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 Brief Report Research

P
erioperative platinum-fluoropyrimidine chemotherapy
is the current standard treatment for patients with lo- Key Points
cally advanced, resectable gastric and gastroesophageal
Question Is treatment with the combination of perioperative
junction (G/GEJ) adenocarcinoma.1,2 Immune checkpoint block- chemotherapy and immune checkpoint blockade active and safe in
ade has established efficacy in the treatment of gastroesopha- patients with locally advanced, resectable gastric or
geal cancers, especially in cases of mismatch repair deficiency gastroesophageal junction adenocarcinoma?
(dMMR) and elevated programmed cell death ligand 1 (PD-L1)
Findings This multicenter, phase 2 nonrandomized controlled trial
expression.3,4 We hypothesized that the addition of pembroli- of perioperative capecitabine, oxaliplatin, and pembrolizumab,
zumab to perioperative chemotherapy in unselected patients followed by maintenance pembrolizumab, included 34 evaluable
with locally advanced G/GEJ adenocarcinoma would result in patients and resulted in a pathologic complete response rate of
increased pathologic complete responses (pCRs) and that the ad- 20.6% and a 2-year disease-free survival rate of 67.8%. With the
dition of maintenance pembrolizumab would further improve exception of diarrhea, this regimen did not result in increased
treatment-related adverse events.
disease-free survival (DFS). Here, we present the results of our
investigator-initiated phase 2 trial testing perioperative cap- Meaning These findings suggest that treatment with
ecitabine, oxaliplatin, and optional epirubicin with pembroli- perioperative capecitabine, oxaliplatin, and pembrolizumab has
zumab (COP) with maintenance pembrolizumab in patients with encouraging activity and acceptable toxicity and warrants further
investigation.
resectable G/GEJ adenocarcinoma.

Figure 1. CONSORT Diagram

Methods
36 Patients enrolled
Study Design and Procedures
The primary objective of this phase 2 nonrandomized con- 2 Excluded
trolled trial was to evaluate the pCR rate of perioperative COP 1 Declined treatment
1 Not evaluable for efficacy because
in patients with locally advanced (T2 or greater or lymph node of metastatic disease after treatment
positive), resectable G/GEJ adenocarcinoma. Secondary end
points included DFS, overall survival (OS), and safety. Forty- 34 Evaluable for efficacy
nine patients were screened and 36 patients were enrolled be-
tween February 10, 2017, and June 17, 2021. One patient 6 Excluded
1 Declined surgery
declined treatment, and another had omental disease on imaging
2 Died before surgery
after treatment initiation. Therefore, 34 patients were deemed 1 Noncurative surgical resection
evaluable for efficacy analysis, with 28 (82.4%) undergoing 2 Metastatic disease during laparoscopy

curative resection (Figure 1). Race and ethnicity were patient

28 Underwent surgical resection
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 chemotherapy was 3%.5 With a sample size of 28 patients,
daily for 21 days; oxaliplatin, 130 mg/m2, intravenously and the study had 80% power to detect an increase in pCR rate
pembrolizumab, 200 mg, intravenously with optional from 3% to 15% based on a 1-sided binomial test with actual
epirubicin, 50 mg/m2) before and after surgery with an addi- α = .051. Because of lower-than-expected accruals during the
tional cycle of pembrolizumab before surgery. Additionally, 14 COVID-19 pandemic and the changing treatment landscape,
doses of pembrolizumab were given after postoperative chemo- the initial primary end point of DFS was changed to pCR on
immunotherapy. The PD-L1 combined positive scoring (CPS) and November 24, 2020 (at which time no formal data analysis
correlative exploratory methods are described in the eMethods had been performed on the end points). All patients who met
in Supplement 1. Tumor response was assessed by Response eligibility criteria and received at least 1 dose of study treat-
Evaluation Criteria in Solid Tumors (RECIST), version 1.1. All pa- ment were considered evaluable for efficacy. All patients who
tients provided written informed consent. This study was ap- received at least 1 dose of study treatment were evaluable for
proved by the institutional review boards at all institutions. The safety (eMethods in Supplement 1). Analyses were conducted
study followed the Transparent Reporting of Evaluations With using R software, version 4.2.1 (R Foundation for Statistical
Nonrandomized Designs (TREND) reporting guideline. The Computing). The Survival package was used to calculate
amended trial protocol is available in Supplement 2. progression-free survival and OS, and the KMunicate package
was used to draw the risk table for Kaplan-Meier plots.
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
Results
survival was defined as the time from treatment initiation to Antitumor Activity
the date of disease progression, recurrence, or death. At the A total of 34 patients (median [range] age, 65.5 [25-90]
time of study activation, the reported pCR rate with doublet years; 23 [67.6%] male and 11 [32.4%] female; 5 [14.7%]

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

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 Chemotherapy and Immune Checkpoint Blockade for Adenocarcinoma Brief Report Research

Figure 3. Disease-Free and Overall Survival

A Disease-free survival B Overall survival

100 100

80 80
Disease-free survival, %

Overall survival, %
60 60

40 40

20 20

0 0
0 20 40 60 80 0 20 40 60 80
Time from start of treatment, mo Time from start of treatment, mo
No. at risk 34 18 6 4 0 No. at risk 34 27 9 5 0
Censored 0 6 18 20 24 Censored 0 3 17 21 26
Events 0 10 10 10 10 Events 0 4 8 8 8

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- Discussion
gery (eTable 4 in Supplement 1). The R0 resection rate,
including those with pCR, was 96.4%. Immune checkpoint blockade in combination with chemo-
By February 28, 2023, the median (range) follow-up time was therapy improves outcomes in patients with metastatic dis-
35.2 (17.4-73.0) months for censored patients. During this time, ease and was recently approved as maintenance therapy fol-
12 patients had events, including 3 deaths without progression lowing chemoradiotherapy and resection in esophageal and
(2 before surgery and 1 due to surgical complication), 2 deaths GEJ cancer.3,6,7 We examined the preliminary activity and
after treatment discontinuation, and 7 progressions or recur- safety of perioperative COP followed by maintenance pem-
rences (3 of whom have died). Five patients progressed at or be- brolizumab in locally advanced G/GEJ adenocarcinoma.
fore surgery. Of the patients who underwent resection, 4 (14.3%) Having found an estimated pCR rate of 20.6% (95% CI,
experienced disease recurrence. Median DFS and OS have not 10.1%-100%), this study provides some evidence of efficacy
been reached (Figure 3A and B). The 2-year survival rates for compared with historical pCR rates of 3% reported with
evaluable patients were 67.8% (95% CI, 0.53%-0.87%) for DFS fluorouracil-cisplatin and 6.3% with capecitabine and
and 80.6% (95% CI, 0.68%-0.96%) for OS. oxaliplatin (CAP OX). 5 , 8 For comparison, the FL OT4
Exploratory quantitative multiplex immunofluores- trial demonstrated pCR in 15% and 6% of patients treated
cence analysis revealed that COP increased tumor CD3+ and with fluorouracil plus leucovorin, oxaliplatin and docetaxel
CD8 + T-cell densities and that the degree of pathologic (FLOT) and epirubicin, cisplatin, and fluorouracil or
response was associated with increased clustering of pan- capecitabine, respectively. 2 We also noted radiologic
CK+ cells to CD3+ cells, suggesting conversion to a more in- responses in 10 of the 16 patients (62.5%) who had RECIST
flamed tumor microenvironment (eResults and eFigure in measurable disease, similar to that reported with CAPOX
Supplement 1). (50%) and FLOT (45.6%).8,9 Four of the 9 patients (44.4%)
who were node negative on baseline endoscopic ultrasonog-
Safety raphy achieved a pCR compared with only 2 of the 16
Three grade 5 events occurred during treatment, 1 due to gas- patients (12.0%) who were initially node positive (Figure 2B
tric hemorrhage (90-year-old patient) and 1 due to gastric per- and C). This finding suggests that patients with bulky dis-
foration (81-year-old patient), both possibly related to therapy. ease would likely benefit from additional neoadjuvant
The third grade 5 event, cardiac arrest (77-year-old patient), therapy if experiencing a radiographic response. The
was attributed to a postoperative surgical complication. Of the interim results of the DANTE study further support our
35 patients included in the safety analysis, 20 (57.1%) devel- findings that the addition of immune checkpoint blockade,
oped grade 3 or higher treatment-related adverse events, and especially in those with elevated PD-L1 expression, is asso-
12 (34.3%) developed grade 3 or higher immune-related ad- ciated with increased pathologic regression.10
verse events (eTable 3 in Supplement 1). Except for diarrhea, With a median follow-up time of 35.2 months, the
the addition of pembrolizumab to chemotherapy did not median DFS and OS have yet to be reached. The 2-year DFS
result in any new or increased treatment-related adverse was 67.8% with COP followed by maintenance pembroli-
events. Treatment tolerability is detailed in the eResults in zumab and is comparable to the 2-year DFS of approxi-
Supplement 1. mately 53% achieved with FLOT.2 Overall, 79.4% of patients

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 Research Brief Report Chemotherapy and Immune Checkpoint Blockade for Adenocarcinoma

completed neoadjuvant COP and underwent surgery, laparoscopic staging, and slower-than-expected accrual as
slightly lower than with FLOT (94%).2 Except for diarrhea, limitations.
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
Conclusions
advanced age at enrollment of several patients. To our knowledge, this is the first completed trial demon-
strating encouraging activity with perioperative CAPOX and
Limitations pembrolizumab with maintenance pembrolizumab in unse-
This study has some limitations. We acknowledge the nonran- lected patients with resectable G/GEJ adenocarcinoma.11-13
domized design, small number of patients, lack of baseline Additional studies on this treatment are warranted.

ARTICLE INFORMATION Park, Oberstein, Shah, Raufi. Gastrointestinal Cancers Symposium; January
Accepted for Publication: July 25, 2023. Other–pathology: Del Portillo. 18-20, 2018; San Francisco, California; and abstract
Conflict of Interest Disclosures: Dr Manji reported presented at the 2022 American Association for
Published Online: October 19, 2023. Cancer Research Annual Meeting; April 11, 2022;
doi:10.1001/jamaoncol.2023.4423 receiving grants from Genentech/Roche, Merck,
Regeneron Pharm, BioLineRx, and Arcus New Orleans, Louisiana.
Author Affiliations: Division of Hematology and Biosciences and serving on the advisory boards for Additional Contributions: We thank all the
Oncology, Columbia University Irving Medical CEND Pharm and Ipsen Pharm outside the patients and their caregivers for their participation
Center and New York Presbyterian Hospital, submitted work. Dr Lee reported consulting for PTC in the trial.
New York (Manji); Herbert Irving Comprehensive Therapeutics. Dr Negri was affiliated with Columbia
Cancer Center, New York, New York (Manji, May, University during the time this research was REFERENCES
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