (13) 2 (13)
Decreased appetite 14 (56) 0 (0) 9 (60) 0 (0) Severe skin 2 (8) 2 (8) 0 (0) 0 (0)
Anemia 11 (44) 2 (8) 10 (67) 3 (20) reactions
White blood cell 10 (40) 4 (16) 3 (20) 1 (7) Thyroiditis 1 (4) 0 (0) 0 (0) 0 (0)
count decreased
AE, adverse event; NCI CTCAE, National Cancer Institute Common
Alanine 9 (36) 0 (0) 5 (33) 0 (0) Terminology Criteria for Adverse Events.
aminotransferase a
Includes all randomized patients who received at least one dose of
increased study treatment, according to the treatment received.
Diarrhea 9 (36) 1 (4) 3 (20) 1 (7) b
No patient in either treatment arm had grade 5 AE.
c
Dry skin 9 (36) 0 (0) 2 (13) 0 (0) AE were graded using NCI CTCAE version 4.0.
d
Aspartate 8 (32) 0 (0) 5 (33) 0 (0) Immune-­mediated AE and infusion reactions are listed irrespective of
aminotransferase attribution to study treatment by the investigator.
increased
Hiccups 7 (28) 0 (0) 5 (33) 0 (0) Saka: Nothing to disclose. Makoto Nishio: Honoraria for lectures and
Lymphocyte count 7 (28) 6 (24) 1 (7) 0 (0) consulting from Ono Pharmaceutical, Bristol-­Myers Squibb, Pfizer,
decreased Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca,
Neutrophil count 7 (28) 5 (20) 2 (13) 0 (0) Boehringer Ingelheim, MSD, and Novartis; Research support from
decreased
MSD, Novartis, Ono Pharmaceutical, Chugai Pharmaceutical,
Stomatitis 7 (28) 0 (0) 4 (27) 0 (0) Bristol-­Myers Squibb, Taiho Pharmaceutical, Eli Lilly, AstraZeneca,
Insomnia 6 (24) 0 (0) 1 (7) 0 (0) and Pfizer. Takaaki Tokito: Personal fees from AstraZeneca, Chugai
Rash 6 (24) 0 (0) 1 (7) 0 (0) Pharmaceutical, MSD, and Boehringer Ingelheim. Toshiaki Takahashi:
Face edema 5 (20) 0 (0) 1 (7) 0 (0) Grants and personal fees from AstraZeneca KK, Chugai Pharmaceutical,
Malaise 5 (20) 0 (0) 4 (27) 0 (0) Eli Lilly Japan KK, Ono Pharmaceutical, and MSD KK; Grants from
Nasopharyngitis 5 (20) 0 (0) 1 (7) 0 (0) Pfizer Japan Inc; Personal fees from Boehringer Ingelheim Japan, Inc
Pyrexia 5 (20) 0 (0) 1 (7) 0 (0) and Roche Diagnostics KK. Kazuo Kasahara: Grants from Boehringer

Alopecia 4 (16) 0 (0) 1 (7) 0 (0) Ingelheim. Yoshihiro Hattori: Lecture fees from Taiho Pharmaceutical;
Grants from Ono Pharmaceutical and MSD. Eiki Ichihara: Honoraria
Back pain 4 (16) 0 (0) 2 (13) 0 (0)
from Boehringer Ingelheim; Research support from MSD. Noriaki
Fatigue 4 (16) 0 (0) 5 (33) 0 (0)
Adachi: Employee of MSD KK. Kazuo Noguchi: Employee of MSD
Dysgeusia 3 (12) 0 (0) 5 (33) 0 (0)
KK. Fabricio Souza: Employee of Merck & Co., Inc. Takayasu Kurata:
Neutropenia 3 (12) 1 (4) 3 (20) 2 (13)
Personal fees from AstraZeneca, MSD, Eli Lilly, Chugai Pharmaceutical,
Peripheral edema 2 (8) 0 (0) 5 (33) 0 (0)
Ono Pharmaceutical, Bristol-­Myers Squibb, Boehringer Ingelheim,
Vomiting 2 (8) 0 (0) 4 (27) 0 (0) and Pfizer; Grants from AstraZeneca, MSD, Chugai Pharmaceutical,
Anxiety 1 (4) 0 (0) 3 (20) 0 (0) Takeda, and Bristol-­Myers Squibb.
Thrombocytopenia 1 (4) 0 (0) 4 (27) 0 (0)
Leukopenia 0 (0) 0 (0) 7 (47) 0 (0) DATA AVA I L A B I L I T Y S TAT E M E N T
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,
Kenilworth, NJ, USA (MSD) is committed to providing qualified scien-
(Continues) tific researchers access to anonymized data and clinical study reports
HORINOUCHI et al. | 11

from the company’s clinical trials for the purpose of conducting legiti- 10. Merck’s KEYTRUDA® (pembrolizumab) receives five new approvals in
Japan, including in advanced non-­small cell lung cancer, as adjuvant
mate scientific research. MSD is also obligated to protect the rights
therapy for melanoma, and in advanced microsatellite instability-­
and privacy of trial participants and, as such, has a procedure in place high tumors. 2019. https://www.merck.com/news/merck​s-­keytr​
for evaluating and fulfilling requests for sharing company clinical trial uda-­pembr​olizu​mab-­recei​ves-­five-­new-­appro​vals-­in-­japan​-­inclu​ding-­
data with qualified external scientific researchers. The MSD data shar- in-­advan​ced-­non-­small​-­cell-­lung-­cance​r-­nsclc​-a­ s-­adjuv​ant-­thera​py-­
ing website (available at: http://engag​ezone.msd.com/ds_docum​entat​ for-­melan​oma-­and-­in-­advan​ced-­micro​sa/. Accessed August 27, 2020.
11. Agency PaMD. Report on the Deliberation Results. 2018. https://www.
ion.php) outlines the process and requirements for submitting a data
pmda.go.jp/files/​00023​1921.pdf. Accessed September 15, 2020.
request. Applications will be promptly assessed for completeness and 12. Paz-­Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemo-
policy compliance. Feasible requests will be reviewed by a commit- therapy for squamous non-­small-­cell lung cancer. N Engl J Med.
tee of MSD subject matter experts to assess the scientific validity of 2018;379:2040-­2051.
13. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and peme-
the request and the qualifications of the requestors. In line with data
trexed with or without pembrolizumab for advanced, non-­squamous
privacy legislation, submitters of approved requests must enter into non-­small-­cell lung cancer: a randomised, phase 2 cohort of the
a standard data-­sharing agreement with MSD before data access is open-­label KEYNOTE-­021 study. Lancet Oncol. 2016;17:1497-­1508.
granted. Data will be made available for request after product approval 14. Gandhi L, Rodriguez-­Abreu D, Gadgeel S, et al. Pembrolizumab plus
chemotherapy in metastatic non-­small-­cell lung cancer. N Engl J
in the US and EU or after product development is discontinued. There
Med. 2018;378:2078-­2092.
are circumstances that may prevent MSD from sharing requested data, 15. Gadgeel S, Rodriguez-­Abreu D, Speranza G, et al. Updated analysis
including country or region-­specific regulations. If the request is de- from KEYNOTE-­189: pembrolizumab or placebo plus pemetrexed
clined, it will be communicated to the investigator. Access to genetic and platinum for previously untreated metastatic nonsquamous
non-­small-­cell lung cancer. J Clin Oncol. 2020;38:1505-­1517.
or exploratory biomarker data requires a detailed, hypothesis-­driven
16. Peng L, Wu YL. Immunotherapy in the Asiatic population: any differ-
statistical analysis plan that is collaboratively developed by the re- ences from Caucasian population? J Thorac Dis. 2018;10:S1482-­S1493.
questor and MSD subject matter experts; after approval of the sta- 17. Soo RA, Kawaguchi T, Loh M, et al. Differences in outcome and
tistical analysis plan and execution of a data-­sharing agreement, MSD toxicity between Asian and Caucasian patients with lung cancer
treated with systemic therapy. Future Oncol. 2012;8:451-­462.
will either perform the proposed analyses and share the results with
18. Soo RA, Loh M, Mok TS, et al. Ethnic differences in survival out-
the requestor or will construct biomarker covariates and add them to a come in patients with advanced stage non-­small cell lung cancer:
file with clinical data that is uploaded to an analysis portal so that the results of a meta-­analysis of randomized controlled trials. J Thorac
requestor can perform the proposed analyses. Oncol. 2011;6:1030-­1038.
19. European Medicines Agency. Guideline on the evaluation of anti-
cancer medicinal products in man. 2017. http://www.ema.europa.
ORCID
eu/docs/en_GB/docum​e nt_libra​r y/Scien​t ific_guide​line/2017/11/
Hidehito Horinouchi https://orcid.org/0000-0001-9090-801X WC500​238764.pdf. Accessed August 26, 2020.
Makoto Nishio https://orcid.org/0000-0003-4969-4165 20. Rodriguez Abreu D, Powell SF, Hochmair MJ, et al. Protocol-­specified
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