Research

JAMA Oncology | Brief Report

Chemotherapy and Immune Checkpoint Blockade

for Gastric and Gastroesophageal Junction Adenocarcinoma
Gulam A. Manji, MD, PhD; Shing Lee, PhD; Armando Del Portillo, MD, PhD; Michael May, MD; Sarah Sta Ana, MBS;
Emily Alouani, MD; Naomi Sender, BS; Tiffany Negri, BA; Katarzyna Gautier, MS; Liner Ge, MS; Weijia Fan, MS;
Mengyu Xie, PhD; Amrita Sethi, MD; Beth Schrope, MD, PhD; Aik Choon Tan, PhD; Haeseong Park, MD;
Paul E. Oberstein, MD; Manish A. Shah, MD; Alexander G. Raufi, MD

Supplemental content
IMPORTANCE Combining immune checkpoint blockade (ICB) with chemotherapy improves
outcomes in patients with metastatic gastric and gastroesophageal junction (G/GEJ)
adenocarcinoma; however, whether this combination has activity in the perioperative setting
remains unknown.
OBJECTIVE To evaluate the safety and preliminary activity of perioperative chemotherapy and
ICB followed by maintenance ICB in resectable G/GEJ adenocarcinoma.

DESIGN, SETTING, AND PARTICIPANTS This investigator-initiated, multicenter, open-label,

single-stage, phase 2 nonrandomized controlled trial screened 49 patients and enrolled 36
patients with resectable G/GEJ adenocarcinoma from February 10, 2017, to June 17, 2021,
with a median (range) follow-up of 35.2 (17.4-73.0) months. Thirty-four patients were deemed
evaluable for efficacy analysis, with 28 (82.4%) undergoing curative resection. This study was
performed at 4 referral institutions in the US.

INTERVENTIONS Patients received 3 cycles of capecitabine, 625 mg/m2, orally twice daily for
21 days; oxaliplatin, 130 mg/m2, intravenously and pembrolizumab, 200 mg, intravenously
with optional epirubicin, 50 mg/m2, every 3 weeks before and after surgery with an
additional cycle of pembrolizumab before surgery. Patients received 14 additional doses of
maintenance pembrolizumab.

MAIN OUTCOMES AND MEASURES The primary end point was pathologic complete response
(pCR) rate. Secondary end points included overall response rate, disease-free survival (DFS),
overall survival (OS), and safety.

RESULTS A total of 34 patients (median [range] age, 65.5 [25-90] years; 23 [67.6%] male)
were evaluable for efficacy. Of these patients, 28 (82.4%) underwent curative resection, 7
(20.6%; 95% CI, 10.1%-100%) achieved pCR, and 6 (17.6%) achieved a pathologic
near-complete response. Of the 28 patients who underwent resection, 4 (14.3%)
experienced disease recurrence. The median DFS and OS were not reached. The 2-year DFS
was 67.8% (95% CI, 0.53%-0.87%) and the OS was 80.6% (95% CI, 0.68%-0.96%).
Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 20
patients (57.1%), and 12 (34.3%) experienced immune-related grade 3 or higher adverse
events.

CONCLUSION AND RELEVANCE In this trial of unselected patients with resectable G/GEJ
adenocarcinoma, capecitabine, oxaliplatin, and pembrolizumab resulted in a pCR rate of
20.6% and was well tolerated. This trial met its primary end point and supports the
development of checkpoint inhibition in combination with perioperative chemotherapy in
locally advanced G/GEJ adenocarcinoma.

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02918162 Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Gulam A.
Manji, MD, PhD, Division of
Hematology and Oncology and
Herbert Irving Comprehensive
Cancer Center, Columbia University
Irving Medical Center,
161 Ft Washington Ave, Ste 8-809,
JAMA Oncol. 2023;9(12):1702-1707. doi:10.1001/jamaoncol.2023.4423 New York, NY 10032 (gam2140@
Published online October 19, 2023. cumc.columbia.edu).

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 Chemotherapy and Immune Checkpoint Blockade for Adenocarcinoma
P
erioperative platinum-fluoropyrimidine chemotherapy
is the current standard treatment for patients with lo-
cally advanced, resectable gastric and gastroesophageal
junction (G/GEJ) adenocarcinoma.1,2 Immune checkpoint block-
ade has established efficacy in the treatment of gastroesopha-
geal cancers, especially in cases of mismatch repair deficiency
(dMMR) and elevated programmed cell death ligand 1 (PD-L1)
expression.3,4 We hypothesized that the addition of pembroli-
zumab to perioperative chemotherapy in unselected patients
with locally advanced G/GEJ adenocarcinoma would result in
increased pathologic complete responses (pCRs) and that the ad-
dition of maintenance pembrolizumab would further improve
disease-free survival (DFS). Here, we present the results of our
investigator-initiated phase 2 trial testing perioperative cap-
ecitabine, oxaliplatin, and optional epirubicin with pembroli-
zumab (COP) with maintenance pembrolizumab in patients with
resectable G/GEJ adenocarcinoma.
Methods
Study Design and Procedures
The primary objective of this phase 2 nonrandomized con-
trolled trial was to evaluate the pCR rate of perioperative COP
in patients with locally advanced (T2 or greater or lymph node
positive), resectable G/GEJ adenocarcinoma. Secondary end
points included DFS, overall survival (OS), and safety. Forty-
nine patients were screened and 36 patients were enrolled be-
tween February 10, 2017, and June 17, 2021. One patient
declined treatment, and another had omental disease on imaging
after treatment initiation. Therefore, 34 patients were deemed
evaluable for efficacy analysis, with 28 (82.4%) undergoing
curative resection (Figure 1). Race and ethnicity were patient
reported and determined during screening (as part of the
census on eligibility checklist). Patients received 3 cycles of
chemoimmunotherapy (capecitabine, 625 mg/m2, orally twice
daily for 21 days; oxaliplatin, 130 mg/m2, intravenously and
pembrolizumab, 200 mg, intravenously with optional
epirubicin, 50 mg/m2) before and after surgery with an addi-
tional cycle of pembrolizumab before surgery. Additionally, 14
doses of pembrolizumab were given after postoperative chemo-
immunotherapy. The PD-L1 combined positive scoring (CPS) and
correlative exploratory methods are described in the eMethods
in Supplement 1. Tumor response was assessed by Response
Evaluation Criteria in Solid Tumors (RECIST), version 1.1. All pa-
tients provided written informed consent. This study was ap-
proved by the institutional review boards at all institutions. The
study followed the Transparent Reporting of Evaluations With
Nonrandomized Designs (TREND) reporting guideline. The
amended trial protocol is available in Supplement 2.
Statistical Analysis
The primary end point was pCR, defined as no invasive
disease within an entirely submitted and evaluated gross
lesion, and histologically negative nodes. Disease-free
survival was defined as the time from treatment initiation to
the date of disease progression, recurrence, or death. At the
time of study activation, the reported pCR rate with doublet
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Brief Report Research
Key Points
Question Is treatment with the combination of perioperative
chemotherapy and immune checkpoint blockade active and safe in
patients with locally advanced, resectable gastric or
gastroesophageal junction adenocarcinoma?
Findings This multicenter, phase 2 nonrandomized controlled trial
of perioperative capecitabine, oxaliplatin, and pembrolizumab,
followed by maintenance pembrolizumab, included 34 evaluable
patients and resulted in a pathologic complete response rate of
20.6% and a 2-year disease-free survival rate of 67.8%. With the
exception of diarrhea, this regimen did not result in increased
treatment-related adverse events.
Meaning These findings suggest that treatment with
perioperative capecitabine, oxaliplatin, and pembrolizumab has
encouraging activity and acceptable toxicity and warrants further
investigation.
Figure 1. CONSORT Diagram
36 Patients enrolled
2 Excluded
1 Declined treatment
1 Not evaluable for efficacy because
of metastatic disease after treatment
34 Evaluable for efficacy
6 Excluded
1 Declined surgery
2 Died before surgery
1 Noncurative surgical resection
2 Metastatic disease during laparoscopy
28 Underwent surgical resection
chemotherapy was 3%.5 With a sample size of 28 patients,
the study had 80% power to detect an increase in pCR rate
from 3% to 15% based on a 1-sided binomial test with actual
α = .051. Because of lower-than-expected accruals during the
COVID-19 pandemic and the changing treatment landscape,
the initial primary end point of DFS was changed to pCR on
November 24, 2020 (at which time no formal data analysis
had been performed on the end points). All patients who met
eligibility criteria and received at least 1 dose of study treat-
ment were considered evaluable for efficacy. All patients who
received at least 1 dose of study treatment were evaluable for
safety (eMethods in Supplement 1). Analyses were conducted
using R software, version 4.2.1 (R Foundation for Statistical
Computing). The Survival package was used to calculate
progression-free survival and OS, and the KMunicate package
was used to draw the risk table for Kaplan-Meier plots.
Results
Antitumor Activity
A total of 34 patients (median [range] age, 65.5 [25-90]
years; 23 [67.6%] male and 11 [32.4%] female; 5 [14.7%]
(Reprinted) JAMA Oncology December 2023 Volume 9, Number 12 1703
 Research Brief Report Chemotherapy and Immune Checkpoint Blockade for Adenocarcinoma

Figure 2. Tumor Response

A COP therapy response before resection Radiologic response

20 Complete
Partial
Stable disease
0
RECIST response before surgery, %

Pathologic response
Complete
–20 Near complete
Partial
Poor
–40
Not available

Pathologic differentiation
–60 Moderate
Poor

–80 Not available

PD-L1 CPS score

>10
–100
1-10
Pathologic response
<1
Pathologic differentiation
Not available
PD-L1 CPS score

B Baseline EUS with pathologic staging by TNM criteria C Correlation of baseline EUS staging with
pathologic response after COP therapy
Tumor staging Lymph node staging

Baseline Surgery Baseline Surgery Baseline Surgery

EUS pathologic EUS pathologic EUS pathologic

T2N0
T4 N3
T2N1
T3 N2 A, Waterfall plot depicting Response
T3N0
T2 N1 Evaluation Criteria in Solid Tumors
T1 N0 T3N1 (RECIST) version 1.1 response to
T3N2 capecitabine, oxaliplatin, and
T0
pembrolizumab (COP) therapy before
T3Nx
resection (n = 16). Corresponding
T4N0
pathologic response by College of
T4N+ American Pathologists (CAP) criteria,
TxN+ pathologic differentiation, and
baseline programmed cell death
Not available
ligand 1 combined positive scoring
(PD-L1 CPS) score are shown. B,
Pathologic response Comparison of baseline endoscopic
Complete Poor ultrasonography (EUS) with
Near complete Not available pathologic staging by TNM criteria (T
Partial stage, left; N stage, right). C,
Correlation of baseline EUS staging
with pathologic response after COP
therapy by CAP criteria.

Asian, 5 [14.7%] Black or African American, 22 [64.7%]
White, and 2 [5.9%] with unknown race or ethnicity) were
evaluable for efficacy, with 28 (82.4%) undergoing curative
resection. Baseline characteristics are presented in eTable 1
in Supplement 1. The PD-L1 CPS was available for 24
patients (70.6%). Of the 28 patients (82.4%) who had MMR
or microsatellite instability (MSI) testing performed, 3 were
classified as having dMMR/MSI-high.
Of the evaluable patients, 7 (20.6%; 95% CI, 10.1%-
100%) achieved a pCR. According to College of American
Pathology classification, 6 patients (17.6%) had a pathologic
near-complete response and 8 (23.5%) had a partial
response (eTable 2 in Supplement 1). In patients with PD-L1
CPS scores of 1 or higher (21 patients), the pCR rate was
23.8%, and in patients with scores of 10 or higher (12
patients) at baseline, the pCR rate was 33.3%. One of the 4
patients (25.0%) with a PD-L1 CPS score of less than 1 and 1
of the 3 (33.3%) who were classified as dMMR/MSI-high
achieved a pCR. Sixteen of 34 evaluable patients had
RECIST measurable disease at baseline, of whom 10 (62.5%)
exhibited a radiologic response, including 2 complete
responses (Figure 2A). Of the 25 patients who underwent
baseline endoscopic ultrasonography, 9 (36.0%) had node-
negative disease. Four of these 9 patients (44.4%) with
node-negative disease on baseline endoscopic ultrasonogra-
phy achieved a pCR, compared with only 2 of the 16 patients
(12.0%) with initial node-positive disease (Figure 2B and C).
At the time of resection, 22 (78.6%) had pathologic node-

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 Chemotherapy and Immune Checkpoint Blockade for Adenocarcinoma
Figure 3. Disease-Free and Overall Survival
A Disease-free survival
100
80
Disease-free survival, %
60
40
20
0 0
0 20 40 60
Time from start of treatment, mo
No. at risk 34 18 6 4
Censored 0 6 18 20
Events 0 10 10 10
Kaplan-Meier curve for disease-free survival and overall survival for the 34 evaluable patients. Median overall survival and disease-free survival were not reached.
negative disease (Figure 2B and C). Overall, 27 patients
(79.4%) completed neoadjuvant COP and underwent sur-
gery (eTable 4 in Supplement 1). The R0 resection rate,
including those with pCR, was 96.4%.
By February 28, 2023, the median (range) follow-up time was
35.2 (17.4-73.0) months for censored patients. During this time,
12 patients had events, including 3 deaths without progression
(2 before surgery and 1 due to surgical complication), 2 deaths
after treatment discontinuation, and 7 progressions or recur-
rences (3 of whom have died). Five patients progressed at or be-
fore surgery. Of the patients who underwent resection, 4 (14.3%)
experienced disease recurrence. Median DFS and OS have not
been reached (Figure 3A and B). The 2-year survival rates for
evaluable patients were 67.8% (95% CI, 0.53%-0.87%) for DFS
and 80.6% (95% CI, 0.68%-0.96%) for OS.
Exploratory quantitative multiplex immunofluores-
cence analysis revealed that COP increased tumor CD3+ and
CD8 + T-cell densities and that the degree of pathologic
response was associated with increased clustering of pan-
CK+ cells to CD3+ cells, suggesting conversion to a more in-
flamed tumor microenvironment (eResults and eFigure in
Supplement 1).
Safety
Three grade 5 events occurred during treatment, 1 due to gas-
tric hemorrhage (90-year-old patient) and 1 due to gastric per-
foration (81-year-old patient), both possibly related to therapy.
The third grade 5 event, cardiac arrest (77-year-old patient),
was attributed to a postoperative surgical complication. Of the
35 patients included in the safety analysis, 20 (57.1%) devel-
oped grade 3 or higher treatment-related adverse events, and
12 (34.3%) developed grade 3 or higher immune-related ad-
verse events (eTable 3 in Supplement 1). Except for diarrhea,
the addition of pembrolizumab to chemotherapy did not
result in any new or increased treatment-related adverse
events. Treatment tolerability is detailed in the eResults in
Supplement 1.
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Brief Report Research
B Overall survival
100
80
Overall survival, %
60
40
20
80 0 20 40 60 80
Time from start of treatment, mo
0 No. at risk 34 27 9 5 0
24 Censored 0 3 17 21 26
10 Events 0 4 8 8 8
Discussion
Immune checkpoint blockade in combination with chemo-
therapy improves outcomes in patients with metastatic dis-
ease and was recently approved as maintenance therapy fol-
lowing chemoradiotherapy and resection in esophageal and
GEJ cancer.3,6,7 We examined the preliminary activity and
safety of perioperative COP followed by maintenance pem-
brolizumab in locally advanced G/GEJ adenocarcinoma.
Having found an estimated pCR rate of 20.6% (95% CI,
10.1%-100%), this study provides some evidence of efficacy
compared with historical pCR rates of 3% reported with
fluorouracil-cisplatin and 6.3% with capecitabine and
oxaliplatin (CAP OX). 5 , 8 For comparison, the FL OT4
trial demonstrated pCR in 15% and 6% of patients treated
with fluorouracil plus leucovorin, oxaliplatin and docetaxel
(FLOT) and epirubicin, cisplatin, and fluorouracil or
capecitabine, respectively. 2 We also noted radiologic
responses in 10 of the 16 patients (62.5%) who had RECIST
measurable disease, similar to that reported with CAPOX
(50%) and FLOT (45.6%).8,9 Four of the 9 patients (44.4%)
who were node negative on baseline endoscopic ultrasonog-
raphy achieved a pCR compared with only 2 of the 16
patients (12.0%) who were initially node positive (Figure 2B
and C). This finding suggests that patients with bulky dis-
ease would likely benefit from additional neoadjuvant
therapy if experiencing a radiographic response. The
interim results of the DANTE study further support our
findings that the addition of immune checkpoint blockade,
especially in those with elevated PD-L1 expression, is asso-
ciated with increased pathologic regression.10
With a median follow-up time of 35.2 months, the
median DFS and OS have yet to be reached. The 2-year DFS
was 67.8% with COP followed by maintenance pembroli-
zumab and is comparable to the 2-year DFS of approxi-
mately 53% achieved with FLOT.2 Overall, 79.4% of patients
(Reprinted) JAMA Oncology December 2023 Volume 9, Number 12 1705
 Research Brief Report
completed neoadjuvant COP and underwent surgery,
slightly lower than with FLOT (94%).2 Except for diarrhea,
the addition of pembrolizumab to chemotherapy did not
result in any new or increased treatment-related adverse
events. The higher-than-expected observed incidence of
grade 5 events may reflect the small sample size and/or
advanced age at enrollment of several patients.
Limitations
This study has some limitations. We acknowledge the nonran-
domized design, small number of patients, lack of baseline
ARTICLE INFORMATION
Accepted for Publication: July 25, 2023.
Published Online: October 19, 2023.
doi:10.1001/jamaoncol.2023.4423
Author Affiliations: Division of Hematology and
Oncology, Columbia University Irving Medical
Center and New York Presbyterian Hospital,
New York (Manji); Herbert Irving Comprehensive
Cancer Center, New York, New York (Manji, May,
Ana, Alouani, Sender, Negri); Department of
Biostatistics, Mailman School of Public Health,
Columbia University, New York, New York
(Lee, Gautier, Ge, Fan); Department of Pathology
and Cell Biology, Columbia University, New York,
New York (Del Portillo); Now with Takeda
Pharmaceuticals, Tokyo, Japan (Negri);
Departments of Oncological Sciences and
Biomedical Informatics, Huntsman Cancer Institute,
University of Utah, Salt Lake City (Xie, Tan);
Department of Gastroenterology, Columbia
University, New York, New York (Sethi);
Department of Surgery, Columbia University,
New York, New York (Schrope); Division of Medical
Oncology, Department of Medicine, Washington
University in St Louis, St Louis, Missouri (Park);
Siteman Cancer Center, St Louis, Missouri (Park);
Division of Hematology and Medical Oncology,
New York University, New York (Oberstein);
Division of Hematology and Medical Oncology,
Weill Cornell University, New York, New York
(Shah); Sandra and Edward Meyer Cancer Center,
New York, New York (Shah); Division of
Hematology-Oncology, Lifespan Cancer Institute,
Warren-Alpert Medical School of Brown University,
Providence, Rhode Island (Raufi).
Author Contributions: Drs Manji and Raufi 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: Manji, Lee, Schrope, Park,
Oberstein, Shah, Raufi.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Manji, Lee, Sta Ana, Del
Portillo, May, Ge, Tan, Park, Shah, Raufi.
Critical review of the manuscript for important
intellectual content: Manji, Lee, Sta Ana, Del Portillo,
May, Alouani, Sender, Gautier, Fan, Xie, Negri, Sethi,
Schrope, Tan, Park, Oberstein, Shah, Raufi.
Statistical analysis: Lee, May, Alouani, Gautier, Ge,
Fan, Xie, Tan, Raufi.
Obtained funding: Oberstein, Raufi.
Administrative, technical, or material support: Manji,
Sta Ana, Del Portillo, Alouani, Sender, Negri, Tan,
Park, Shah, Raufi.
Supervision: Manji, Del Portillo, Alouani, Schrope,
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Chemotherapy and Immune Checkpoint Blockade for Adenocarcinoma
laparoscopic staging, and slower-than-expected accrual as
limitations.
Conclusions
To our knowledge, this is the first completed trial demon-
strating encouraging activity with perioperative CAPOX and
pembrolizumab with maintenance pembrolizumab in unse-
lected patients with resectable G/GEJ adenocarcinoma.11-13
Additional studies on this treatment are warranted.
Park, Oberstein, Shah, Raufi.
Other–pathology: Del Portillo.
Conflict of Interest Disclosures: Dr Manji reported
receiving grants from Genentech/Roche, Merck,
Regeneron Pharm, BioLineRx, and Arcus
Biosciences and serving on the advisory boards for
CEND Pharm and Ipsen Pharm outside the
submitted work. Dr Lee reported consulting for PTC
Therapeutics. Dr Negri was affiliated with Columbia
University during the time this research was
conducted and completed; the research discussed
in this publication represents work completed prior
to her current employment with Takeda, which
sponsors an unrelated clinical trial. The opinions
expressed in this publication solely represent the
views of the authors and do not reflect the opinions
or interests of Takeda. Dr Sethi reported receiving
personal fees from Boston Scientific, Medtronic
Consulting, and Interscope Consulting and research
support from ERBE, Fujifilm, and Olympus outside
the submitted work. Dr Park reported receiving
grants from Ambrx, Aprea Therapeutics, Bayer
Corporation, BeiGene Company Limited, BJ
Biosciences Inc, Bristol-Myers Squibb, Daiichi
Sankyo Inc, Genentech Inc, GlaxoSmithKline,
Gossamer Bio, ImmuneOncia, Incyte Corporation,
Jounce Therapeutics Inc, Eli Lilly and Company,
MacroGenics Inc, Mabspace Biosciences, Mirati
Therapeutics, Merck Sharp and Dohme LLC,
Novartis Pharmaceuticals Corporation, Oncologie,
Puma Biotechnology, Pfizer Inc, PsiOxus
Therapeutics Ltd, Regeneron Pharmaceuticals,
Synermore Biologics Company Ltd, EMD Serono,
Seattle Genetics, TopAlliance Biosciences Inc,
Turning Point Therapeutics, Vedanta Biosciences
Inc, Xencor Inc, Bolt, Mersana, Tizona, and Exelixis.
Dr Shah reported receiving grants from Merck,
Bristol Meyers Squibb, and Oncolys Biopharma
outside the submitted work. No other disclosures
were reported.
Funding/Support: This study was supported and
funded by Merck Pharmaceuticals, which also
provided pembrolizumab. Correlative work was in
part funded by the 2019 Young Investigator Award
from the Conquer Cancer Foundation (Dr Raufi) and
by grants R38 CA231577 and T32CA203703 from
the National Cancer Institute (Dr May).
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Meeting Presentations: Poster presented at the
2018 American Society of Clinical Oncology
Gastrointestinal Cancers Symposium; January
18-20, 2018; San Francisco, California; and abstract
presented at the 2022 American Association for
Cancer Research Annual Meeting; April 11, 2022;
New Orleans, Louisiana.
Additional Contributions: We thank all the
patients and their caregivers for their participation
in the trial.
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