Original Investigation | Oncology

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab

in Patients With Early Triple-Negative Breast Cancer
A Secondary Analysis of a Randomized Clinical Trial
Masato Takahashi, MD; Javier Cortés, MD; Rebecca Dent, MD; Lajos Pusztai, MD; Heather McArthur, MD; Sherko Kümmel, MD; Carsten Denkert, MD; Yeon Hee Park, MD;
Seock-Ah Im, MD; Jin-Hee Ahn, MD; Hirofumi Mukai, MD; Chiun-Sheng Huang, MD; Shin-Cheh Chen, MD; Min Hwan Kim, MD; Liyi Jia, PhD; Xin Tong Li, PhD;
Konstantinos Tryfonidis, MD; Vassiliki Karantza, MD; Hiroji Iwata, MD; Peter Schmid, MD

Abstract Key Points

Question What are the outcomes of
IMPORTANCE In the phase 3 KEYNOTE-522 study, addition of pembrolizumab to neoadjuvant
neoadjuvant pembrolizumab or placebo
chemotherapy followed by adjuvant pembrolizumab significantly increased pathologic complete
plus chemotherapy followed by
response (pCR) and event-free survival (EFS) vs neoadjuvant chemotherapy in patients with early
adjuvant pembrolizumab or placebo
triple-negative breast cancer.
among patients with early triple-
negative breast cancer enrolled in East/
OBJECTIVE To evaluate efficacy and safety outcomes for patients enrolled in East/Southeast Asia
Southeast Asia (Asia) in the KEYNOTE-
(Asia) in KEYNOTE-522.
522 study?

DESIGN, SETTING, AND PARTICIPANTS KEYNOTE-522, a multicenter, double-blind, randomized Findings In this secondary analysis of a
clinical trial, enrolled 1174 patients between March 7, 2017, and September 13, 2018. For interim EFS phase 3, double-blind randomized
and overall survival (OS) analyses (data cutoff, March 23, 2021), median follow-up was 39.8 months clinical trial, among the 216 patients
(range, 30.4-46.9 months) for pembrolizumab plus chemotherapy and 40.8 months (range, 30.1- enrolled in Asia, there was a bigger
46.9 months) for placebo plus chemotherapy. Data cutoff for pCR analysis was September 24, 2018. difference in pathologic complete
This secondary analysis included adults enrolled in Asia with newly diagnosed, previously untreated, response with pembrolizumab vs
nonmetastatic triple-negative breast cancer (tumor stage T1c and nodal stage N1-2 or tumor stage placebo (58.7% vs 40.0%) and better
T2-4 and nodal stage N0-2) and Eastern Cooperative Oncology Group performance status of 0 to 1, event-free survival (91.2% vs 77.2% at
regardless of programmed cell death ligand 1 (PD-L1) status. 36 months) compared with the overall
study population; safety was as
INTERVENTION Patients were randomized 2:1 to 4 cycles of pembrolizumab (200 mg every 3 anticipated.
weeks) or placebo plus carboplatin and paclitaxel and another 4 cycles of pembrolizumab or placebo
Meaning Outcomes in the
plus doxorubicin or epirubicin and cyclophosphamide before surgery. After definitive surgery,
KEYNOTE-522 study for patients
patients received pembrolizumab or placebo every 3 weeks for 9 cycles or until recurrence or
enrolled in Asia were consistent with
unacceptable toxic effects.
those in the overall study population;
these findings support the use of this
MAIN OUTCOMES AND MEASURES The main outcome was pCR (no evidence of primary tumor
therapy regimen as standard of care for
after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph
patients in Asia.
node involvement after neoadjuvant therapy) at the time of definitive surgery and EFS.

RESULTS A total of 216 of 1174 randomized patients (all female; median [range] age, 46.0 [24.0- + Visual Abstract
71.0] years) were from Korea, Japan, Taiwan, and Singapore (136 in the pembrolizumab plus
chemotherapy group and 80 in the placebo plus chemotherapy group). Of these patients, 104
+ Supplemental content
Author affiliations and article information are
(76.5%) in the pembrolizumab plus chemotherapy group and 60 (75.0%) in the placebo plus
listed at the end of this article.
chemotherapy group had a tumor PD-L1 combined positive score of 1 or greater. Pathologic complete
response was 58.7% (95% CI, 46.7%-69.9%) with pembrolizumab plus chemotherapy and 40.0%
(95% CI, 26.4%-54.8%) with placebo plus chemotherapy; benefit was observed regardless of PD-L1
status. Thirteen patients (9.6%) in the pembrolizumab plus chemotherapy group and 20 patients

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY-NC-ND License.

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Abstract (continued)

(25.0%) in the placebo plus chemotherapy group had EFS events (hazard ratio, 0.35; 95% CI, 0.17-
0.71). The 36-month EFS rate was 91.2% (95% CI, 85.0%-94.9%) with pembrolizumab plus
chemotherapy and 77.2% (95% CI, 66.3%-85.0%) with placebo plus chemotherapy. Grade 3 to 4
treatment-related adverse events occurred in 109 patients (80.1%) receiving pembrolizumab plus
chemotherapy and 64 patients (81.0%) receiving placebo plus chemotherapy.

CONCLUSIONS AND RELEVANCE In this subgroup analysis of patients enrolled in Asia in KEYNOTE-
522, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to
clinically meaningful improvements in pCR and EFS vs neoadjuvant chemotherapy alone. These
findings support the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant
pembrolizumab as a standard-of-care therapy for patients in Asian countries with early triple-
negative breast cancer.

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03036488

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Introduction
Triple-negative breast cancer (TNBC) has a poor prognosis and is recognized as the most difficult-to-
treat breast cancer subtype.1,2 Neoadjuvant chemotherapy is standard-of-care treatment for early
TNBC.3-5 The short-term goal of such therapy is to achieve a pathologic complete response (pCR)
because of its association with significant improvements in long-term clinical outcomes. A meta-
analysis of 25 studies in early TNBC demonstrated an 81% lower risk of death and a 76% lower risk of
progression, recurrence, or death among patients who attain a pCR after neoadjuvant
chemotherapy.6 However, median pCR rates were only 35.0% (range, 16.7%-67.0%) among the
cohort studies and 41.0% (range, 26.7%-62.0%) among the clinical trials included in the
meta-analysis.6 These findings underscore the need for new treatment approaches for patients with
early TNBC to reduce disease recurrence and prolong survival.
In the phase 3 KEYNOTE-522 study (Study of Pembrolizumab [MK-3475] Plus Chemotherapy vs
Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant
Therapy in Participants With Triple Negative Breast Cancer), addition of the anti–programmed cell
death protein 1 monoclonal antibody pembrolizumab to neoadjuvant chemotherapy followed by
adjuvant pembrolizumab significantly increased pCR and event-free survival (EFS) vs neoadjuvant
chemotherapy alone in patients with early TNBC. In the overall study population, the pCR rate was
64.8% (95% CI, 59.9%-69.5%) in the pembrolizumab and neoadjuvant chemotherapy group vs
51.2% (95% CI, 44.1%-58.3%) in the neoadjuvant chemotherapy alone group (P < .001 for between-
group difference),7 and EFS at 36 months was 84.5% (95% CI, 81.7%-86.9%) in the pembrolizumab
and neoadjuvant chemotherapy group vs 76.8% (95% CI, 72.2%-80.7%) in the neoadjuvant
chemotherapy alone group (hazard ratio [HR], 0.63; 95% CI, 0.48-0.82; P < .001).8 Benefits were
observed regardless of tumor programmed cell death ligand 1 (PD-L1) expression.7,8 On the basis of
these results, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab
after surgery for the treatment of patients with high-risk, early-stage TNBC has received regulatory
approval in several countries.9-11
The incidence of breast cancer has decreased over the past 2 decades in the US and most of
Europe but has increased in many countries in Asia, with mean annual increases of 0.37% in
Singapore, 1.28% in Japan, 2.65% in Korea, and 2.76% in China.12 Although there has been evidence
of decreasing breast cancer mortality in the US and Europe, mortality rates have remained stable or
have increased across many countries in Asia.12,13 In 2020 alone, it was estimated that more than 1
million women were diagnosed with breast cancer in Asian countries and nearly 350 000 women

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died of breast cancer, accounting for 45.4% of global breast cancer cases and 50.5% of global breast
cancer deaths.14 Additionally, evidence suggests that the genomic profile and tumor
microenvironment can differ between Asian and non-Asian patients with breast cancer,15-18 which
could, in turn, influence responses to treatment. Considering these potential differences and the
high burden of breast cancer in the Asia population,19 we conducted a subgroup analysis to evaluate
efficacy and safety outcomes for patients enrolled in countries in East and Southeast Asia (hereafter
referred to as Asia) in KEYNOTE-522.

Methods
Study Design and Patients
KEYNOTE-522 is an ongoing phase 3, double-blind, placebo-controlled, international randomized
clinical trial that enrolled 1174 patients between March 7, 2017, and September 13, 2018. Detailed
methods were previously published7,8 and are available in the protocol (Supplement 1). Demographic
information, including race and ethnicity, was previously reported for the entire study population in
the primary publication.7,8 The inclusion criterion for the current subgroup analysis was
geographically specific and thus not broken down by race or ethnicity. Briefly, eligible patients were
18 years or older with centrally confirmed, newly diagnosed, previously untreated, nonmetastatic
TNBC (tumor stage T1c, nodal stage N1-2 or tumor stage T2-4, nodal stage N0-2 per the American
Joint Committee on Cancer20) as determined by investigator radiologic or clinical assessment.
Patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and
a tissue sample available for PD-L1 assessment. Patients were eligible for the study regardless of
PD-L1 expression. An external, independent data monitoring committee oversaw the study,
periodically assessed safety, and assessed efficacy at prespecified interim analyses. The study
protocol and its amendments were approved by institutional review boards or independent ethics
committees at each study site. The study was conducted in accordance with the standards of Good
Clinical Practice. All patients provided written informed consent before enrollment. This study
followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Randomization and Study Treatment

Patients were stratified before randomization based on nodal status (positive or negative), tumor
size (T1-T2 or T3-T4), and schedule of carboplatin administration (weekly or every 3 weeks).
Randomization (block size of 6) was performed using a central interactive voice-response system
with an integrated Web-response system from March 23, 2017, to September 23, 2018, with a data
cutoff date for interim EFS and overall survival (OS) of March 24, 2021. Patients, investigators, the
sponsor, and other study site staff were blinded to treatment assignment. A total of 1174 patients
were randomized 2:1 to receive pembrolizumab or placebo. In the first neoadjuvant phase (cycles
1-4), patients received intravenous pembrolizumab (200 mg every 3 weeks) or placebo in
combination with carboplatin (area under the concentration time curve, 5 mg/mL/min every 3 weeks
or 1.5 mg/mL/min weekly) plus paclitaxel (80 mg/m2 weekly). In the second neoadjuvant phase
(cycles 5-8), patients continued treatment with pembrolizumab or placebo in combination with
doxorubicin or epirubicin (60 mg/m2 or 90 mg/m2, respectively, every 3 weeks) and
cyclophosphamide (600 mg/m2 every 3 weeks). After surgery, patients received adjuvant therapy
with intravenous pembrolizumab (200 mg every 3 weeks) or placebo for 9 cycles. Patients who
completed or discontinued the first neoadjuvant treatment could start the second neoadjuvant
treatment or undergo surgery; patients who completed or discontinued the second neoadjuvant
treatment could proceed to surgery. Adjuvant therapy with capecitabine was not permitted. Patients
discontinued treatment if they had disease progression, recurrence, or unacceptable adverse
events (AEs).

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End Points
The study’s primary end points were pCR (no evidence of primary tumor after neoadjuvant therapy
or carcinoma in situ after neoadjuvant therapy [ypT0/Tis] and no regional lymph node involvement
after neoadjuvant therapy [ypN0]) at the time of definitive surgery and EFS. Secondary end points
included pCR (ypT0/Tis ypN0) and EFS in patients who had tumors that were PD-L1 positive, pCR
(ypT0 ypN0) and pCR (ypT0/Tis) in all patients and in patients who had tumors that were PD-L1
positive, OS, and safety.

Assessments
After completion of neoadjuvant therapy, pCR was assessed according to the definitions of the
pathologic stages ypT0/Tis ypN0, ypT0 ypN0, and ypT0/Tis, as determined by a local pathologist
who was blinded to treatment group assignment. Follow-up for disease status and survival occurred
every 3 months for the first 2 years, every 6 months from years 3 to 5, and yearly thereafter. Event-
free survival was assessed by the investigator and defined as time from randomization to first
occurrence of disease progression that precluded definitive surgery, local or distant recurrence, a
second primary cancer, or death from any cause. Overall survival was defined as time from
randomization to death from any cause.
Expression of PD-L1 in tumor samples was determined using immunohistochemical analysis
(PD-L1 IHC 22C3 pharmDx, Agilent Technologies). The combined positive score (CPS) was defined as
the number of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) divided by the total
number of tumor cells multiplied by 100. Tumors with a CPS of 1 or greater were considered PD-L1
positive.
Adverse events were monitored throughout the study and for 30 days after discontinuation of
treatment (90 days for serious AEs). Adverse events were graded according to the National Cancer
Institute Common Terminology Criteria for Adverse Events, version 4.0. Immune-mediated AEs were
based on a prespecified list of Medical Dictionary for Regulatory Activities terms.

Statistical Analysis
The study was powered to test hypotheses in the global population; no α was assigned to analyses in
the subgroup of patients enrolled in Asia; therefore, the results reported herein are descriptive only.
Efficacy was assessed in the intention-to-treat population (all randomized patients); safety was
assessed in all randomized and treated patients based on the treatment received. For pCR, the
estimated treatment difference was based on the unstratified Miettinen and Nurminen method;
patients without pCR data for any reason or who received neoadjuvant chemotherapy not specified
in the protocol were counted as non-pCR. For EFS and OS, HRs and associated 95% CIs were
estimated based on an unstratified Cox proportional hazards regression model with the Efron
method of tie handling and treatment as a covariate. Analyses were conducted using SAS version 9.4
(SAS Institute).

Results
Patients
Of 1174 patients randomized in KEYNOTE-522 between March 23, 2017, and September 24, 2018, the
subgroup of patients enrolled in Asia included 216 patients (18.4%; 136 receiving pembrolizumab
plus chemotherapy and 80 receiving placebo plus chemotherapy) in Korea (n = 86), Japan (n = 76),
Taiwan (n = 50), and Singapore (n = 4). The list of countries that enrolled patients in the global
KEYNOTE-522 study is provided in eTable 1 in Supplement 2. Patient disposition and analysis
populations are shown in Figure 1. Patient demographics and baseline disease characteristics were
generally similar between the treatment groups (Table 1). All patients were female, and the median
age was 46.0 years (range, 24.0-71.0 years). Of the 216 patients, 189 (87.5%) had an ECOG
performance status score of 0. A total of 164 patients (75.9%) had tumors that were PD-L1 positive

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Figure 1. Patient Disposition and Analysis Populations: Subgroup of Patients Enrolled in Asia

216 Patients randomized 2:1 from March 2017 to September 2018

Pembrolizumab plus chemotherapy followed Placebo plus chemotherapy followed by placebo

by pembrolizumab 80 Allocated
136 Allocated 79 Started carboplatin/paclitaxel; 3 discontinued due to
135 Started carboplatin/paclitaxel; 7 discontinued (3 with progressive disease (98.8%)
AEs, 2 patient withdrawals, 1 physician decision, 75 Started AC or EC; 1 discontinued due to AE (93.8%)
1 with progressive disease) (99.3%) 78 Had documented surgerya (97.5%)
129 Started AC or EC; 9 discontinued (6 with AEs, 2 patient 68 Started adjuvant treatment; 7 discontinued (5 with
withdrawals, 1 with progressive disease) (94.9%) recurrence, 1 with AE, 1 patient withdrawal) (85.0%)
136 Had documented surgerya (100%) AC indicates doxorubicin-cyclophosphamide; AE,
112 Started adjuvant treatment; 11 discontinued
(4 physician decision, 3 with AEs, 3 with recurrence, adverse event; EC, epirubicin-cyclophosphamide; and
1 patient withdrawal) (82.4%) EFS, event-free survival.
a
Patients did not have to complete all neoadjuvant
Analysis populations Analysis populations therapy to undergo surgery.
136 EFS analysis 80 EFS analysis b
Includes all patients who received at least 1 dose of
136 Safety evaluationb 79 Safety evaluationb
study treatment or underwent surgery.

Table 1. Patient Demographics and Baseline Characteristics: Subgroup of Patients Enrolled in Asiaa
Pembrolizumab plus Placebo plus
Characteristic chemotherapy (n = 136) chemotherapy (n = 80)
Sex
Female 136 (100.0) 80 (100.0)
Male 0 0
Age, median (range), y 46.0 (26.0-71.0) 47.0 (24.0-71.0)
Aged <65 y 129 (94.9) 71 (88.8)
Menopausal status
Premenopausal 85 (62.5) 43 (53.8)
Postmenopausal 51 (37.5) 37 (46.3)
ECOG PS
0 118 (86.8) 71 (88.8)
1 18 (13.2) 9 (11.3)
ERBB2 (previously HER2/neu) status
0-1+ by IHC 119 (87.5) 68 (85.0)
2+ by IHC (but FISH negative) 16 (11.8) 12 (15.0)
Tumor PD-L1 CPS
<1 32 (23.5) 19 (23.8)
≥1 104 (76.5) 60 (75.0)
≥10 56 (41.2) 32 (40.0)
Carboplatin schedule
Weekly 91 (66.9) 47 (58.8)
Every 3 wk 45 (33.1) 33 (41.3)
Tumor size
T1/T2 109 (80.1) 66 (82.5)
T3/T4 27 (19.9) 14 (17.5)
Nodal involvement
Positive 64 (47.1) 41 (51.3)
Abbreviations: CPS, combined positive score; ECOG
Negative 72 (52.9) 39 (48.8) PS, Eastern Cooperative Oncology Group performance
Enrollment location status; FISH, fluorescence in situ hybridization; IHC,
Korea 56 (41.2) 30 (37.5) immunohistochemistry; PD-L1, programmed cell death
ligand 1.
Japan 45 (33.1) 31 (38.8)
a
Taiwan 33 (24.3) 17 (21.3) Data are presented as number (percentage) of
participants unless otherwise indicated. Data cutoff
Singapore 2 (1.5) 2 (2.5)
date was March 23, 2021.

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(ie, PD-L1 CPS ⱖ1), including 104 (76.5%) in the pembrolizumab plus chemotherapy group and 60
(75.0%) in the placebo plus chemotherapy group; 175 patients (81.0%) had a baseline tumor size of
T1 or T2. At the data cutoff date for the interim EFS and OS analyses (March 23, 2021), median time
from randomization to data cutoff was 39.8 months (range, 30.4-46.9 months) in the
pembrolizumab plus chemotherapy group and 40.8 months (range, 30.1-46.9 months) in the
placebo plus chemotherapy group.

Efficacy
The data cutoff date for the pCR analysis (interim analysis 1) was September 24, 2018. Pathologic
complete response was achieved in 44 of 75 patients (58.7%; 95% CI, 46.7%-69.9%) in the
pembrolizumab plus chemotherapy group and 20 of 50 patients (40.0%; 95% CI, 26.4%-54.8%) in
the placebo plus chemotherapy group, for a treatment difference of 18.7% (95% CI, 0.7%-35.4%)
(Figure 2A). Results by PD-L1 expression are shown in Figure 2B. In patients with PD-L1 CPS of 1 or
higher, pCR was attained in 35 of 57 patients (61.4%; 95% CI, 47.6%-74.0%) in the pembrolizumab
plus chemotherapy group and 15 of 36 patients (41.7%; 95% CI, 25.5%-59.2%) in the placebo plus
chemotherapy group, for a treatment difference of 19.7% (95% CI, −1.2% to 39.0%). In patients with
PD-L1 CPS less than 1, pCR was achieved in 9 of 18 patients (50.0%) in the pembrolizumab plus
chemotherapy group and 5 of 14 patients (35.7%) in the placebo plus chemotherapy group, for a
treatment difference of 14.3% (95% CI, −20.4% to 45.3%).
The data cutoff date for the EFS and OS analyses (interim analysis 4) was March 23, 2021. A total
of 13 of 136 patients (9.6%) in the pembrolizumab plus chemotherapy group and 20 of 80 patients
(25.0%) in the placebo plus chemotherapy group experienced an EFS event (HR, 0.35; 95% CI, 0.17-
0.71) (eTable 2 in Supplement 2; Figure 3A). The most common first EFS event in both treatment
groups was distant recurrence, which occurred in 8 patients (5.9%) in the pembrolizumab plus
chemotherapy group and 15 patients (18.8%) in the placebo plus chemotherapy group (eTable 2 in
Supplement 2). Median EFS was not reached in either treatment group. At 36 months, the EFS rate
was 91.2% (95% CI, 85.0%-94.9%) in the pembrolizumab plus chemotherapy group and 77.2%
(95% CI, 66.3%-85.0%) in the placebo plus chemotherapy group (Figure 3A).
Event-free survival according to the outcome (yes or no) of pCR (ypT0/Tis ypN0) was a
prespecified, nonrandomized, exploratory analysis. In patients with a pCR, 1 of 82 patients (1.2%)
experienced an EFS event and the 36-month EFS rate was 100% (95% CI, 100%-100%) in the
pembrolizumab plus chemotherapy group, and 2 of 36 patients (5.6%) experienced an EFS event and
the 36-month EFS rate was 94.4% (95% CI, 79.6%-98.6%) in the placebo plus chemotherapy group
(Figure 3B). In patients without a pCR, 12 of 54 patients (22.2%) in the pembrolizumab plus
chemotherapy group had an EFS event, and the 36-month EFS rate was 77.7% (95% CI,

Figure 2. Pathologic Complete Response (pCR) in the Overall Subgroup of Patients Enrolled in Asia
and by Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS)

A Overall B By PD-L1 CPS

100 100

80 80
pCR, % (95% CI)

pCR, % (95% CI)

60 60

40 40

20 20
Pathologic complete response was defined as no
0 0 evidence of primary tumor after neoadjuvant therapy
Pembrolizumab Placebo plus Pembrolizumab Placebo plus Pembrolizumab Placebo plus
or carcinoma in situ after neoadjuvant therapy and no
plus chemotherapy chemotherapy plus chemotherapy chemotherapy plus chemotherapy chemotherapy
regional lymph node involvement after neoadjuvant
PD-L1 CPS ≥1 PD-L1 CPS <1 therapy. Data cutoff date was September 24, 2018.

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64.1%-86.7%); 18 of 44 patients (40.9%) in the placebo plus chemotherapy group had an EFS event,
and the 36-month EFS rate was 62.8% (95% CI, 46.6%-75.3%).
Six of 136 patients (4.4%) died in the pembrolizumab plus chemotherapy group, and 14 of 80
patients (17.5%) died in the placebo plus chemotherapy group (HR, 0.24; 95% CI, 0.09-0.62)
(eFigure in Supplement 2). The 36-month OS rate was 95.6% (95% CI, 90.4%-98.0%) in the
pembrolizumab plus chemotherapy group and 81.6% (95% CI, 70.9%-88.7%) in the placebo plus
chemotherapy group.

Safety
The data cutoff date for the safety analysis (interim analysis 4) was March 23, 2021. In the combined
neoadjuvant and adjuvant phases, treatment-related AEs of any grade were reported in 135 of 136
patients (99.3%) in the pembrolizumab plus chemotherapy group and 79 of 79 patients (100%) in
the placebo plus chemotherapy group. The most common treatment-related AEs in patients who

Figure 3. Event-Free Survival (EFS) in the Overall Subgroup of Patients Enrolled in Asia
and by Pathologic Complete Response (pCR)

A EFS

100 Pembrolizumab plus chemotherapy

80

Placebo plus chemotherapy

60
EFS, %

40

20
HR for event or death, 0.35 (95% CI, 0.17-0.71)
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time, mo
No. at risk
Pembrolizumab plus 136 136 136 134 130 130 128 125 123 123 123 105 84 67 43 1 0 0
chemotherapy
Placebo plus 80 78 78 76 74 70 66 64 63 62 61 51 42 35 20 2 0 0
chemotherapy

B EFS by pCR
Pembrolizumab plus chemotherapy (pCR)
100
Placebo plus chemotherapy (pCR)
80
Pembrolizumab plus chemotherapy (no pCR)
EFS by pCR, %

60
Placebo plus chemotherapy (no pCR)
40

20

0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time, mo
No. at risk
Pembrolizumab plus 82 82 82 82 82 82 82 82 82 82 82 68 54 42 28 0 0
chemotherapy (pCR)
Placebo plus 36 36 36 36 36 35 35 35 34 34 33 26 22 18 12 0 0 Pathologic complete response was defined as no
chemotherapy (pCR) evidence of primary tumor after neoadjuvant therapy
Pembrolizumab plus 54 54 54 52 48 48 46 43 41 41 41 37 30 25 15 1 0 or carcinoma in situ after neoadjuvant therapy and no
chemotherapy (no pCR)
Placebo plus 44 42 42 40 38 35 31 29 29 28 28 25 20 17 8 2 0 regional lymph node involvement after neoadjuvant
chemotherapy (no pCR) therapy. Data cutoff date was March 23, 2021.

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received pembrolizumab were alopecia, nausea, and anemia (Table 2). Grade 3 or 4 treatment-
related AEs were experienced by 109 patients (80.1%) in the pembrolizumab plus chemotherapy
group and 64 patients (81.0%) in the placebo plus chemotherapy group. There were no treatment-
related AEs leading to death. Treatment-related AEs leading to discontinuation of any study
treatment occurred in 19 patients (14.0%) in the pembrolizumab plus chemotherapy group and 7
patients (8.9%) in the placebo plus chemotherapy group. In the adjuvant phase, treatment-related
AEs of any grade occurred in 40 of 112 patients (35.7%) in the pembrolizumab plus chemotherapy
group and 22 of 68 patients (32.4%) in the placebo plus chemotherapy group. Grade 3 or 4
treatment-related AEs occurred in 6 patients (5.4%) in the pembrolizumab plus chemotherapy group
and 1 patient (1.5%) in the placebo plus chemotherapy group, and treatment-related AEs of any grade
that led to discontinuation of study treatment occurred in 1 patient (0.9%) in the pembrolizumab
plus chemotherapy group and 0 patients in the placebo plus chemotherapy group.
Immune-mediated AEs and infusion reactions in the combined neoadjuvant and adjuvant
phases were reported in 50 of 136 patients (36.8%) in the pembrolizumab plus chemotherapy group
and 17 of 79 patients (21.5%) in the placebo plus chemotherapy group; the most common events in
patients who received pembrolizumab were hypothyroidism, infusion reactions, hyperthyroidism,
and severe skin reactions (Table 2). Grade 3 or 4 immune-mediated AEs and infusion reactions were
experienced by 17 patients (12.5%) in the pembrolizumab plus chemotherapy group and 1 patient
(1.3%) in the placebo plus chemotherapy group. Immune-mediated AEs and infusion reactions
leading to discontinuation of any study treatment occurred in 9 patients (6.6%) in the
pembrolizumab plus chemotherapy group and 1 patient (1.3%) in the placebo plus chemotherapy
group. In the adjuvant phase, immune-mediated AEs and infusion reactions of any grade occurred in
8 patients (7.1%) in the pembrolizumab plus chemotherapy group and 4 patients (5.9%) in the
placebo plus chemotherapy group. Grade 3 or 4 immune-mediated AEs and infusion reactions
occurred in 4 patients (3.6%) in the pembrolizumab plus chemotherapy group and 0 patients in the
placebo plus chemotherapy group, and immune-mediated AEs and infusion reactions of any grade
that led to discontinuation of study treatment occurred in 1 patient (0.9%) in the pembrolizumab
plus chemotherapy group and 0 patients in the placebo plus chemotherapy group.

Discussion
KEYNOTE-522 is the first prospective, phase 3 randomized clinical study of pembrolizumab in
patients with early TNBC in the neoadjuvant and adjuvant settings. Results of this subgroup analysis
of patients enrolled in countries in Asia showed that treatment with neoadjuvant pembrolizumab
plus chemotherapy followed by adjuvant pembrolizumab led to clinically meaningful improvements
in pCR and EFS compared with neoadjuvant chemotherapy alone. Adverse events were consistent
with the known safety profiles of each agent.
Importantly, efficacy outcomes in the subgroup of patients enrolled in Asia were generally
consistent with those of the overall study population. Although both the overall population and the
subgroup had higher pCR in the pembrolizumab plus chemotherapy group than in the placebo plus
chemotherapy group, pCR was numerically lower among patients enrolled in Asia (58.7% vs 40.0%)
than the overall study population (64.8% vs 51.2%).7 However, the between-group difference in pCR
in favor of pembrolizumab plus chemotherapy was numerically larger in patients enrolled in Asia
relative to the overall study population (18.7% vs 13.6%).7 The prespecified, nonrandomized,
exploratory analysis of EFS was conducted according to the outcome (yes or no) of pCR (ypT0/Tis
ypN0). The proportion of patients in the pembrolizumab plus chemotherapy group with an
improvement in EFS at 36 months vs placebo plus chemotherapy was numerically higher in the
subgroup of patients enrolled in Asia (91.2% for pembrolizumab plus chemotherapy and 77.2% for
placebo plus chemotherapy) than in the overall study population (84.5% for pembrolizumab plus
chemotherapy and 76.8% for placebo plus chemotherapy).8 At the time of this analysis, data on OS
were immature, and further follow-up is ongoing. Thus far, favorable trends in OS have been

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Table 2. Summary of AEs in Combined and Adjuvant Phases: Subgroup of Patients Enrolled in Asiaa
Pembrolizumab plus Placebo plus
chemotherapyb chemotherapyc
AE Any grade Grade 3 or 4d Any grade Grade 3 or 4d
Combined phases
Treatment-related AEs 135 (99.3) 109 (80.1) 79 (100.0) 64 (81.0)
Led to discontinuation 19 (14.0) 12 (8.8) 7 (8.9) 5 (6.3)
of any study drug
Most common AEs (≥20%
in either treatment group)
Alopecia 111 (81.6) 0 59 (74.7) 0
Nausea 93 (68.4) 2 (1.5) 49 (62.0) 0
Anemia 76 (55.9) 30 (22.1) 40 (50.6) 10 (12.7)
Peripheral sensory 75 (55.1) 3 (2.2) 39 (49.4) 3 (3.8)
neuropathy
Neutrophil count 70 (51.5) 61 (44.9) 42 (53.2) 34 (43.0)
decreased
Rash 53 (39.0) 3 (2.2) 14 (17.7) 1 (1.3)
Constipation 52 (38.2) 0 27 (34.2) 0
Pyrexia 46 (33.8) 3 (2.2) 15 (19.0) 0
ALT level increased 44 (32.4) 9 (6.6) 24 (30.4) 3 (3.8)
White blood cell count 38 (27.9) 24 (17.6) 21 (26.6) 11 (13.9)
decreased
Neutropenia 38 (27.9) 37 (27.2) 24 (30.4) 24 (30.4)
Vomiting 37 (27.2) 0 17 (21.5) 1 (1.3)
Fatigue 35 (25.7) 0 14 (17.7) 1 (1.3)
Myalgia 35 (25.7) 0 23 (29.1) 0
Pruritus 34 (25.0) 0 12 (15.2) 0
Decreased appetite 33 (24.3) 3 (2.2) 14 (17.7) 1 (1.3)
Stomatitis 33 (24.3) 0 16 (20.3) 0
AST level increased 30 (22.1) 3 (2.2) 16 (20.3) 1 (1.3)
Diarrhea 29 (21.3) 0 10 (12.7) 0
Febrile neutropenia 29 (21.3) 29 (21.3) 12 (15.2) 12 (15.2)
Immune-mediated AEs 50 (36.8) 17 (12.5) 17 (21.5) 1 (1.3)
and infusion reactions
Led to discontinuation 9 (6.6) 7 (5.1) 1 (1.3) 0
of any study drug
Hypothyroidism 19 (14.0) 0 5 (6.3) 0
Infusion reactions 17 (12.5) 3 (2.2) 7 (8.9) 0
Hyperthyroidism 8 (5.9) 1 (0.7) 1 (1.3) 0
Severe skin reactions 8 (5.9) 6 (4.4) 3 (3.8) 1 (1.3)
Pneumonitis 6 (4.4) 2 (1.5) 2 (2.5) 0
Thyroiditis 4 (2.9) 0 1 (1.3) 0
Vasculitis 4 (2.9) 0 0 0
Adrenal insufficiency 2 (1.5) 1 (0.7) 0 0
Colitis 2 (1.5) 0 0 0
Pancreatitis 2 (1.5) 2 (1.5) 0 0
Type 1 diabetes 2 (1.5) 2 (1.5) 0 0
Myocarditis 1 (0.7) 1 (0.7) 0 0
Hypophysitis 0 0 1 (1.3) 0
Adjuvant phase
Treatment-related AEs 40 (35.7) 6 (5.4) 22 (32.4) 1 (1.5)
Led to discontinuation 1 (0.9) 1 (0.9) 0 0
of study drug

(continued)

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Table 2. Summary of AEs in Combined and Adjuvant Phases: Subgroup of Patients Enrolled in Asiaa (continued)
Pembrolizumab plus Placebo plus
chemotherapyb chemotherapyc
AE Any grade Grade 3 or 4d Any grade Grade 3 or 4d
Most common (≥2% in either
treatment group)
Pruritus 5 (4.5) 0 2 (2.9) 0
Rash 5 (4.5) 1 (0.9) 1 (1.5) 0
ALT level increased 3 (2.7) 0 1 (1.5) 0
Arthralgia 3 (2.7) 0 2 (2.9) 0
Fatigue 3 (2.7) 0 0 0
Hypothyroidism 1 (0.9) 0 3 (4.4) 0
Neutrophil count decreased 1 (0.9) 0 2 (2.9) 0
Ejection fraction decreased 0 0 2 (2.9) 1 (1.5)
Headache 0 0 3 (4.4) 0
Rash (maculopapular) 0 0 4 (5.9) 0
White blood cell count 0 0 2 (2.9) 0
decreased
Immune-mediated AEs 8 (7.1) 4 (3.6) 4 (5.9) 0
and infusion reactions
Led to discontinuation of any 1 (0.9) 1 (0.9) 0 0
study drug Abbreviations: AE, adverse event; ALT, alanine
aminotransferase; AST, aspartate aminotransferase.
Pneumonitis 3 (2.7) 1 (0.9) 0 0
a
Data are presented as number (percentage) of
Severe skin reactions 2 (1.8) 1 (0.9) 0 0
participants unless otherwise indicated. Data cutoff
Hypothyroidism 1 (0.9) 0 3 (4.4) 0 date was March 23, 2021.
Infusion reactions 1 (0.9) 0 0 0 b
Includes 136 patients in the combined phase and 112
Pancreatitis 1 (0.9) 1 (0.9) 0 0 patients in the adjuvant phase.
c
Type 1 diabetes 1 (0.9) 1 (0.9) 0 0 Includes 79 patients in the combined phase and 68
patients in the adjuvant phase.
Hyperthyroidism 0 0 1 (1.5) 0
d
There were no treatment-related AEs leading
Thyroiditis 0 0 1 (1.5) 0
to death.

observed in the pembrolizumab plus chemotherapy group in both the overall study population8 and
in the subgroup of patients enrolled in Asia.
The types and severity of treatment-related AEs were similar in both the overall study
population8 and in the subgroup of patients enrolled in Asia during the combined neoadjuvant and
adjuvant phases. In both populations, the most common treatment-related AEs of any grade in the
pembrolizumab plus chemotherapy group were nausea, alopecia, and anemia, and the most frequent
treatment-related AEs of grade 3 or greater were neutropenia and decreased neutrophil count.8 In
both treatment groups, the rate of discontinuation due to treatment-related AEs was somewhat
lower in the subgroup of patients enrolled in Asia (placebo, 8.9%; pembrolizumab, 14.0%) compared
with the overall study population (placebo, 14.1%; pembrolizumab, 27.7%)8 during the combined
neoadjuvant and adjuvant phases. Additionally, the incidence of pneumonitis was not substantially
elevated in the subgroup of patients enrolled in Asia compared with the overall study population.
This finding suggests that tolerability was at least as good in the subgroup of patients enrolled in Asia
compared with the overall study population.
Other studies have evaluated the addition of PD-L1 inhibitors to neoadjuvant chemotherapy in
patients with early TNBC. In the phase 3 IMpassion031 study (Study to Investigate Atezolizumab and
Chemotherapy Compared With Placebo and Chemotherapy in the Neoadjuvant Setting in
Participants With Early Stage Triple Negative Breast Cancer), 88 of 333 patients (26%) were Asian.21
In that subgroup, pCR was achieved in 57% of patients in the atezolizumab plus chemotherapy group
(n = 47) and 34% of patients in the placebo plus chemotherapy group (n = 41), for a treatment
difference of 23% (95% CI, 3%-44%). The EFS and OS data were immature at the time of analysis.21
The pCR results from IMpassion031 are consistent with the analysis described herein. Results from

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 JAMA Network Open | Oncology Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Breast Cancer

other studies evaluating the addition of a PD-L1 inhibitor to neoadjuvant chemotherapy in patients
with early TNBC include the phase 2 I-SPY2 (Neoadjuvant and Personalized Adaptive Novel Agents to
Treat Breast Cancer) (durvalumab, olaparib, and chemotherapy),22 GeparNuevo (Addition of PD-L1
Antibody MEDI4736 to a Taxane-Anthracycline Chemotherapy in Triple Negative Breast Cancer)
(durvalumab priming then durvalumab and chemotherapy),23 and the phase 3 NeoTRIPaPDL1 study
(Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1) (atezolizumab and
chemotherapy).24 However, in these latter studies, fewer patients received combination therapy,
and results were not available in patients from Asian countries.
Analysis of biomarkers in future studies could potentially provide insight into our findings. The
current results complement those seen with pembrolizumab in the phase 3 KEYNOTE-355 study,
which enrolled patients with previously untreated, locally recurrent and inoperable, or metastatic
TNBC. In this setting, among the 160 patients enrolled in countries in Asia, treatment with
pembrolizumab plus chemotherapy led to clinically meaningful improvement in OS and PFS
compared with placebo plus chemotherapy overall and in patients with PD-L1 CPS of 1 or
greater tumors.25

Limitations
This study has certain limitations. This secondary analysis was exploratory, and no formal statistical
testing was performed. Furthermore, this analysis included the subgroup of patients enrolled in
certain Asian countries (Korea, Japan, Taiwan, and Singapore) that were defined by geographic
region of enrollment. As such, generalizability of the current results beyond these countries should
be approached with caution.

Conclusions
In this secondary analysis of patients enrolled in KEYNOTE-522 in East and Southeast Asia,
neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to
clinically meaningful improvements vs neoadjuvant chemotherapy alone. These results support the
use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a
standard-of-care therapy in patients in countries in Asia with early TNBC, consistent with the global
population.

ARTICLE INFORMATION
Accepted for Publication: September 21, 2023.
Published: November 15, 2023. doi:10.1001/jamanetworkopen.2023.42107
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2023
Takahashi M et al. JAMA Network Open.
Corresponding Author: Masato Takahashi, MD, Department of Breast Surgery, Hokkaido University Hospital,
Kita14 Nishi5, Kita-ku, Sapporo, Hokkaido 060-8648, Japan ([email protected]).
Author Affiliations: Department of Breast Surgery, Hokkaido University Hospital, Sapporo, Japan (Takahashi);
International Breast Cancer Center, Pangaea Oncology, Quironsalud Group, Barcelona, Spain (Cortés); Medical
Scientia Innovation Research (MEDSIR), Barcelona, Spain (Cortés); Faculty of Biomedical and Health Sciences,
Department of Medicine, Universidad Europea de Madrid, Madrid, Spain (Cortés); National Cancer Center
Singapore, Duke-NUS Medical School, Singapore (Dent); Yale Cancer Center, Yale University School of Medicine,
New Haven, Connecticut (Pusztai); Department of Internal Medicine, UT Southwestern Medical Center, Dallas,
Texas (McArthur); Breast Unit, Department of Gynecology with Breast Center, Kliniken Essen-Mitte, Essen,
Germany (Kümmel); Charité–Universitätsmedizin Berlin, Berlin, Germany (Kümmel); Institute of Pathology,
Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, Germany (Denkert); Hematology-
Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea (Park); Cancer
Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
(Im); Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (Ahn); National Cancer Center

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 JAMA Network Open | Oncology Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Breast Cancer

Hospital East, Kashiwa-shi, Japan (Mukai); National Taiwan University Hospital, Taipei, Taiwan (Huang); Chang
Gung Memorial Hospital, Taoyuan, Taiwan (Chen); Yonsei University College of Medicine, Seoul, Korea (Kim);
Merck & Co Inc, Rahway, New Jersey (Jia, Li, Tryfonidis, Karantza); Aichi Cancer Center Hospital, Nagoya, Japan
(Iwata); Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London,
London, United Kingdom (Schmid).
Author Contributions: Drs Takahashi and Jia had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis.
Concept and design: Takahashi, Cortés, Dent, Kümmel, Denkert, Im, Li, Tryfonidis, Karantza, Schmid.
Acquisition, analysis, or interpretation of data: Takahashi, Dent, Pusztai, McArthur, Kümmel, Denkert, Park, Im,
Ahn, Mukai, Huang, Chen, Kim, Jia, Li, Tryfonidis, Karantza, Iwata, Schmid.
Drafting of the manuscript: Dent, Kümmel, Park, Jia, Li, Schmid.
Critical review of the manuscript for important intellectual content: All authors.
Statistical analysis: Dent, Chen, Jia, Li, Schmid.
Administrative, technical, or material support: Takahashi, Im, Huang, Kim, Iwata.
Supervision: Takahashi, Cortés, Dent, Park, Mukai, Huang, Tryfonidis, Karantza.
Conflict of Interest Disclosures: Dr Takahashi reported receiving nonfinancial support from Merck & Co Inc during
the conduct of the study and personal fees from AstraZeneca, Eli Lilly, Pfizer, and Eisai and grants from Eisai,
Kyowa-Hakko Kirin, Nippon Kayaku, and Taiho outside the submitted work. Dr Cortés reported receiving personal
fees from Merck Sharp & Dhome LLC, a subsidiary of Merck & Co Inc, Rahway, New Jersey (MSD), during the
conduct of the study and personal fees from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi
Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim,
Ellipeses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion
Biotechnologies, Jazz Pharmaceuticals, AbbVie, Novartis, Eisai, Pfizer, and Samsung Bioepis, receiving grants from
Ariad Pharmaceuticals, Baxalta GMBH/Servier Affaires, Bayer HealthCare, Guardant, Piqur Therapeutics, Iqvia, and
Queen Mary University of London, and having capital stock in MAJ3 outside the submitted work; in addition, Dr
Cortés had patents for pharmaceutical combinations of a Pi3k inhibitor and microtubule destabilizing agent and for
HER2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Dr Dent reported
receiving personal fees from MSD, AstraZeneca, Roche, Novartis, Pfizer, and DKSH during the conduct of the study
and receiving personal fees from MSD, AstraZeneca, Roche, Novartis, Pfizer, and DKSH outside the submitted
work. Dr Pusztai reported receiving personal fees from Merck & Co Inc during the conduct of the study and
receiving consulting fees for advisory board participation from Pfizer, AstraZeneca, Novartis, Bristol Myers Squibb,
Stemline-Menarini, GSK, Genentech/Roche, Personalis, Daiichi Sankyo, Natera, and Exact Sciences. Dr McArthur
reported receiving personal fees and grants from MSD outside the submitted work. Dr Kümmel reported receiving
personal fees from Roche, AstraZeneca, Eli Lilly, Pfizer, Gilead, Stryker, Novartis, Somatex, Exact Science, Agendia,
Daiichi Sankyo, MSD, and Seagen and travel support from Eli Lilly, Roche, and Daiichi Sankyo during the conduct
of the study and having leadership or fiduciary roles with Arbeitsgemeinschaft Gynäkologische Onkologie,
European Society for Medical Oncology, and West German Study Group outside the submitted work. Dr Denkert
reported receiving personal fees from MSD Oncology during the conduct of the study and personal fees from
Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Eli Lilly, and Diaceutics and grants from European
Commission, German Cancer Aid Translational Oncology, and German Breast Group outside the submitted work;
in addition, Dr Denkert had a patent for VNscope digital pathology with royalties paid, a patent for
WO2020109570A1 pending, a patent for WO2015114146A1 pending, and a patent for WO2010076322A1 pending.
Dr Park reported receiving nonfinancial support from MSD during the conduct of the study and grants from Pfizer,
AstraZeneca, Roche, Novartis, Genomie Insight, and NGenBio, personal fees from AstraZeneca, Roche, Novartis,
Eli Lilly, and Daiichi Sankyo, and nonfinancial support from Pfizer, Roche, Novartis, Daiichi Sankyo, Eisai, and Gilead
outside the submitted work. Dr Im reported having an advisory role with MSD during the conduct of the study and
receiving grants from AstraZeneca, Daewoong Pharm, Boryung Pharm, Eisai, Pfizer, and Roche and having
advisory roles with AstraZeneca, Hanmi, Bertis, Novartis, Eli Lilly, Pfizer, Roche, and Daiichi Sankyo outside the
submitted work. Dr Mukai reported receiving grants from MSD during the conduct of the study. Dr Huang reported
receiving grants from MSD during the conduct of the study and grants from AstraZeneca, Daiichi Sankyo, EirGenix,
Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, Novartis, Seagen, Gilead, and Aston Sci, personal fees from AstraZeneca,
Daiichi Sankyo, EirGenix, Eli Lilly, Pfizer, Roche, Novartis, and Gilead, and nonfinancial support from AstraZeneca,
Daiichi Sankyo, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, and Novartis outside the submitted work. Dr Jia reported
receiving personal fees from Merck & Co Inc for full-time employment and stock outside the submitted work. Dr Li
reported being an employee of the Merck Research Lab during the conduct of the study and outside the submitted
work. Dr Tryfonidis reported being an employee of MSD, and holding stock/stock options in Merck & Co Inc during
the conduct of the study. Dr Karantza reported being an employee of MSD and holding stock/stock options in
Merck & Co Inc during the conduct of the study and outside the submitted work. Dr Iwata reported receiving

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 JAMA Network Open | Oncology Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Breast Cancer

grants from MSD during the conduct of the study and personal fees from MSD, Daiichi Sankyo, Chugai,
AstraZeneca, Pfizer, Taiho, Eisai, and Kyowa Kirin and grants from AstraZeneca, Pfizer, and Daiichi Sankyo outside
the submitted work. No other disclosures were reported.
Funding/Support: This study was supported by MSD.
Role of the Funder/Sponsor: The sponsor was involved in the design and conduct of the study (ie, drafting the
study protocol and site monitoring of the study); collection, management, analysis, and interpretation of the data
(ie, acquisition and review of data for accuracy, completeness, and consistency and performing statistical analysis);
preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Meeting Presentation: Presented in part at the 19th Annual Meeting of the Japanese Society of Medical
Oncology; February 17, 2022 (abstract PS2-3); Kyoto, Japan.
Data Sharing Statement: See Supplement 3.
Additional Contributions: Medical writing assistance was provided by Michael S. McNamara, MS, and Miranda
Tradewell, PhD, of ICON plc. This assistance was funded by MSD. We thank the patients and their families and
caregivers for participating in this study, along with all investigators and site personnel.

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SUPPLEMENT 1.
Trial Protocol and Statistical Analysis Plan

SUPPLEMENT 2.
eTable 1. List of Countries that Enrolled Patients in the Global KEYNOTE-522 Study
eTable 2. First EFS Events by Category: Subgroup of Patients Enrolled in Asia
eFigure. Overall Survival: Subgroup of Patients Enrolled in Asia

SUPPLEMENT 3.
Data Sharing Statement

JAMA Network Open. 2023;6(11):e2342107. doi:10.1001/jamanetworkopen.2023.42107 (Reprinted) November 15, 2023 14/14

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