Gastric Cancer Treatment: Recent Progress and Future Perspectives

Guan et al.
Journal of Hematology & Oncology (2023) 16:57 Journal of

https://doi.org/10.1186/s13045-023-01451-3
Hematology & Oncology
REVIEW Open Access
Gastric cancer treatment: recent progress

and future perspectives
Wen‑Long Guan1,2†, Ye He1,2† and Rui‑Hua Xu1,2*
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced
stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC,
including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For
resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are explor‑
ing the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For meta‑
static disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently.
Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instabil‑
ity (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who
may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the charac‑
terization of GC genetic profiles and the identification of new potential molecular targets. This review systematically
summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and
presents future perspectives.
Keywords Gastric cancer, Perioperative chemotherapy, Immunotherapy, Targeted therapy
Background African regions [2]. Notably, the incidence of gastric can-

Gastric cancer (GC) is the fifth most common malig- cer among young adults (aged < 50 years) in recent years
nant tumor and the fourth leading cause of cancer- has been progressively rising in both low-risk and high-
associated death worldwide [1, 2]. The incidence varies risk countries. Aside from Helicobacter Pylori infection,
geographically across the globe, with the highest inci- the occurrence of GC has been linked to genetic risk fac-
dence in Eastern Asia (Japan and Mongolia) and East- tors as well as lifestyle factors, such as alcohol consump-
ern Europe, whereas incidence rates in Northern Europe tion and smoking [3–6].
and Northern America are generally low, comparable to Despite the high incidence of GC, most patients are
unfortunately diagnosed at advanced stages with dis-
mal prognoses due to the lack of distinguishing clinical
†
Wen-Long Guan and Ye He have contributed equally. indications [7, 8]. Systemic chemotherapy is the main-
*Correspondence: stay treatment for metastatic GC (mGC), with a median
Rui‑Hua Xu overall survival (OS) of ~ 12 months for patients treated
[email protected] with conventional chemotherapy [9]. Intratumoral and
1
Department of Medical Oncology, State Key Laboratory of Oncology
in South China, Collaborative Innovation Center for Cancer Medicine, intertumoral heterogeneity are the prominent features
Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, of GC that partly contribute to its poor prognosis.
Guangzhou 510060, People’s Republic of China However, histological classifications alone are insuf-
2
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal
Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, ficient to effectively stratify patients for individual-
People’s Republic of China ized treatment and improve patients’ clinical outcomes
[10]. Therefore, cutting-edge diagnostic techniques and
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Guan et al. Journal of Hematology & Oncology (2023) 16:57 Page 2 of 28
drugs are of fundamental importance for better char- the treatment of patients with locally advanced stage
acterizing molecular profiles and identifying potential GC.
novel therapeutic targets for GC patients [11–13]. The treatment landscape of gastric cancer has evolved
Trastuzumab, a monoclonal antibody targeting significantly in the past few years, with the emergence of
Human Epidermal Receptor 2 (HER2), was the first new immunotherapy and targeted therapies for patients
approved targeted therapy for GC. However, after the at various stages of the disease (Fig. 1). In this review, we
ToGA study, progress in the development of treat- systematically summarize the pivotal clinical trials in GC
ments for gastric cancer stalled for nearly a decade [14]. treatment and provide an update on the management of
Emerging advances in immunotherapy, particularly in localized and metastatic gastric cancer. We also discuss
anti-HER2 therapy, and various biomarker-directed the developments in immunotherapy and targeted ther-
therapies in GC have recently broken this trend. For apy and highlight current individualized treatments and
example, anti-programmed cell death 1 (PD-1) anti- future perspectives.
bodies have demonstrated impressive efficacy and
prolonged survival in untreated MSI-H/dMMR mGC Management for localized GC
patients [15]. Substantial breakthroughs in the treat- Radical surgery is the primary treatment for resectable
ment of gastric cancer have been achieved with novel gastric cancer. Several therapeutic approaches have been
anti-HER2 therapeutic agents, such as T-DXd and established to lower the risk of recurrence and improve
disitamab vedotin (RC48) [16]. In addition, in light of long-term survival, including perioperative chemother-
the success of immunotherapy and targeted therapy as apy, adjuvant chemotherapy, and adjuvant chemoradio-
first-line treatments for advanced gastric cancer, ongo- therapy (Table 1). They are listed as the recommended
ing research is investigating their potential to advance treatments for resectable localized GC in current
Fig. 1 Updated immunotherapy and targeted therapy for gastric cancer. This algorithm provides guidance for selecting currently available
immunotherapy and targeted therapy based on different biomarkers
Table 1 Summary of the key phase III clinical trials of perioperative and adjuvant chemotherapy in resectable GC
Therapy line Trial Stage Experimental arm Control arm Primary Result References
endpoints (Experimental vs.
Control)
Perioperative chemotherapy MAGIC Stage II or higher 3 × ECF → Sur‑ Surgery OS PFS: HR 0.66; 95% CI [19]
gery → 3 × ECF 0.53–0.81; P < 0.001;
5-year OS: 36%
vs. 23% (HR 0.75;
95% CI 0.60–0.93;
P = 0.009)
FNCLCC & FFCD Resectable 2–3 × CF → Sur‑ Surgery OS 5-year DFS: 34% [20]
gery → 3–4 × CF v 19% (HR, 0.65;
95% CI 0.48 -0.89;
P = 0.003) 5-year
Guan et al. Journal of Hematology & Oncology
OS: 38% v 24% (HR,

0.69; 95% CI 0.50
-0.95; P = 0.02)
FLOT4-AIO cT2 or higher or 4 × FLOT → Sur‑ 3 × ECF/ECX → Sur‑ OS PFS: 30 vs. [21]
N+ gery → 4 × FLOT gery → 3 × ECF/ECX 18 months (HR 0.75;
95% CI 0.62–0.91;
(2023) 16:57
P = 0.0036); OS: 50
vs. 35 months (HR
0.77; 95% CI 0.63–
0.94; P = 0.012)
PRODIGY cT2-3N + , or 3 × DOS → Sur‑ Surgery → S-1 PFS 3-year PFS: 66.3% [22]
cT4Nany gery → 8 × S-1 vs. 60.2% (HR 0.70;
95% CI, 0.52–0.95;
P = 0.023); 3-year
OS: 74.2% vs.
73.4% (HR 0.84;
95% CI, 0.60–1.19;
P = 0.338)
RESOLVE cT4aN + or cT4b‑ Arm C: 3 × SOX → Sur‑ Arm A: Sur‑ DFS 3-year DFS: 59.4% [24]
Nany gery → 5 × SOX → 3 × S-1 gery → 8 × CAPOX vs. 51.1% (HR 0.77;
95% CI, 0.61–0.97;
P = 0.028)
Adjuvant chemotherapy ACTS-GC Stage II or III Surgery → S-1 for 1 year Surgery OS 5-year OS: 71.7% [27]
vs. 61.1% (HR 0.669;
95% CI, 0.540 to
0.828)
CLASSIC Stage II-IIIB Surgery → 8 × CAPOX Surgery DFS 5-year DFS: 68% [25] [26]
vs. 53% (HR 0.58;
95% CI, 0.47 to 0.72;
P < 0.0001) 5-year
OS: 78% vs. 69% (HR
0.66; 95% CI, 0.51 to
0.85; P = 0.0015)
Page 3 of 28
Table 1 (continued)
Therapy line Trial Stage Experimental arm Control arm Primary Result References
(2023) 16:57
endpoints (Experimental vs.

Control)
JACCRO GC-07 Stage III Sur‑ Surgery → S-1 for RFS 3-year RFS: 66% [23]
gery → 1 × S-1 → 7 × Doc‑ 1 year vs. 50% (HR 0.632;
etaxel plus S-1 → S-1 for 99.99% CI, 0.400 to
1 year 0.998; P < 0.001)
RESOLVE cT4aN + or cT4b‑ Arm B: Surgery → 8 × SOX Arm A: Sur‑ DFS 3-year DFS: 56.5% [24]
Nany gery → 8 × CAPOX vs. 51.1% (HR 0.86;
95% CI, 0.68 to 1.07;
P = 0.17)
Page 4 of 28
guidelines[5, 17, 18]. Further, the addition of targeted was improved in the perioperative arm compared to the
therapy and/or immune checkpoint inhibitors (ICIs) adjuvant arm (HR 0.70; 95% CI 0.52–0.95; P = 0.023).
is currently being studied in the neoadjuvant/adjuvant The major criticism of this study was that the adjuvant
setting. S-1 monotherapy was insufficient for stage III patients,
considering another phase III study had demonstrated
Perioperative chemotherapy the superiority of docetaxel plus S-1 to S-1 for 3-year
Perioperative chemotherapy has become the standard relapse-free survival (RFS) in stage III gastric cancer [23].
treatment for resectable localized GC. Several clinical tri- Recently, the phase III RESOLVE trial conducted in China
als have demonstrated that perioperative chemotherapy investigated the role of perioperative S-1 plus oxaliplatin
could improve the prognosis of patients with resectable (SOX) chemotherapy versus upfront surgery followed by
GC compared to surgery alone. adjuvant chemotherapy [24]. This study recruited over
The MAGIC trial marked a significant advancement 1,000 patients with cT4aN + or cT4bNany gastric or GEJ
in the field of perioperative chemotherapy for resectable adenocarcinoma, of whom over 60% had gastric cancer.
GC. In this phase 3 study, 503 patients were enrolled with Patients in the intervention group received perioperative
resectable gastric, gastroesophageal junction (GEJ), or SOX (three preoperative cycles and five postoperative
lower esophageal adenocarcinoma. Patients in the experi- cycles followed by three cycles of S-1 monotherapy). The
mental group received three preoperative and three post- two adjuvant groups received surgery followed by SOX
operative cycles of epirubicin, cisplatin, and fluorouracil or CAPOX (capecitabine and oxaliplatin) chemother-
(ECF) [19]. The results showed that the perioperative apy. These results suggested that the perioperative SOX
ECF regimen could decrease tumor stage and signifi- chemotherapy could improve the 3-year disease-free sur-
cantly improve progression-free survival (PFS, HR 0.66; vival (DFS) rate compared to adjuvant CAPOX therapy
95% CI 0.53–0.81, P < 0.001) and overall survival (OS, (59.4% vs. 51.1%, respectively, P = 0.028).
HR 0.75; 95% CI 0.60–0.93, P = 0.009). Another phase III Based on the evidence shown above, perioperative
trial conducted in 28 French centers compared radical chemotherapy has become the standard treatment in
surgery with or without perioperative cisplatin and fluo- many countries. The FLOT regimen is the most com-
rouracil (CF) chemotherapy and showed that periopera- monly used in Western countries according to the evi-
tive chemotherapy led to a higher 5-year overall survival dence from the FLOT4-AIO study[21], while the SOX
rate versus surgery alone (38% versus 24%, respectively; regimen is more recommended in China, based on the
HR 0.69; 95% CI 0.50–0.95, P = 0.02) [20]. Recently, the results of the RESOLVE study[24]. However, periopera-
randomized phase II/III FLOT4-AIO study compared tive chemotherapy is less recommended in Japan, since
perioperative FLOT regimen (fluorouracil, leucovorin, evidence of the superiority of neoadjuvant chemotherapy
oxaliplatin, and docetaxel) with previous standard ECF/ is still lacking among Japanese patients[25].
ECX (epirubicin, cisplatin, and fluorouracil/capecitabine)
regimen in gastric or GEJ cancer patients who had cT2 or Adjuvant chemotherapy
higher and nodal positive (cN +) disease [21]. The results Adjuvant chemotherapy is recommended for patients
suggested that the FLOT regimen could improve overall who undergo primary surgery and have stage II or stage
survival (50 months versus 35 months), confirming the III disease due to improvement in survival demonstrated
role of the FLOT regimen as the new standard periopera- by several clinical trials, particularly in Asian patients.
tive treatment for resectable gastric cancer [5, 18]. The multi-center phase III CLASSIC trial undertaken in
Since most of the clinical trials mentioned above were South Korea, China, and Taiwan compared upfront D2
conducted in western countries, these perioperative surgery followed by CAPOX adjuvant chemotherapy ver-
regimens (ECF, CF, and FLOT) are less frequently used sus D2 gastrectomy alone in patients with stage II-IIIB
in Asia. In the phase III PRODIGY trial, 530 Korean gastric cancer [26, 27]. Adjuvant CAPOX chemotherapy
patients with cT2-3N + or cT4Nany gastric or GEJ cancer significantly improved both 5-year DFS (68% vs. 53%; HR
were randomly randomized to the neoadjuvant or adju- 0.58; 95% CI, 0.47 to 0.72; P < 0.0001) and OS (78% vs.
vant group. Patients in the neoadjuvant arm underwent 69%; HR 0.66; 95% CI, 0.51 to 0.85; P = 0.0015) compared
preoperative DOS (docetaxel, oxaliplatin, and S-1) fol- with surgery alone. Another similar phase III ACTS-GC
lowed by surgery and S-1 adjuvant chemotherapy, while trial from Japan randomly assigned 1,059 stage II or III
those in the adjuvant arm received upfront radical sur- GC patients to undergo D2 surgery followed by S-1 mon-
gery followed by S-1 chemotherapy [22]. The periopera- otherapy or D2 surgery alone and showed that adjuvant
tive chemotherapy group had significantly higher rates S-1 monotherapy for one year led to a better 3-year OS
of R0 resection and pathological complete response than surgery alone (80.1% vs. 70.1%; HR 0.68; 95% CI,
(pCR) (95% and 10.4%, respectively). Moreover, PFS 0.52 to 0.87; P = 0.003). The survival benefit persisted
after five years of follow-up [28]. Moreover, the phase radiation (5 × 5). Overall, CRT did prolong the OS com-
III JACCRO GC-07 trial investigated the superiority of pared to surgery alone (36 vs. 27 months, respectively;
adjuvant docetaxel plus S-1 over S-1 monotherapy for P = 0.005). However, most patients in this study received
pathological stage III gastric cancer [23]. The addition D0 or D1 lymphadenectomy and only 10% had D2 lym-
of docetaxel to S-1 after surgery showed a better 3-year phadenectomy. The extent of dissection might affect the
RFS (66% vs. 50%; HR 0.632; 99.99% CI, 0.400 to 0.998; outcome of the surgery-only group. The phase III ART-
P < 0.001) in the second interim analysis, and the study IST trial from Korea evaluated the role of postoperative
was terminated as recommended by the independent CRT based on the D2 dissection backbone [31]. Four
data and safety monitoring committee. The RESOLVE hundred fifty-eight patients who received D2 lymphad-
trial also investigated the non-inferiority of adjuvant SOX enectomy and R0 resection were enrolled and randomly
chemotherapy compared with the CAPOX regimen. The assigned to the adjuvant chemotherapy arm (capecit-
3-year DFS was statistically comparable between the two abine plus cisplatin, XP) or the adjuvant CRT arm (XP-
groups (56.5% vs. 51.1%; HR 0.86; 95% CI, 0.68 to 1.07; XRT-XP). Unfortunately, the addition of radiotherapy
P = 0.17) [24]. Based on the results of the phase III tri- postoperatively did not improve their DFS (P = 0.0862).
als presented above, several cytotoxic regimens could However, in the subgroup analysis, DFS was significantly
be used as adjuvant treatments for stage II-III GC after prolonged in the CRT arm in the patients with lymph
radical surgery, including S-1, CAPOX, SOX, and DS. node-positive (N +) disease (3-year DFS rate: 77.5%
The choice of regimens depends on many factors, includ- vs.72.3%, HR 0.69, 95% CI 0.474–0.995, P = 0.0365).
ing the pathological staging, patient performance status, Based on these findings, the subsequent ARTIST II trial
and toxicity profile. In general, S-1 monotherapy is more further explored the role of adjuvant CRT in patients
recommended for stage II disease or for patients with with lymph node-positive GC [32]. Five hundred forty-
poor performance status. Combination therapies such as six patients after D2 dissection were randomly assigned
CAPOX, SOX, or DS are often recommended for patho- to adjuvant S-1, adjuvant SOX, and adjuvant SOX plus
logical stage III disease[17, 25]. radiotherapy (SOXRT) in a 1:1:1 ratio. However, there
GC with microsatellite instability-high (MSI-H) or was no significant difference in DFS between the adju-
mismatch-repair deficiency (dMMR) is a distinct subtype vant SOX and SOXRT treatments (3-year DFS rate:
[11]. Recently, an individual-patient-data meta-analysis 72.8% vs.74.3%; HR 0.97, 95% CI 0.66–1.42, P = 0.879).
including data from four large phase III studies (CLAS- Therefore, according to current results from these clini-
SIC, ARTIST, MAGIC, and ITACA-S trial) explored the cal trials, adjuvant CRT is not recommended in patients
role of adjuvant chemotherapy in the MSI-H subtype who received D2 lymphadenectomy and R0 resection.
[29]. It showed that for resectable MSI-H/dMMR GC
patients, the prognosis of patients who received surgery Novel perioperative therapies
alone was better than those who underwent surgery fol- Perioperative targeted therapy
lowed by adjuvant chemotherapy, even though the sam- Anti-HER2 and anti-vascular endothelial growth factor
ple size of MSI-H/dMMR in this meta-analysis was very (VEGF) therapies have been recommended as the stand-
modest (N = 121). Based on this result, adjuvant chemo- ard treatments for advanced GC in the first- and second-
therapy is not recommended for resectable MSI-H/ line setting, respectively. However, the role of targeted
dMMR GC patients in the latest ESMO guideline [5]. therapy in the perioperative or adjuvant setting is still
Additionally, the updated CSCO guidelines suggest that unclear and is currently under investigation.
either observation or adjuvant chemotherapy could be
considered after a thorough discussion with the patients Anti‑HER2 therapy According to the ToGA study, add-
regarding the possible risks and benefits [17]. ing trastuzumab to chemotherapy improved the OS in
patients with metastatic HER2-positive GC [14]. How-
Adjuvant chemoradiotherapy ever, the role of anti-HER2 therapy in resectable GC was
Unlike chemotherapy, the role of radiotherapy for resect- unclear. In the multicenter phase II HER-FLOT study,
able GC in the adjuvant setting is controversial. Adjuvant patients with HER2-positive esophagogastric adenocar-
chemoradiotherapy (CRT) was once adopted in North cinoma received perioperative FLOT chemotherapy for
America, according to the results of the phase III INT- four cycles preoperatively and four cycles postopera-
0116 trial [30]. In this study, 556 patients with resectable tively, followed by 9 cycles of trastuzumab monotherapy
GC or GEJ adenocarcinoma were randomly assigned to [33]. The pCR rate was 21.4%, and the median DFS was
the upfront surgery plus adjuvant CRT group or the sur- 42.5 months. The phase II randomized PETRARCAstudy
gery group. Patients in the experimental arm received investigated the efficacy of adding trastuzumab and per-
adjuvant fluorouracil chemotherapy plus 4500 cGy of tuzumab to perioperative FLOT chemotherapy in patients
with ≥ cT2 or cN + resectable GC [34]. The pCR rate was in various clinical trials. In the randomized phase II
significantly improved with trastuzumab and pertuzumab DANTE trial, patients with resectable GC were assigned
(35% vs. 12%, P = 0.02), and the R0 resection rate and sur- to the experimental arm with the PD-L1 inhibitor atezoli-
gical morbidity were comparable between both groups. zumab plus FLOT chemotherapy and the control arm
However, adding targeted therapy to perioperative chem- with standard FLOT chemotherapy [39]. The R0 resec-
otherapy did not improve DFS or OS and caused more tion rate, surgical morbidity and mortality were com-
severe adverse events (≥ grade 3), especially diarrhea (41% parable in both groups. Atezolizumab combined with
vs. 5%) and leukopenia (23% vs. 13%). Based on these chemotherapy was associated with tumor downstage and
results, the trial did not proceed to phase III. Another pathological regression, which were more pronounced
phase II NEOHX study recruited 36 HER2-positive GC in patients with a higher PD-L1 combined positive score
patients who received perioperative CAPOX plus trastu- (CPS).
zumab treatment, followed by 12 cycles of trastuzumab Several single-arm phase II clinical trials explored
maintenance therapy [35]. The pCR rate, 18-month DFS the efficacy of perioperative ICIs combined with dif-
rate, and 5-year OS rate were 9.6%, 71%, and 58%, respec- ferent treatments (chemotherapy, targeted therapy, or
tively. The randomized phase II INNOVATION trial radiotherapy) in resectable GC [40–44]. The pCR rates
assigned patients to 3 groups: perioperative chemother- ranged from 10 to 41%. In the phase III ATTR ACTION-5
apy, chemotherapy plus trastuzumab, and chemotherapy trial (NCT03006705), the use of nivolumab in the adju-
plus trastuzumab and pertuzumab [36]. According to the vant setting was investigated. Patients who have under-
investigators’ choice, the chemotherapy could be FLOT, gone D2 surgery will receive either S-1 for one year or
CAPOX, FOLFOX, or XP. The primary endpoint was CAPOX for six months, with nivolumab added to the
major pathological response (MPR) rate, and the result is adjuvant therapy in the intervention arm. The primary
pending. In general, adding anti-HER2 therapy to chemo- endpoint of the study is relapse-free survival (RFS). The
therapy showed certain efficacy in the perioperative set- result was announced recently. Unfortunately, the addi-
ting, but the associated survival benefit should be further tion of nivolumab did not extend the RFS compared
investigated in a larger randomized trial. with adjuvant chemotherapy alone. Additionally, the
role of pembrolizumab in combination with periopera-
Anti‑VEGF therapy As for anti-VEGF therapy, the rand- tive chemotherapy for resectable GC is being examined
omized, open-label, phase II/III ST03 trial recruited 1,063 in the phase III clinical trial, KEYNOTE-585 [45]. The
resectable esophagogastric adenocarcinoma patients and chemotherapy regimens under investigation are XP, FP,
randomly assigned them to perioperative chemotherapy or FLOT, and the primary endpoints of the study are OS,
(ECX) group or perioperative chemotherapy plus bevaci- event-free survival (EFS), and pCR rate. The potential
zumab group [37]. The result showed that adding beva- survival benefits and efficacy of ICI are also being evalu-
cizumab did not improve the 3-year OS (48.1% vs. 50.3% ated in the double-blind, randomized phase III MAT-
for chemotherapy alone; HR 1.08; 95% CI, 0.91 to 1.29; TERHORN study, which is based on the FLOT backbone
P = 0.36). Besides, adding bevacizumab was associated [46]. Patients with resectable GC will receive either
with higher rates of postoperative anastomotic leak (24% perioperative FLOT or FLOT plus durvalumab (a PD-L1
vs. 10%). Ramucirumab, a VEGF receptor 2 inhibitor, has antibody). The primary endpoint of the study is EFS, with
become one of the standard choices in the second-line secondary endpoints including OS and pCR rate.
treatment of GC [5, 17, 18]. The RAMSES/FLOT7 evalu- For the dMMR/MSI-H subgroup, as discussed above,
ated the efficacy of adding ramucirumab to perioperative the value of chemotherapy was controversial. Consider-
FLOT for resectable GC [38]. The R0 resection rate in the ing dMMR/MSI-H is a predictive biomarker for immu-
intervention group was improved compared to the chem- notherapy in advanced GC, treatment with immune
otherapy group (96% vs. 82%, P = 0.0093). The median checkpoint inhibitors in the perioperative setting has
DFS was prolonged in the FLOT plus ramucirumab group the potential to improve the response rate and sur-
(32 months vs. 21 months), while the OS was similar in vival. The phase II GERCOR NEONIPIGA study evalu-
both groups (46 months vs. 45 months). ated the response rate and safety of the combination of
neoadjuvant nivolumab and low-dose ipilimumab fol-
Perioperative immunotherapy lowed by adjuvant nivolumab in patients with dMMR/
Based on several phase III clinical trials, programmed MSI-H locally advanced G/GEJ adenocarcinoma. Among
death 1 (PD-1) inhibitors were approved for first- and 29 patients who underwent surgery, 17 (58.6%; 90% CI,
third-line treatment of unresectable/metastatic GC in 41.8–74.1) achieved pCR[47]. Similarly, the pCR rate of
different countries [5, 17, 18]. However, the role of ICI in tremelimumab plus durvalumab was 60% in the neo-
resectable GC remains unclear and is being investigated adjuvant setting (cohort 1) in the phase II INFINITY
study[48]. Based on these encouraging results, it is pos- 0.75–1.08) but was superior in the CPS ≥ 10 popula-
sible for patients who achieved pCR after neoadjuvant tion (median OS 17.4 vs. 10.8 months; HR, 0.62; 95%
immunotherapy to avoid surgery. Cohort 2 of the INFIN- CI, 0.45–0.86) [54]. However, the combination of pem-
ITY study has started enrollment to investigate the activ- brolizumab and chemotherapy did not bring OS ben-
ity of tremelimumab plus durvalumab as the definitive efit compared to chemotherapy alone in either CPS ≥ 1
treatment for dMMR/MSI-H locally advanced GC. (12.5 vs. 11.1 months; HR, 0.85; 95% CI, 0.71–1.02) or
CPS ≥ 10 (12.3 vs. 10.8 months; HR, 0.76; 95% CI, 0.56–
Management for unresectable/metastatic GC 1.03) subgroup [54]. In another double-blind, placebo-
Chemotherapy controlled phase III KEYNOTE-859 study, the addition
Cytotoxic agents, including fluoropyrimidine, plati- of pembrolizumab to chemotherapy (FP or CAPOX)
num, taxanes and irinotecan, are the main treatment in demonstrated slight survival benefit compared with
advanced gastric cancer. Generally, fluoropyrimidine chemotherapy alone (OS 12.9 vs. 11.5 months, HR,
(fluorouracil, capecitabine, and S-1) combined with 0.78; 95% CI, 0.70–0.87. PFS 6.9 vs. 5.6 months, HR,
platinum is used as the backbone therapy in the first line. 0.76; 95% CI, 0.67–0.85). The results were generally
Oxaliplatin is considered to be as effective as cisplatin. consistent in different PD-L1 CPS subgroups[55].
In the phase III SOX-GC trial, the SOX regimen showed CheckMate-649 is another global, randomized, phase
improved survival compared to the SP regimen in diffuse III trial investigating the effects of ICIs (nivolumab plus
or mixed-type GC[49]. For patients who are not fit for ipilimumab, a CTLA-4 inhibitor) or ICI (nivolumab)
intensive chemotherapy (older age or poor performance plus chemotherapy versus chemotherapy (CAPOX
status), the phase III GO2 trial showed that a modified or FOLFOX) alone in metastatic HER2-negative GC
dose of two-drug chemotherapy (60% of the full dose) patients [56]. One thousand five hundred eighty-one
provided a better tolerance but did not compromise the patients were assigned to nivolumab plus chemo-
clinical outcome[50]. Paclitaxel, docetaxel, and irinote- therapy arm or chemotherapy arm. The addition of
can are commonly used in the second line of chemother- nivolumab to chemotherapy improved the OS (14.4
apy. In the ABSOLUTE phase III clinical trial conducted vs. 11.1 months; HR 0.71; 98.4% CI, 0.59 to 0.86;
in Japan, weekly use of albumin-bound paclitaxel (nab- P < 0.0001) and PFS (7.7 vs. 6.05 months; HR 0.68; 98%
paclitaxel) was not inferior to weekly solvent-based CI, 0.56 to 0.81; P < 0.0001) for the patients with PD-L1
paclitaxel in terms of overall survival[51]. In third-line CPS ≥ 5; therefore both primary endpoints were met.
treatment, trifluridine-tipiracil (TAS-102), an oral cyto- For all-randomized patients, nivolumab combined with
toxic agent, has been proven in the phase III TAGS trial chemotherapy also improved OS (13.8 vs. 11.6 months;
to improve overall survival compared with placebo (5.7 HR 0.80; 99.3% CI, 0.68 to 0.94; P = 0.0002). Moreover,
vs.3.6 months, HR 0.69, 95% CI 0.56–0.85)[52]. all CPS subgroups exhibited an increased objective
response rate in the nivo-chemotherapy arm. How-
Immune Checkpoint Inhibitors (ICIs) in unresectable/ ever, the chemo-free treatment with nivolumab and
metastatic GC ipilimumab did not show OS improvement compared
Immune checkpoint inhibitors (ICIs) (monotherapy or to chemotherapy alone [57]. Based on these findings,
combined with other treatments) have shown anti-tumor nivolumab combined with chemotherapy was listed as
effects across a spectrum of solid tumors, including gas- one of the recommended first-line treatments in the
trointestinal tumors. Here, we present an overview of NCCN, ESMO, and CSCO guidelines [5, 17, 18].
current evidence of ICI treatment in GC (Table 2) and ATTR ACTION-04 was a randomized, double-blind,
discuss different predictive biomarkers for ICIs. placebo-controlled, multicenter phase II/III trial that
evaluated the effects of nivolumab plus chemother-
First line
apy (SOX or CAPOX) compared with chemotherapy
KEYNOTE-062 was the first global, randomized phase alone in the first-line treatment for HER2-negative
III trial to compare the efficacy and safety of immuno- advanced GC in the Asian population, regardless of
monotherapy (pembrolizumab) or immunotherapy PD-L1 expression [58]. The combination therapy sig-
plus chemotherapy versus standard chemotherapy in nificantly improved the PFS (HR 0·68; 98·51% CI
HER2-negative advanced GC in the first-line setting 0·51–0·90; P = 0·0007) but not the OS (both groups
[53]. According to the last update in ASCO 2022, it achieved > 17 months of median OS). One of the pos-
was suggested that pembrolizumab monotherapy was sible reasons for the different results of OS between
non-inferior to chemotherapy alone (cisplatin and fluo- ATTR ACTION-04 and CheckMate-649 could be the
rouracil/capecitabine) in patients with PD-L1 CPS ≥ 1 subsequent anticancer therapies, whereby the propor-
(median OS 10.6 vs. 11.1 months, HR 0.90, 95% CI tion of patients who received subsequent anticancer
Table 2 Summary of the key phase III clinical trials of ICIs in metastatic GC
Therapy line Trial Agent Experimental arm Control arm Primary endpoints Result (Experimental vs. References
Control)
First line (HER2-negative) KEYNOTE-062 Pembrolizumab Pembrolizumab monother‑ Chemotherapy (PF or XP) OS and PFS in pts with Pembro vs. Chemo: OS: 10.6 [53, 54]
apy; Pembrolizumab plus CPS ≥ 1 vs. 11.1 months (HR, 0.91;
chemotherapy (PF or XP) 99.2% CI, 0.69–1.18); PFS:
2.0 vs. 6.4 months (HR, 1.66;
95% CI, 1.37–2.01); Pem‑
bro + chemo vs. Chemo: OS:
12.5 vs. 11.1 months (HR,
0.85; 95% CI, 0.70–1.03); PFS:
6.9 vs. 6.4 months (HR, 0.84;
95% CI, 0.70–1.02)
CheckMate-649 Nivolumab Nivolumab plus chemother‑ Chemotherapy (XELOX or OS and PFS in pts with Nivo + chemo vs. Chemo: [56, 86]
apy (XELOX or FOLFOX) FOLFOX) CPS ≥ 5 OS: 14.4 vs. 11.1 months (HR
0.71; 98.4% CI, 0.59–0.86);
PFS: 7.7 vs. 6.05 months
(HR 0.68; 98% CI, 0.56–0.81);
Nivo + ipi vs. Chemo: OS:
11.2 vs. 11.6 months (HR,
(2023) 16:57
0.89; 95% CI, 0.71–1.10); PFS:

2.8 vs. 6.3 months (HR, 1.42;
95% CI, 1.42–1.76)
ATTRACTION-4 Nivolumab Nivolumab plus chemo‑ Chemotherapy (SOX or OS and PFS OS: 17.45 vs. 17.15 months [58]
therapy (SOX or CAPOX) CAPOX) (HR 0·90; 95% CI 0·75–1·08);
PFS: 10.45 vs. 8.34 months
(HR 0·68; 98·51% CI
0·51–0·90)
ORIENT-16 Sintilimab Sintilimab plus chemother‑ Chemotherapy (CapeOX) OS in pts with CPS ≥ 5 OS: 18.4 vs. 12.9 months (HR [59]
apy (CapeOX) 0.660; 95% CI 0.505–0.864);
RATIONALE-305 Tislelizumab Tislelizumab plus chemo‑ Chemotherapy (XELOX OS and PFS In the PD-L1 + (i.e., PD-L1 [60, 61]
therapy (XELOX or PF) or PF) TAP score ≥ 5%) population:
OS: 17.2 vs. 12.6 months (HR
0·74; 95% CI 0·59–0·94); PFS:
7.2 vs. 5.9 months (HR 0·67;
95% CI 0·55–0·83)
KEYNOTE-859 Pembrolizumab Pembrolizumab plus chem‑ Chemotherapy (CAPOX OS OS: 12.9 vs. 11.5 months (HR [55]
otherapy (CAPOX or PF) or PF) 0·78; 95% CI 0·70–0·87); PFS:
6.9 vs. 5.6 months (HR 0·76;
95% CI 0·67–0·85)
JAVELIN Gastric 100 Avelumab Avelumab maintenance Continued chemotherapy OS OS: 10.4 vs. 10.9 months (HR [60, 62]
after 12 weeks of 1st-line (FOLFOX) 0.91; 95% CI, 0.74–1.11)
chemotherapy (FOLFOX)
First line (HER2-positive) KEYNOTE-811 Pembrolizumab Pembrolizumab plus trastu‑ Trastuzumab plus chemo‑ OS and PFS ORR (74.4% vs. 51.9%); [73]
zumab and chemotherapy therapy (XELOX or PF) results of PFS and OS are
(XELOX or PF) immature
Page 9 of 28
Table 2 (continued)
(2023) 16:57
Therapy line Trial Agent Experimental arm Control arm Primary endpoints Result (Experimental vs. References
Control)
Sencond line KEYNOTE-061 Pembrolizumab Pembrolizumab Chemotherapy (paclitaxel) OS and PFS in pts with OS: 9.1 vs. 8.3 months (HR [84]
CPS ≥ 1 0·82; 95% CI 0·66–1·03); PFS:
1.5 vs. 4.1 months ((HR 1·27,
95% CI 1·03–1·57)
Third line ATTRACTION-2 Nivolumab Nivolumab Placebo OS OS: 5.3 vs. 4.1 months (HR [64]
0·63, 95% CI 0·51–0·78)
JAVELIN Gastric 300 Avelumab Avelumab Chemotherapy (paclitaxel or OS OS: 4.6 vs. 5.0 months (HR [65]
irinotecan) 1.1, 95% CI 0·9–1.4)
Page 10 of 28
treatments or ICIs therapy was much higher in ATT monotherapy was associated with the PD-L1 CPS level.
RACTION-04 (66% vs. 39% in CheckMate-649). Patients with CPS ≥ 10 had a better outcome in the pem-
The efficacy of immunotherapy plus chemotherapy was brolizumab group than in the chemotherapy group.
further confirmed in the Asian phase III ORIENT-16 KEYNOTE-059 was a phase II study that explored the
trial, which compared sintilimab plus chemotherapy effect of pembrolizumab in patients with advanced GC
(CAPOX) to chemotherapy alone as the first-line treat- after progression from ≥ 2 lines of treatment [63]. Among
ment [59]. The pre-specified interim result was reported the 259 patients enrolled, the ORR and median duration
at ESMO 2021. Sintilimab plus chemotherapy showed a of response (DoR) was 11.6% and 8.4 months, respec-
survival benefit versus chemotherapy alone in patients tively. Moreover, pembrolizumab showed higher efficacy
with CPS ≥ 5 (18.4 vs. 12.9 months; HR 0.660; 95% CI in the subgroup with PD-L1-positive cancer (CPS ≥ 1)
0.505–0.864) and all randomized patients (15.2 vs. compared to PD-L1-negative cancers (ORR 15.5% vs.
12.3 months; HR 0.766; 95% CI 0.626–0.936). Another 6.4%; DoR 16.3 vs. 6.9 months, respectively). The phase
PD-1 antibody, tislelizumab, is currently being inves- III ATTR ACTION-2 study compared nivolumab mono-
tigated in the phase III RATIONALE-305 trial [60]. therapy versus placebo in advanced GC patients after
Advanced GC patients are randomized to receive tisleli- two lines of therapy, regardless of the PD-L1 expression
zumab plus chemotherapy (CAPOX/FP regimen) or [64], and survival benefit was observed in the nivolumab
chemotherapy alone. The primary endpoints are PFS and group (OS 5.3 vs. 4.1 months; HR 0·63, 95% CI 0·51–0·78;
OS. Results from the interim analysis of the PD-L1 + (i.e., P < 0·0001). Based on the results of this study, nivolumab
PD-L1 TAP score ≥ 5%) population were represented at is recommended as monotherapy in third-line treatment
2023 ASCO-GI, showing that tislelizumab plus chemo- for GC in the CSCO guideline but not in the ESMO or
therapy led to significant OS (17.2 vs. 12.6 months; HR NCCN guidelines due to the patients enrolled being
0·74; 95% CI 0·59–0·94) and PFS (7.2 vs. 5.9 months; exclusively Asian. The role of avelumab in the third-line
HR 0·67; 95% CI 0·55–0·83) improvement compared to treatment for advanced GC was investigated in the phase
chemotherapy alone[61]. The ITT population outcomes III JAVELIN Gastric 300 trial [65]. Though avelumab
will be reported after the final analysis. showed a more manageable safety than the physician’s
In summary, in first-line treatment for HER2-nega- choice of chemotherapy, it did not improve OS (primary
tive advanced GC, the addition of anti-PD-1 therapy endpoint, 4.6 vs. 5.0 months; HR 1.1, 95% CI 0·9–1.4;
could improve clinical outcomes in patients with high P = 0.81), PFS, or ORR.
PD-L1 expression, according to the results from Check-
Mate-649, ORIENT-16, and RATIONALE-305. For Molecular Biomarkers of Immunotherapy in GC
patients with low PD-L1 expression or unknown PD-L1 HER2 HER2-positive GC, defined as immunohisto-
status, the survival benefit of adding PD-1 antibodies is chemical (IHC) expression 3+ or 2 + combined with
still controversial (discussed below), and the risk–ben- positive fluorescent in situ hybridization (FISH) verifi-
efit balance of ICIs treatment should be considered, and cation, accounts for approximately 15–20% of gastric or
decisions should be discussed case by case. gastroesophageal cancer. The phase III ToGA study has
The role of maintenance therapy with ICIs after first- established trastuzumab combined with chemotherapy
line chemotherapy was evaluated in the phase III JAVE- as the standard first-line treatment for HER2-positive
LIN Gastric 100 trial [62]. Patients with HER2-negative advanced GC [14]. In preclinical models, HER2 signaling
advanced GC without progression after at least 12 weeks could regulate the recruitment and activation of tumor-
of first-line chemotherapy (oxaliplatin plus fluoropy- infiltrating immune cells [66]. Besides, trastuzumab has
rimidine) were randomly assigned to avelumab (a PD-L1 been shown to upregulate the expression of PD-1 and
inhibitor) maintenance or continued chemotherapy. Ave- PD-L1 [67, 68], and anti-PD-1 antibodies could signifi-
lumab maintenance did not show OS benefit compared cantly increase the therapeutic activity of HER2 inhibitors
to chemotherapy (24-month OS rate: 22.1% versus 15.5%; [69]. Several phase I/II studies demonstrated the prom-
HR 0.91; 95% CI, 0.74–1.11; P = 0.1779). ising efficacy of the addition of ICIs to trastuzumab and
chemotherapy in HER2-positive GC. In the phase Ib Ni-
Second line and beyond HIGH study conducted in Japan, patients with HER2-pos-
The randomized, open-label, phase III KEYNOTE-061 itive advanced GC received nivolumab, trastuzumab, and
trial compared pembrolizumab monotherapy with pacli- chemotherapy (CAPOX or SOX regimen) in the first-line
taxel in patients with advanced GC or GEJ cancer in the setting, and the ORR was 75%, as reported at ASCO 2020
second-line setting [53]. Though the primary endpoints [70]. The multi-institutional phase Ib/II PANTHERA
(the OS and PFS in patients with PD-L1 CPS ≥ 1) were not trial explored the efficacy and safety of the combination
met, it was suggested that the efficacy of pembrolizumab of pembrolizumab, trastuzumab and chemotherapy as
first-line therapy for HER2-positive advanced GC [71]. Besides, the ORR was much higher in the immunotherapy
The updated data at ASCO-GI 2021 showed that the ORR groups. In another meta-analysis including four phase III
was 76.7% (CR 16.3%, PR 60.5%), the PFS was 8.6 months trials (KEYNOTE-062, CheckMate-649, JAVELIN Gastric
(95% CI 7.2–16.5 months), and the OS was 19.3 months 100, and KEYNOTE-061), 2545 patients with known MSI
(95% CI 16.5-NR). The striking efficacy was also reported status were enrolled, and the proportion of MSI-H was
in another phase II study, in which patients with HER2- 4.8% [76]. In the MSI-H group, the HR for OS benefit with
positive GC received pembrolizumab, trastuzumab and immunotherapy was 0.34 (95% CI 0.21–0.54), compared
chemotherapy (oxaliplatin/cisplatin + capecitabine/5-FU) to 0.85 (95% CI 0.71–1.00) for the MSS group. Among the
[72]. Overall, the ORR was 91% and DCR was 100%. The patients with MSI-H status, the HR for PFS was 0.57 (95%
median PFS and OS was 13·0 months and 27·3 months, CI 0.33–0.97; P = 0.04), and the odds ratio (OR) for ORR
respectively, which was much better than the OS reported was 1.76 (95% CI 1.10–2.83; P = 0.02). Altogether, these
in the ToGA study. Recently, the randomized, double- findings suggested that MSI-H status was a predictive
blind, placebo-controlled phase III KEYNOTE-811 trial biomarker for immune checkpoint inhibitor treatments,
reported the results of its first interim analysis [73], in regardless of the line of therapy.
which patients with metastatic HER2-positive GC or GEJ
cancer received pembrolizumab or placebo plus trastu- EBV Epstein-Barr virus-associated GC (EBVaGC) is
zumab and chemotherapy. The results showed that add- another distinct molecular subtype of the TCGA classifi-
ing pembrolizumab to trastuzumab and chemotherapy cation [11], accounting for about 9% of GC in the TCGA
could markedly increase the ORR (74.4% vs. 51.9%; the cohort and approximately 5% in China [77, 78]. EBV has
estimated difference between the two groups was 22.7%; been linked to CD8+ T cell infiltration and increased
95% CI, 11.2–33.7%; P = 0.00006). Based on this result, expression of PD-L1 and PD-L2 [11, 79], making it a
the FDA approved pembrolizumab combined with tras- potential biomarker for ICI treatment. While a Korean
tuzumab and chemotherapy as the first-line treatment for study with a small sample size (n = 6) once reported a
advanced HER2-positive gastric or GEJ adenocarcinoma. 100% response rate in EBV-positive advanced GC [80],
The results of the primary endpoints (PFS and OS) are still several other studies did not demonstrate a high response
immature. rate [81–83]. Differences in response rates across studies
may be attributed to confounding factors such as tumor
MSI MSI-H tumor is one of the four subtypes of GC mutational burden (TMB) and PD-L1 expression. There-
according to The Cancer Genome Atlas (TCGA) Research fore, the role of EBV positivity in immunotherapy for GC
Network [11]. The incidence of MSI-H status in GC was remains unclear and requires further investigation.
reported to range from 8 to 25%, which was much lower
in metastatic disease [74]. Mismatch repair (MMR) pro- PD‑L1 As discussed earlier, the level of PL-L1 expres-
teins are supposed to fix the errors that occur during sion, especially the CPS score, has been considered a pre-
DNA replication. When MMR proteins are deficient, the dictive biomarker for response to ICIs. However, the reli-
defects of DNA replication will lead to the accumulation able cut-off value to predict the benefit of immunotherapy
of mutations and the expression of neoantigens, which is needed to be determined. The cut-off points often used
may act as potential targets of immune cells [75]. Hence, in clinical trials are 1, 5 and 10. In the KEYNOTE-059
it is reasonable that tumors with MSI-H/dMMR status trial, CPS ≥ 1 was used to separate the patients that could
may attract more immune cell infiltration and enhance benefit from third-line pembrolizumab treatment [63].
the effect of immune checkpoint inhibitors. A post hoc However, this benefit was not seen compared to chemo-
analysis of KEYNOTE-059 (third-line treatment), KEY- therapy in the KEYNOTE-061/062 trials [53, 84]. In KEY-
NOTE-061 (second-line treatment), and KEYNOTE-062 NOTE-061/062, CPS ≥ 10 effectively differentiated the
(first-line treatment) was conducted to evaluate the effi- response to pembrolizumab. Patients with CPS ≥ 10 had
cacy of pembrolizumab versus chemotherapy in the better OS benefits than those with CPS ≥ 1. A comprehen-
patients with MSI-H advanced G/GEJ adenocarcinoma sive analysis of patients with CPS ≥ 10 in KEYNOTE-059,
[15]. Overall, 7 of 174 patients (4.0%) in KEYNOTE-059, 061 and 062 also showed consistent improvement toward
27 of 514 (5.3%) in KEYNOTE-061, and 50 of 682 (7.3%) better outcomes with pembrolizumab in different lines of
in KEYNOTE-062 with MSI-H status were enrolled. By treatment in this subgroup [85]. In the CheckMate-649
the time of analysis, the OS of the patients with MSI-H and ORIENT-16 studies, CPS ≥ 5 was used as the cut-off
was not reached for pembrolizumab monotherapy in value for the primary endpoint OS. Though the OS ben-
KEYNOTE-059, 061 and 062, or for pembrolizumab com- efit of nivolumab plus chemotherapy was also observed in
bined with chemotherapy in KEYNOTE-062, compared all randomized patients in CheckMate-649, the subgroup
with an OS of around 8 months for chemotherapy alone. analysis suggested that the benefit was insignificant in the
CPS < 5 or < 1 group [86]. A recent study reconstructed status of HER2, fibroblast growth factor receptor (FGFR),
unreported Kaplan–Meier plots of PD-L1 CPS subgroups Claudin18.2 (CLDN18.2), PD-L1 and EGFR.
of three phase III trials (CheckMate-649, KEYNOTE-062,
and KEYNOTE-590) and investigated the outcome of low Anti‑HER2 therapy
CPS subgroup [87]. The result suggested that patients with HER2, also known as ERBB2, is a member of the ERBB
low PD-L1 expression (CPS 1–4 and CPS 1–9) did not protein families that includes the epidermal growth fac-
benefit from adding ICIs to chemotherapy. In summary, tor receptor (EGFR or HER1), HER3, and HER4 [91].
although the predictive role of PD-L1 CPS for immuno- HER2 overexpression or amplification has been found
therapy efficacy has been demonstrated in multiple clini- in a range of 7.3% to 20.2% in advanced gastric and
cal trials, there is still a need to determine the optimal cut- gastroesophageal junction adenocarcinomas, with the
off value for CPS and to develop further classifications for overexpression rate varying globally [92]. In addition,
patients with low CPS scores. Recently, the result of the intestinal-type gastric cancers and those arising from the
phase III RATIONALE-305 trial suggested that the TAP proximal stomach or gastroesophageal junction are more
score > 5% also had predictive value for ICI treatment in likely to exhibit HER2 positivity. [11, 93].
gastric cancer[61], and further exploration is needed. Trastuzumab is a humanized monoclonal antibody that
targets HER2 extracellular domain 4, then inhibits down-
Tumor mutation burden (TMB) It is hypothesized that stream signal activation and cancer cell proliferation.
a high TMB status results in the high expression of neo- Trastuzumab plus chemotherapy has been established
antigens, which are immunogenic and can induce the as the standard first-line treatment for HER2-positive
response of the immune system and potentially increase advanced GC. The landmark ToGA trial revealed that
the efficacy of ICI treatment. In a phase Ib/II study that trastuzumab plus chemotherapy significantly improved
explored the efficacy of the PD-1 antibody toripali- the overall survival of patients with advanced GC [14],
mab in patients with advanced GC, patients with TMB- especially for patients with HER2 positivity, who were
high (TMB-H, TMB ≥ 12 mut/Mb) showed a higher ORR identified as having HER2 immunohistochemistry
and better OS compared with patients with TMB-L status (IHC) scores of 2 + and fluorescence in situ hybridiza-
(ORR 33.3% vs. 7.1%, P = 0.017; OS 14.6 vs. 4.0 months, tion (FISH)-positive or HER2 IHC 3 + based on a post-
P = 0.038)[88]. In the subgroup analysis of the KEY- hoc exploratory analysis [92]. The EVIDENCE trial has
NOTE-061 study, the TMB status (≥ 10 or < 10 mut/Mb) demonstrated that combining first-line trastuzumab with
was associated with response rate, PFS, and OS in patients chemotherapy was associated with improved clinical out-
treated with pembrolizumab. In the TMB-H subgroup, comes in Chinese patients with HER2-positive metastatic
pembrolizumab demonstrated a better OS compared GC, providing real-world evidence. [94].
with paclitaxel, and this benefit remained even when However, subsequent attempts of HER2-targeted ther-
MSI-H patients were excluded[89]. Though FDA granted apy in advanced GC were not as successful as expected.
approval for the use of pembrolizumab in patients with Even though pertuzumab [95, 96], trastuzumab emtan-
TMB-H (i.e., TMB ≥ 10 mutations/Mb) advanced solid sine (T-DM1) [97], and lapatinib [98, 99] were all inves-
tumors that progressed after standard treatments, accord- tigated in several first-line and second-line trials, no
ing to the subgroup analysis of KEYNOTE-158 study[90], survival improvement was observed in any of these trials.
the evidence is still not enough for the use of ICIs in Additionally, trastuzumab beyond progression also failed
TMB-H gastric cancer, and phase III studies to illustrate to show a survival benefit in pre-treated HER2-positive
the predictive value of TMB are needed. GC patients in the T-ACT trial [100].
Potential resistance mechanisms of HER2‑targeted ther‑

Molecular targeted therapy in unresectable/metastatic GC apy Primary or acquired resistance is a major impedi-
Molecular targeted therapy remains an essential treatment to the management of mGC patients, while mecha-
ment option for patients with advanced GC, aimed to nisms underlying the poor efficacy of HER2-directed
inhibit tumor proliferation and increase survival rates. therapy in GC are not fully understood. Multiple poten-
Targeted therapies, including anti-HER2, anti-angio- tial resistance mechanisms have been researched, as
genesis, and other biomarker-directed therapies, have listed below, and further studies are warranted to improve
demonstrated promising efficacy in treating GC, with treatment resistance in GC patients treated with HER2-
significant benefits observed in biomarker-enriched targeted therapy in clinical settings.
patients (Table 3). Therefore, next-generation sequencing HER2 heterogeneity
or ctDNA detection is crucial for mGC patients to estab- Intratumoral HER2 heterogeneity is observed in 23%
lish a comprehensive molecular profile, including the to 79% of GC patients and is associated with patients’
Table 3 Selected key clinical trials of targeted therapies for mGC patients
Trial Phase Treatment Outcomes References
HER2
ToGA III Capecitabine or 5- FU plus cisplatin with vs without ORR 47% vs. 35%, P = 0.0017; mOS 13.8 vs. [14]
trastuzumab as first-line therapy 11.1 months (HR 0.74, 95% CI 0.60–0.91; P = 0.0046);
mPFS 6.7 vs 5.5 months (HR 0.71, 95% CI 0.59–0.85;
P = 0.0002)
DESTINY-Gastric01 II Trastuzumab deruxtecan vs chemotherapy (Irinote‑ ORR 51% vs. 14%, P < 0.001; mOS 12.5 vs. 8.4 months [132]
can or Paclitaxel) as third or later-line therapy (HR 0.59; 95% CI, 0.39 to 0.88; P = 0.01); mPFS 5.6 vs.
3.5 months (HR 0.47; 95% CI, 0.31 to 0.71)
DESTINY-Gastric02 II Trastuzumab deruxtecan as second-line therapy ORR 41.8%, mPFS 5.6 months (95% CI 4.2– [134]
8.3 months); mOS 12.1 months (95% CI 9.4–
15.4 months)
RC48-C008 II RC48 as third-line therapy and beyond ORR 24.8% (95% CI 17.5%-33.3%); mPFS 4.1 months [137]
(95% CI 3.7–4.9 months); mOS 7.9 months (95% CI
6.7–9.9 months)
VEGF/ VEGFR
RAINBOW III Paclitaxel with vs without ramucirumab as second- ORR 28% vs. 16%, P = 0.0001; mOS 9.6 vs 7.4 months [145]
line therapy (HR 0.81, 95% CI 0.68–0.96; P = 0.017); mPFS 4.4 vs.
2.9 months (HR 0.64, 95% CI 0.54–0.75; P = 0.0001)
REGARD III Ramucirumab vs placebo as second-line therapy ORR 3% vs. 3%, P = 0.76; mOS 5.2 vs. 3.8 months [144]
(HR 0.78, 95% CI 0.61–0.1; P = 0.047); mPFS 2.1 vs.
1.3 months (HR 0.48, 95% CI 0.38–0.62; P < 0.0001)
RAINBOW-Asia III Ramucirumab plus paclitaxel vs placebo plus pacli‑ mPFS 4.14 vs 3.15 months (HR 0.765, 95% CI [146]
taxel as second-line therapy 0.613–0.955, P = 0.0184); mOS 8.71 vs 7.92 months
(HR 0.963, 95% CI 0.771–1.203, P = 0.7426)
Li et al III Apatinib vs placebo as third or later-line therapy ORR 2.84% vs. 0.00%, P = 0.17; mOS 6.5 vs. 4.7 months [152]
(HR 0.71, 95% CI 0.54–0.94; P = 0.015); mPFS 2.6 vs.
1.8 months (HR 0.44, 95% CI 0.33–0.6; P < 0.001)
ANGEL III Apatinib + BSC vs placebo + BSC as third or later-line In ≥ 3rd-line patients: mOS 5.78 vs. 5.13 months [153]
therapy (HR = 0.93; 95% CI 0.74–1.15; P = 0.4850); mPFS
2.83 vs. 1.77 months (HR = 0.57; 95% CI 0.46–0.79;
P < 0.0001); ORR 6.87% vs. 0%, P = 0.0020; DCR 42.37%
vs. 13.08%, P < 0.0001
In ≥ 4th-line patients: mOS 6.43 vs. 4.73 months
(HR = 0.65; 95% CI 0.46–0.92; P = 0.0195); mPFS
3.52 vs 1.71 moths (HR = 0.38; 95% CI 0.27–0.53;
P < 0.0001)
CLDN18.2
SPOTLIGHT III Zolbetuximab + mFOLFOX6 vs placebo + mFOLFOX6 mPFS 10.61 vs. 8.67 months (HR 0.751, P = 0.0066) [162]
as first-line therapy in patients with CLDN18.2- mOS 18.23 vs. 15.54 months (HR 0.750, P = 0.0053)
positive and HER-2-negative advanced gastric or GEJ
cancer
GLOW III Zolbetuximab + CAPOX vs placebo + CAPOX as first- mPFS (8.21 vs 6.80 months, HR 0.687, P = 0.0007) and [163]
line therapy in patients with CLDN18.2-positive and mOS (14.39 vs. 12.16 months, HR 0.771, P = 0.0118)
HER-2-negative advanced gastric or GEJ cancer
FGFR
FIGHT II Bemarituzumab + mFOLFOX6 vs placebo + mFOL‑ ORR 47% vs. 33%; mOS not reached vs. 12.9 months [172]
FOX6 as first-line therapy (HR 0.58, 95% CI 0.35–0.95; P = 0.027); mPFS 9.5 vs.
7.4 months (HR 0.68, 95% CI 0.44–1.04; P = 0.073)
5- FU, 5- fluorouracil; HR, hazard ratio; mOS, median overall survival; mPFS, median progression- free survival; ORR, objective response rate; DCR, disease control rate;
mDoR, median duration of response; CI, confidence interval; NE, not evaluable; BSC, best supportive care
survival [101–103]. Specifically, Shusuke et al. reported and eventually take control, leading to tumor recur-
prolonged survival in homo-HER2 positive GC patients, rence. As a result, resistance to HER2-targeted therapy
defined as all tumor cells overexpressing HER2 in biopsy has been associated with the heterogeneity of HER2
specimens [101]. Tumor cells with HER2 overexpression expression [101, 104, 105]. Discordance between next-
or amplification are killed during HER2-targeted therapy, generation sequencing and FISH/IHC may also indicate
while residual drug-resistant colonies keep proliferating intratumoral heterogeneity and result in an unfavorable
treatment outcome. In addition, there still exist discrep- cal trials have explored newer agents and combinations.
ancies in HER2 status between primary tumor and meta- The following innovative HER2-targeted agents for
static sites, which increases the risk of HER2-targeted advanced metastatic GC are currently under investiga-
therapy failure due to false-positive HER2 detection [106, tion (Table 4): monoclonal antibodies (mAbs) (e.g., mar-
107]. getuximab), bispecific antibodies (BsAbs) (e.g., ZW25,
Loss of HER2 expression KN026), antibody–drug conjugates (ADCs) (e.g.,
For mGC patients experiencing progression on tras- T-DXd, Disitamab vedotin, ARX788), tyrosine kinase
tuzumab, 29–69% of them may experience loss of HER2 inhibitors (TKIs) (e.g., tucatinib), and other novel thera-
expression, which is an important factor responsible for peutic approaches.
resistance [108–110]. Given the risk of HER2 expres-
sion loss during treatment, patients should re-evaluate Monoclonal antibodies
HER2 status upon progression after anti-HER2 therapy Margetuximab
to determine the most optimal treatment. Margetuximab is an Fc-engineered anti-HER2 mAb
Gene amplification that targets the same epitope as trastuzumab but with
Receptor tyrosine kinase (RTK) amplification was com- a higher affinity for single-nucleotide polymorphisms
monly detected in MET-amplified metastatic GC, with of the activating Fc receptor (CD16A) [119, 120]. Mar-
40% to 50% of cases exhibiting co-amplification of either getuximab can recruit CD16A-expressing natural killer
HER2 or EGFR. These patients did not usually respond cells, macrophages and monocytes and further promote
to HER2-targeted therapy, but MET and HER2 combina- antibody-dependent cell-mediated cytotoxicity (ADCC)
tion inhibition could sometimes bring extra clinical ben- [119]. The first phase I study of margetuximab in humans
efit [111]. CCNE1, which encodes the cell cycle regulator illustrated that margetuximab was well-tolerated with
cyclin E1, is another oncogene co-amplified with HER2 in promising efficacy in relapsed HER2-overexpressing car-
metastatic GC. CCNE1 co-amplification has been found cinoma [121]. Later in the phase Ib/II CP-MGAH22-05
to be more strongly related to HER2-positive AGC than study, patients with previously treated HER2-positive
to HER2-positive breast cancer [112]. In a phase II study GC responded effectively to a chemotherapy-free treat-
of lapatinib with capecitabine and oxaliplatin in HER2- ment consisting of margetuximab plus pembrolizumab.
positive AGC patients, CCNE1 amplification was dem- Patients with HER2 IHC3 + and PD-L1 positive (CPS ≥ 1,
onstrated to play a role in resistance to HER2-targeted by IHC) had an ORR of 44% and a DCR of 72% [122].
therapy [113]. A high level of copy number variation for More recently, the phase II/III MAHOGANY trial has
CCNE1 has also been associated with worse survival in reported the efficacy of margetuximab plus anti-PD-1
patients with HER2-positive metastatic GC treated with antibody retifanlimab (Cohort A) for the first-line treat-
trastuzumab [114]. Other studies have also reported that ment of patients with G/GEJ adenocarcinoma, with
deletion of ErbB2 16 exon and co-mutation and/or ampli- an ORR and a DCR of 53% and 73% [123]. The ORR
fication of KRAS, HER3, EGFR, PI3K or PTEN could reported in this trial was superior to the ORR observed
contribute to the resistance of anti-HER2 therapy [109, with other history chemotherapy-free treatments; none-
113, 115, 116]. theless, given that chemotherapy-based regimens remain
Alterations in intracellular signaling the predominant treatment for GC, the MAHOGANY
HER2-targeted therapy suppresses downstream signal- trial has been halted for commercial reasons.
ing pathways by blocking the binding of HER2 receptors
and ligands, which inhibits the migration and prolifera- Bispecific antibodies (BsAbs)
tion of tumor cells and leads to apoptosis. RTK/RAS/ Zanidatamab (ZW25)
PI3K signaling alterations have been shown to be involved Zanidatamab (ZW25) is a novel HER2-targeted bispe-
in the development of resistance to trastuzumab. [109]. cific antibody that binds to HER2 extracellular domain
Furthermore, activation of the bypass pathway might also (ECD) II and IV. According to a phase I study, ZW25
result in resistance. Sampera et al. discovered that SRC- was well tolerated with durable response in heavily pre-
mediated persistent activation of the MAPK-ERK and treated GEA patients (including prior HER2-targeted
PI3K-mTOR pathways was connected to the treatment therapy) [86]. Later in a phase II trial involving patients
resistance in HER2-positive GC cell lines [117]. NRF2 with advanced/metastatic HER2-positive GEA, zanidata-
has also been associated with HER2 resistance by activat- mab plus chemotherapy (CAPOX or FP) showed a con-
ing the PI3K-mTOR signaling pathway [118]. firmed ORR of 75%, mDOR of 16.4 months and mPFS of
12.0 months in the first-line setting [124]. Based on these
Newer HER2‑targeted agents To overcome intrinsic findings, a global phase III study (HERIZON-GEA-01)
and acquired resistance to trastuzumab, various clini- has been designed to assess the efficacy and safety
Table 4 Selected investigational HER2–targeted agents for mGC
Approach Agents Trial Phase Lines Treatment Outcomes References
Monoclonal antibody Margetuximab MAHOGANY II/III 1st line Margetuximab ± PD-1 inhibi‑ Cohort A (margetuximab plus [123]
tor ± chemotherapy ± dual check‑ retifanlimab): ORR 53% (95% CI
point inhibitor 36.1–68.5); DCR 73% (95% CI
56.1–85.4); mPFS 6.4 months (95% CI
6.0-NE); mOS not reached
Bispecific antibodies Zanidatamab (ZW25) Ku, G., et al II 1st line ZW25 + chemotherapy (CAPOX or ORR 75%; mDOR 16.4 months; mPFS [124]
FP) 12.0 months
HERIZON-GEA-01 III 1st line ZW25 + chemotherapy with or Ongoing [125]
without tislelizumab vs. trastu‑
zumab + chemotherapy
KN026 Xu et al II 2nd or later lines KN026 Cohort 1(HER2 IHC3 + or IHC [127]
2 + ISH +): ORR 56% (95% CI 35%-
76%); mDoR 9.7 months (95% CI
4.2- NE); mPFS 8.3 months (95% CI
4.2–11.4); mOS 16.3 months (95%
(2023) 16:57
CI 11.0- NE) Cohort 2 (HER2 IHC

1 + /2 + ISH- or IHC 0/1 + ISH +):
ORR 14% (95% CI 2%-43%); mDoR
6.2 months (95% CI 3.2-NE); mPFS
1.4 months (95% CI 1.4–4.1); mOS
9.6 months (95% CI 3.5–14.9)
PRS-343 - II 2nd or later lines PRS-343 + ramucirumab + paclitaxel; Ongoing NCT05190445
PRS-343 + tucatinib
ADC Trastuzumab deruxtecan (T-Dxd) DESTINY-Gastric01 II 3rd or later lines T-Dxd vs. chemotherapy (Irinotecan ORR 51% vs. 14%, P < 0.001; mOS [132]
or Paclitaxel) 12.5 vs. 8.4 months (HR 0.59; 95%
CI, 0.39 to 0.88; P = 0.01); mPFS 5.6
vs. 3.5 months (HR 0.47; 95% CI, 0.31
to 0.71)
DESTINY-Gastric02 II 2nd line T-Dxd ORR 41.8%, mPFS 5.6 months (95% CI [134]
4.2–8.3 months); mOS 12.1 months
(95% CI 9.4–15.4 months)
RC48 RC48-C008 II 3rd or later lines RC48 ORR 24.8% (95% CI 17.5%-33.3%); [137]
mPFS 4.1 months (95% CI 3.7–
4.9 months); mOS 7.9 months (95%
CI 6.7–9.9 months)
ARX788 Zhang, Y., et al I 2nd or later lines ARX788 ORR 37.9% (95% CI 20.7%-57.7%); [138]
DCR 55.2% (95% CI 35.7%-73.6%);
mPFS 4.1 months (95% CI 1.4-
6.4 months); mOS 10.7 months (95%
CI 4.8-not reached)
Page 16 of 28
Table 4 (continued)
(2023) 16:57
Approach Agents Trial Phase Lines Treatment Outcomes References
TKI Tucatinib MOUNTAINEER-02 II/III 2nd-line Phase II: Tucatinib + trastu‑ Ongoing NCT04499924
zumab + ramucirumab + paclitaxel
Phase III: Arm A: Tucatinib + trastu‑
zumab + ramucirumab + paclitaxel
Arm B: Placebo + ramu‑
cirumab + paclitaxel
Arm C: Tucatinib + ramu‑
cirumab + paclitaxel
Page 17 of 28
profiles of zanidatamab plus chemotherapy with or with- overall survival in patients with HER2 + advanced GC
out tislelizumab versus standard of care (trastuzumab compared with chemotherapy in the later-line settings
plus chemotherapy) for patients with metastatic HER2- [132]. Interestingly, the efficacy and safety of T-DXd
positive GEAs in first-line settings [125]. were also evaluated in exploratory cohorts of patients
KN026 with HER2-low G/GEJ cancers in the DESTINY-Gas-
KN026 mimics the dual effects of trastuzumab and tric01 trial (cohort 1, IHC 2 + /ISH–; cohort 2, IHC 1 +).
pertuzumab by simultaneously binding to HER2 ECD II The confirmed ORR was 26.3% in Cohort 1 and 9.5% in
and IV [126]. In a phase II clinical study, KN026 showed Cohort 2. The median OS was 7.8 months in cohort 1 and
favorable results in patients with HER2-overexpressing 8.5 months in cohort 2[133]. These results provide initial
G/GEJ adenocarcinoma (IHC3 + or IHC 2 + ISH +) with evidence that T-DXd has clinical benefits in patients with
an ORR of 56% [127]. The ongoing phase II/III trial heavily pretreated HER2-low G/GEJ cancers.
(KN026-001) is planned to evaluate the survival benefit Similarly, T-Dxd in the DESTINY-Gastric02 trial also
of KN026 plus chemotherapy in patients with HER2-pos- achieved encouraging results in 2L western GC patients
itive unresectable or advanced G/GEJ adenocarcinoma with a cORR of 41.8% and a median PFS of 5.6 months
upon progression after trastuzumab-containing treat- [134]. Other trials, such as phase III 2L DESTINY-Gas-
ment (NCT05427383). Most recently, the preliminary tric04 and phase III 1L DESTINY-Gastric03, are also in
data presented at ESMO 2022 illustrated that KN026 progress (NCT04379596, NCT04704934).
plus KN046, a recombinant humanized PD-L1/CTLA-4 Disitamab vedotin (RC48)
bispecific antibody, had remarkable efficacy and tolerable Disitamab vedotin (RC48) is a novel HER2-ADC drug
safety in HER2-positive G/GEJ patients without prior independently developed in China, which is composed
systemic treatment [128]. In this phase II study, the ORR of three parts: anti-HER2 extracellular domain anti-
was 77.8%, and the DCR was 92.6%, indicating the need body, MC-Val-Cit-PAB linker, and cytotoxin monome-
for a future randomized clinical trial to confirm the effi- thyl auristatin E (MMAE) [135]. This novel antibody has
cacy of KN026 plus KN046 treatment versus standard of a stronger affinity to HER2 than the standard of care.
care. Unlike T-DM1, disitamab vedotin has a bypass-killing
Other BsAbs effect on nearby tumor cells regardless of HER2 status,
PRS-343 is a BsAb that targets HER2 and the costim- which could help overcome spatial heterogeneity and
ulatory immunoreceptor 4-1BB on immune cells. In enhance anti-tumor effects. RC48 was well tolerated and
patients with advanced HER2-positive solid tumors, showed promising antitumor activity in patients with
including GC, PRS-343 showed anticancer efficacy both HER2-positive advanced GC in a phase I trial [136]. The
alone and in combination with the anti-PD-L1 antibody phase II RC48-C008 trial revealed a significant benefit of
atezolizumab in a phase I clinical study [129]. A phase II RC48 with HER2-overexpressing GC patients who had
study (NCT05190445) is ongoing to investigate the effi- undergone at least two prior lines of therapy, in which
cacy of PRS-343 in combination with ramucirumab and the ORR was 24.8%, mPFS was 4.1 months and mOS was
paclitaxel in patients who have already received treat- 7.9 months [137]. Of note, the ORR of RC48 in patients
ment for HER2-high (IHC 3+ or IHC 2+ with HER2/ with HER2 IHC2 + /FISH- was 16.7%, slightly lower
neu gene amplification) G/GEJ adenocarcinoma and in than in HER2-positive patients. These findings indicated
combination with tucatinib in HER2-low (IHC 1+ or that RC48 exerted considerable anti-tumor effective-
IHC 2+ without HER2/neu gene amplification) G/GEJ ness and tolerable safety in patients with HER2-positive
adenocarcinoma. GC, as well as in those with HER2 low expression GC.
In June 2021, disitamab vedotin was approved in China
Antibody–drug conjugates (ADCs) for the treatment of patients with HER2-overexpressing
Trastuzumab deruxtecan (T-DXd) advanced or metastatic G/GEJ adenocarcinoma who
Trastuzumab deruxtecan (T-DXd) is an antibody–drug received at least two systemic chemotherapy regimens.
conjugate (ADC) composed of an anti-HER2 antibody The ongoing phase III RC48-C007 (NCT04714190)
connected to a cytotoxic topoisomerase I inhibitor via trial aims to evaluate the efficacy and safety of RC48
a cleavable tetrapeptide-based linker [130]. Different as a third-line treatment and beyond in patients with
from T-DM1, T-DXd has a bystander effect on nearby advanced HER2-positive GC.
cells, including those not expressing HER2, thus greatly Other ADCs
enhancing the antitumor effect [131]. This action method ARX788 is another investigational anti-HER2 anti-
is inspiring, particularly for advanced GC patients with body–drug conjugate consisting of HER2-targeted mon-
diverse intratumoral HER2 expression. In the Asia DES- oclonal antibody (mAb) coupled with a highly effective
TINY-Gastric01 trial, T-DXd significantly improved tubulin inhibitor (AS269). ARX788 was well tolerated
and had a promising anti-tumor effect in HER2-positive study also supported the application of ramucirumab
GC patients previously treated with trastuzumab-based plus paclitaxel as second-line therapy in a predominantly
regimens in a phase I multicenter dosage expansion Chinese population with advanced gastric or GEJ adeno-
trial [138]. The ORR was confirmed to be 37.9%, and carcinoma [146]. However, neither ramucirumab nor
the DCR was 55.2%. With a median follow-up period of bevacizumab brought extra survival benefits when added
10 months, the mPFS and OS were 4.1 and 10.7 months, to platinum or fluoropyrimidine chemotherapy in GC
respectively. On March 18, 2021, the FDA granted patients in the first-line settings [147, 148].
ARX788 as an orphan drug for treating HER2-positive Regorafenib is an oral multi-kinase inhibitor tar-
GC. A randomized controlled, multicenter, open-label geting angiogenic, stromal and oncogenic receptor
phase II/III study is underway to assess the efficacy of tyrosine kinases (RTK). Results from a phase III trial
ARX788 as second-line treatment for HER2-positive (INTEGRATE IIa) presented at ASCO GI 2023 dem-
advanced G/GEJ adenocarcinoma (Chinadrugtrials.org. onstrated that regorafenib significantly improved OS
cn: CTR20211583). (4.5 months vs. 4.0 months; HR = 0.52; P = 0.011) in
patients with advanced gastro-oesophageal cancer
Tyrosine kinase inhibitors (AGOC) in later-line settings [149]. Meanwhile, other
Tucatinib studies exploring the efficacy of anti-VEGF and anti-PD1
Tucatinib, a highly selective HER2-directed tyrosine combination in GC populations are also under investi-
kinase inhibitor (TKI), was approved by FDA for HER2- gation. The combination of regorafenib and nivolumab
positive metastatic breast cancer in 2020 and is under had a manageable safety profile and effective antitumor
exploration in GC. In preclinical studies, tucatinib plus activity in a phase I trial for the GC subgroup [150].
trastuzumab demonstrated superior activity compared to INTEGRATE IIb ((NCT0487936)), an international ran-
a single agent in GEC xenograft models [139]. Recently, domized phase 3 trial, is ongoing to compare regorafenib
the phase II/III MOUNTAINEER-02 (NCT04499924) plus nivolumab to standard chemotherapy in pre-treated
was initiated to evaluate the efficacy of tucatinib, tras- patients with AGOC. Besides, lenvatinib plus pembroli-
tuzumab combined with ramucirumab, and paclitaxel in zumab showed promising anti-tumor activity with an
previously treated HER2 + advanced G/GEJ adenocarci- ORR of 69% in the first-line and second-line treatment of
noma [140]. advanced GC [151].
Other novel therapeutic approaches are being under Apatinib is a small molecule VEGFR inhibitor with
investigation, including anti-HER2 CAR-T-cell ther- China Food and Drug Administration (CFDA) approval
apy (NCT04511871, NCT04650451), CAR-natural for the treatment of advanced or metastatic chemother-
killer cell (NK) therapy [141], and CAR-macrophage apy-refractory GC. Apatinib improved median PFS and
(CAR-M) therapy (NCT04660929), B-cell and mono- OS versus placebo in Chinese patients with advanced gas-
cyte-based immunotherapeutic vaccines (BVAC-B), tric or gastroesophageal junction adenocarcinoma in the
BAY2701439 and CAM-H2 targeted HER2 radiother- third line and beyond[152]. Most of the patients in this
apy (NCT04147819, NCT04467515). These widespread trial did not receive prior antiangiogenic therapies since
attempts at HER2-targeted CAR cell therapy in solid they were not standard treatments in China at that time,
tumors may hopefully lead to the development of new so clinical evidence is still lacking for the use of apatinib
drug candidates in patients with HER2-positive GC. in patients who previously received ramucirumab. Unfor-
tunately, no significant improvements were observed in
overall survival (OS) in western populations in the phase
Antiangiogenic therapy III ANGEL clinical trial [153].
Blocking angiogenesis is a key strategy in GC therapy, Fruquintinib is a highly selective VEGFR family kinase
including anti-VEGF monoclonal antibodies, VEGF- inhibitor that targets VEGFR1, 2 and 3 and is indepen-
binding proteins, and VEGF receptor TKIs (Table 5) dently developed in China. Fruquintinib was approved
[142]. Ramucirumab, a typical antiangiogenic monoclo- in China by the NMPA in September 2018 and com-
nal antibody, targets VEGFR-2 and is approved by the mercially launched in late November 2018 as a third-
FDA for treating advanced GC [143]. In the second-line line treatment for patients with metastatic colorectal
REGARD trial, ramucirumab demonstrated significant cancer. In a phase Ib/II study, adding fruquintinib to
improvement in patient OS and PFS versus best support- paclitaxel as second-line treatment for mGC patients at
ive care in metastatic GC [144]. In the RAINBOW trial, recommended phase 2 dose (RP2D) showed an mPFS
when coupled with paclitaxel, ramucirumab significantly of 4 months and mOS of 8.5 months. In the 4 mg dose
prolonged overall survival compared to paclitaxel alone cohort of 27 patients with evaluable tumor response,
[145]. Similarly, results from RAINBOW-Asia bridging the ORR was 25.9% and the DCR was 66.7%[154]. A
Table 5 Summary of other important investigational targeted therapies for HER2-negative mGC
Target Approach Agent Trial Phase Lines Treatment Outcomes References
CLDN18.2 CAR T CT041 Shen et al I 2nd line and CLDN18.2-targeted CAR T ORR 57.1%; [165]
beyond cells (CT041) DCR 75.0%;
6-month
OS rate
81.2%; mPFS
4.2 months (GC
cohort)
VEGFR TKI Levantinib EPOC1706 II 1st and 2nd- Levantinib + pembroli‑ ORR 69%; [151]
line zumab mPFS
7.1 months
LEAP-005 II 3rd line and Levantinib + pembroli‑ ORR 10%; DCR [192]
beyond zumab 48%; mPFS
2.5 months;
mOS
5.9 months (GC
cohort)
Regorafenib REGONIVO Ib 3rd line and Regorafenib + nivolumab ORR 44%; [150]
beyond mPFS
5.6 months
INTEGRATE IIa III 3rd line and Regorafenib vs. placebo mOS 4.5 vs. [149]
beyond 4.0 months;
mPFS 1.8 vs.
1.6 months
Fruquintinib Zhang, Y., et al Ib/II 2nd line Fruquintinib + paclitaxel mPFS [154]
4 months; mOS
8.5 months;
ORR 25.9%;
DCR 66.7% (in
the 4 mg dose
cohort)
FRUTIGA III 2nd line Fruquintinib + paclitaxel Ongoing NCT03223376
vs. placebo + paclitaxel
FGFR Monoclonal Bemaritu‑ FIGHT II 1st line Bemarituzumab + mFOL‑ ORR 47% vs. [172]
antibody zumab FOX6 vs placebo + mFOL‑ 33%; mPFS 9.5
FOX6 vs. 7.4 months
TKI Futibatinib Meric-Bern‑ I 3rd line and Futibatinib ORR 22.2%; [169]
stam, F., et al beyond DCR 55.6% (GC
cohort)
randomized phase III FRUTIGA study has investigated EGFR inhibitors as effective targeted therapies to treat
fruquintinib plus paclitaxel versus paclitaxel alone in advanced GC (Table 5). Although emerging innovative
patients with advanced gastric or gastroesophageal junc- drugs have made remarkable progress in GC treatments,
tion (GEJ) adenocarcinoma who had progressed after extensive clinical explorations are needed to advance pre-
first-line standard chemotherapy (NCT03223376). Initial cision medicine.
results from FRUTIGA showed that fruquintinib com-
bined with paclitaxel showed significant improvements CLAUDIN 18.2‑targeted therapy Claudin 18.2 (CLDN18.2),
in PFS, ORR and DCR. Full detailed results are still being a component of intercellular junctions [155], is exclusively
analyzed and will be revealed soon. detected in gastric mucosa and absent from other healthy tis-
sues. Upon malignant transformation, CLDN18.2 expression
can be retained in various tumor tissues, including G/GEJ
Other biomarker‑targeted therapy cancer and especially diffuse-type GC [156]. The prevalence
Novel diagnostic techniques have contributed to char- of CLDN18.2 overexpression in GC varies wildly among
acterizing the genetic profile of GC and identifying studies ranging from 14.1% to 72% [157–159].
new potential molecular targets. Recently, researchers Zolbetuximab is a chimeric IgG1 monoclonal antibody
have looked into Claudin-18.2-targeted therapy, fibro- that binds to CLDN18.2 and induces antibody-dependent
blast growth receptor (FGFR) pathway inhibitors, and and complement-dependent cytotoxicity [160]. To date,
zolbetuximab has shown great potential to become a val- FGFR‑targeted therapy FGFR1 mutations, FGFR2
uable target in GC. In the phase II MONO study, single- amplifications, and FGFR3 rearrangements are the most
agent zolbetuximab achieved an ORR of 9% and a disease common FGFR alterations in GC [166]. Different types
control rate of 23% in 43 patients with previously treated of FGFR targeting agents were explored or developed in
oesophageal or G/GEJ cancers [161]. A randomized GC, including multikinase inhibitors, pan-FGFR inhibi-
phase II study (FAST) indicated that zolbetuximab plus tors, FGFR1-3 inhibitors, selective FGFR inhibitors and
first-line chemotherapy significantly improved PFS and ADC. Nevertheless, most multikinase inhibitor studies
OS in patients with CLDN18.2-positive G/GEJ cancer were preclinical or single case reports in GC without
[159]. Subgroup analysis indicated a correlation between robust clinical evidence [167]. Futibatinib, an irrevers-
moderate-to-strong CLDN18.2 expression and a better ible and highly selective FGFR1–4 inhibitor that perma-
overall survival rate. In the phase III SPOTLIGHT trial, nently disables FGFR2, has been tested in a phase II trial
zolbetuximab plus mFOLFOX6 significantly improved involving patients with advanced-stage solid tumors har-
mPFS (10.61 vs 8.67 months, HR 0.751, P = 0.0066) and boring FGFR alterations, including those with FGFR2-
mOS (18.23 vs 15.54 months, HR 0.750, P = 0.0053) in amplified G/GEJ cancers [168]. Although the ORR was
patients with CLDN18.2-positive and HER-2-negative reported to be 22.2% in the GC cohort [169], more data
advanced G/GEJ cancer[162]. are needed to support the efficacy of multiple FGFR
GLOW (NCT03653507) is another phase III trial inves- inhibitors in different FGFR gene alterations in GC.
tigating zolbetuximab plus CAPOX as first-line treatment Currently, bemarituzumab has shown some promising
in patients with CLDN18.2-positive, HER2-negative, results in the treatment of mGC [170]. It is a first-in-class
locally advanced unresectable or metastatic gastric or GEJ afucosylated monoclonal antibody against the FGFR2b
cancer. In this study, zolbetuximab plus CAPOX showed splice variant frequently overexpressed in FGFR2- ampli-
a significant improvement in mPFS (8.21 vs 6.80 months, fied G/GEJ cancers. In a phase I trial, 17.9% of patients
HR 0.687, P = 0.0007) and mOS (14.39 vs 12.16 months, with FGFR2 amplifications had a confirmed response to
HR 0.771, P = 0.0118) compared to placebo plus bemarituzumab [171]. Based on the safety and activity
CAPOX[163]. Additionally, zolbetuximab is also being profile of bemarituzumab monotherapy in GC, the phase
studied in combination with immunotherapy in patients II FIGHT trial was designed to evaluate the efficacy of
with CLDN18.2-positive advanced gastric or GEJ cancer bemarituzumab plus mFOLFOX6 regimen in previously
in the ILUSTRO study (NCT03505320). untreated, FGFR2b-overexpressing advanced-stage G/
Another promising therapeutic approach targeting GEJ cancers [172]. The trial showed a 2-month improve-
CLDN18.2 employs CLDN18.2-specific chimeric anti- ment in PFS, and the OS was not reached (NR) in the
gen receptor (CAR) T cells. CLDN18.2-specific CAR experimental arm (bemarituzumab + mFOLFOX6).
T cells achieved partial or complete tumor regression in However, the experimental arm had a higher incidence of
CLDN18.2-positive PDX models [164]. A phase I study of adverse events than the control chemotherapy arm, par-
CLDN18.2-specific CAR T cells in gastrointestinal can- ticularly in regard to ocular toxicity.
cers conducted by Prof. Shen Lin’s team demonstrated
that in GC patients, the ORR and DCR were 57.1% and EGFR‑targeted therapy Approximately 5–10% of patients
75.0%, respectively, and the 6-month overall survival rate with G/GEJ cancers have EGFR amplifications or EGFR
was 81.2% [165]. Claudin 18.2 served as a new target for overexpression, both of which are associated with poor
the later-line treatment of GC, with considerable ORR prognosis [173]. Previous large randomized clinical trials
improvement achieved in Claudin 18.2 CAR-T therapy, have failed to demonstrate any significant survival ben-
which has become a hallmark event for cellular immu- efit with EGFR-targeted agents [92, 174], perhaps because
notherapy in solid tumors. Currently, several new drugs most of the studies were performed in unselected patient
focusing on Claudin 18.2, such as Claudin 18.2 bispecific populations regardless of EGFR status. Besides, biomarker
antibodies (Claudin 18.2/CD3, Claudin 18.2/PD-L1) and analysis of the EXPAND and COG trials suggests activity
ADC analogs, are being developed. Although these drugs in patients with tumors expressing high levels of EGFR,
have not been approved for clinical applications, some of thus supporting the significance of patient selection for
them showed promising preclinical data and are being future trials [175, 176]. In a prospective cohort, patients
widely studied in different clinical trials. Since Claudin with metastatic gastroesophageal adenocarcinoma were
18.2 is also expressed on the normal gastric mucosal epi- screened for EGFR amplification and subsequently treated
thelial surface, the risk of adverse reactions and whether with anti-EGFR therapy (cetuximab). The ORR was 58%
ADC drugs may aggravate normal mucosal damage (4 of 7 patients), and the DCR was 100% (7 of 7 patients),
should also be a concern. implying that EGFR inhibition should be further studied in
selected patients [177]. Many of the ongoing EGFR inhibi- progress aim to identify individuals at risk of recurrence
tor studies should test EGFR alterations in the GC patients after treatment. Circulating tumor DNA (ctDNA) can
prior to enrollment to overcome resistance to EGFR-tar- be detected in the circulation of cancer patients and has
geted therapies. the potential to predict minimal residual disease [187].
Liquid biopsies can detect a broader spectrum of abnor-
MET/HGF pathway inhibitors c-Mesenchymal-Epithe- malities in a heterogeneous tumor compared to conven-
lial Transition (c-MET) is a tyrosine kinase receptor from tional tissue biopsies. According to a study investigating
MET families, and hepatocyte growth factor (HGF) is perioperative therapies in patients in the CRITICS trial
the common ligand to c-MET [178]. MET/HGF pathway with resectable GC, the presence of ctDNA could predict
activation is associated with tumor invasiveness and poor recurrence when analyzed within nine weeks after pre-
disease prognosis. The anti-MET monoclonal antibody, operative treatment and after surgery in patients eligible
onartuzumab, has been studied in a phase III trial of onar- for multimodal treatment [187]. These findings high-
tuzumab plus mFOLFOX6 vs placebo plus mFOLFOX6 in light the significance of ctDNA as a biomarker for pre-
patients with metastatic HER2-negative G/GEJ cancers. dicting patient outcomes following perioperative cancer
However, the addition of onartuzumab to mFOLFOX6 treatment and surgical resection in patients with GC. In
did not improve clinical outcomes in the ITT population another 1630-patient cohort of ctDNA results, genomic
or in the MET-positive population [179]. Rilotumumab is alterations were correlated with clinicopathologic charac-
a humanized monoclonal antibody targeting HGF. Two teristics and outcomes and provided prognostic and pre-
phase III trials (RILOMET-1 and RILOMET-2) inves- dictive information [188]. As for advanced GC, ctDNA
tigated rilotumumab plus chemotherapy in advanced also serves as a potential biomarker of immunotherapy
MET-positive G/GEJ cancers. Unfortunately, both stud- response, and its potential role in predicting irAEs is
ies were terminated due to increased number of deaths worth further investigation [189]. Further research aimed
in the rilotumumab group[180, 181]. Additionally, several at prospectively collecting ctDNA is needed to confirm
selective/non-selective c-MET TKIs, such as tinvatinib, these findings. The existence of persistent ctDNA fol-
AMG 337 and foretinib, have also been tested in MET- lowing curative-intent treatment of GC may indicate
positive GC, but no significant benefit was seen in clinical minimal residual disease, and trials are underway to
trials[182–184]. determine whether additional adjuvant therapy can result
in the clearance of ctDNA.
Challenges and future perspectives Intratumoral, intrapatient, and interpatient hetero-
Even though substantial advances have been made in geneity in GC is the major barrier to drug development
the treatment of GC, further research and development for systemic therapies. Most GC patients are not suscep-
are still necessary. Improving early detection, reducing tible to immune checkpoint inhibitor monotherapies.
recurrence and optimizing treatment strategies are the Thus, one of the major challenges in systemic treat-
primary challenges and prospects for GC management. ments for GC is overcoming resistance to ICI therapy.
To increase GC early detection and promote patients’ One strategy is to develop novel ICIs with better efficacy.
overall survival, endoscopic screening programs should Recently, many novel immune checkpoint modulators
be implemented in high-risk regions, and more precise have been widely investigated, including LAG-3, VISTA,
early detection technologies are of great value. In a previ- TIM-3, TIGIT, CD38, CD39, and CD73[190]. Another
ous study, we demonstrated an artificial intelligence (AI) key strategy is combining ICI and other therapies, such
diagnostic platform, GRAIDS, to detect upper gastro- as other ICI, targeted therapies, other immune-modu-
intestinal cancers using real-world endoscopic imaging lating agents, chemotherapy (as discussed above), and
data from six Chinese hospitals with varying experience radiotherapy [191]. As mentioned above, in the Check-
in the endoscopic diagnosis of upper gastrointestinal Mate-649 study, the combination of anti-PD-1 and anti-
cancer [185]. GRAIDS provided both real-time and ret- CTLA-4 agents (nivolumab plus ipilimumab) failed to
rospective assistance for enhancing the effectiveness of improve treatment outcomes compared to traditional
upper gastrointestinal cancer screening and diagnosis, chemotherapy [57]. In the EPOC1706 study, lenvatinib,
with high diagnostic accuracy and sensitivity in detect- an anti-angiogenic multiple receptor tyrosine kinase
ing upper gastrointestinal cancers. In the near future, the inhibitor, combined with pembrolizumab showed an
AI system will help many physicians in community-based exciting activity with an ORR of 69% in the first-line and
hospitals identify upper gastrointestinal cancers more second-line treatment of advanced GC[151]. ICI com-
efficiently and accurately [186]. bined with other anti-immunosuppressive factor agents,
In addition, recurrence of GC remains common such as anti-transforming growth factor-β (TGF-β), is
despite the multimodality treatment, so many studies in also being investigated in clinical trials (NCT04856774).
To fully understand the mechanism of resistance to CPS Combined positive score

CRT Chemoradiotherapy
immunotherapy, factors such as epigenetics, metabolism, CSCO Chinese Society for Clinical Oncology
immune suppression, and microbiota must be consid- ctDNA Circulating tumor DNA
ered. Therefore, the development of combined therapies CTLA-4 Cytotoxic T lymphocyte antigen-4
DCR Disease control rate
should be based on understanding the underlying mecha- DFS Disease-free survival
nisms of immune modulation and resistance, rather than dMMR Mismatch-repair deficiency
simply combining available therapies in a haphazard DoR Duration of response
DOS Docetaxel, oxaliplatin, and S-1
manner. EBV Epstein-Barr virus
Rapid developments are ongoing in the clinical use of EBVaGC Epstein-Barr virus-associated gastric cancer
ADCs and are now considered one of the current hot ECD Extracellular domain
ECF Epirubicin, cisplatin, and fluorouracil
spots for antitumor drug development. In particular, EFS Event-free survival
ADCs have emerged as a new era of targeted therapy in EGFR Epidermal growth factor receptor
the field of GC treatment. The latest generation of ADCs EOX Epirubicin and oxaliplatin
ERBB Erythroblastic leukemia viral oncogene homolog
has expanded the treatment population to include novel ERK Extracellular regulated protein kinase
targets and demonstrated superior clinical outcomes ESMO European Society for Medical Oncology
compared to traditional chemotherapy drugs. Neverthe- FDA Food and Drug Administration
FGFR Fibroblast growth factor receptor
less, certain aspects of ADCs remain to be addressed. FISH Fluorescent in situ hybridization
Firstly, it is necessary to explore ways to advance FLOT Fluorouracil, leucovorin, oxaliplatin, and docetaxel
ADCs as first-line therapy to benefit a larger number FOLFOX Fluorouracil, leucovorin, and oxaliplatin
FP Fluorouracil and cisplatin
of patients. Secondly, to make better use of medical GC Gastric cancer
resources, a more differentiated target layout needs to be GEA Gastroesophageal junction adenocarcinoma
established, moving beyond the focus on distinct targets GEJ Gastroesophageal junction
HER2 Human epidermal growth factor receptor 2
such as HER2. To address these challenges, optimiza- HR Hazard ratio
tion of the toxin, linker and toxicity of ADCs is essential, ICI Immune checkpoint inhibitor
along with the development of ADC-combination thera- IHC Immunohistochemistry
KRAS Kirsten rats sarcomaviral oncogene homolog
pies to improve efficacy. We anticipate the discovery of LAG-3 Lymphocyte-activation gene 3
more potential ADC drugs and expect a breakthrough in mAbs Monoclonal antibodies
first-line treatment. MAPK Mitogen-activated protein kinase
MET Mesenchymal epithelial transition
Currently, many clinical trials have complex treat- MMAE Cytotoxin monomethyl auristatin E
ment regimens, including mono-immunotherapy, dou- MSI Microsatellite instability
ble-checkpoint inhibitors, anti-angiogenic drugs, and mTOR Mammalian target of rapamycin
NCCN National Comprehensive Cancer Network
biomarker-directed therapies [190, 192]. However, the NE Not evaluable
challenge of determining the optimal treatment strat- NK Natural killer
egy and the appropriate timing of molecular biomarker ORR Objective response rate
OS Overall survival
screening has yet to be resolved. We expect that exten- pCR Pathological complete response
sive translational research, preclinical investigations, PD-1 Programmed cell death 1
and multi-omics-based clinical trials will lead to break- PD-L1 Programmed cell death ligand 1
PFS Progression-free survival
throughs in the diagnosis and treatment of GC. There- PI3K Phosphatidylinositol-3-kinase
fore, we eagerly anticipate future studies that have the PTEN Phosphatase and tensin homolog
potential to improve clinical practice in the coming years. RFS Relapse-free survival
RP2D Recommended phase 2 dose
RTK Receptor tyrosine kinase
SOX S-1 and oxaliplatin
Abbreviations
SOXRT S-1, oxaliplatin and radiotherapy
ADC Antibody–drug conjugates
SP S-1 and cisplatin
ADCC Antibody-dependent cell-mediated cytotoxicity
TAP Tumor area positivity
AGOC Advanced gastro-oesophageal cancer
TCGA The Cancer Genome Atlas
AI Artificial intelligence
T-DM1 Trastuzumab emtansine
ASCO American Society of Clinical Oncology
T-DXd Trastuzumab deruxtecan
BsAbs Bispecific antibodies
TGF-β Transforming growth factor-β
BSC Best supportive care
TIGIT T cell immunoreceptor with Ig and ITIM domain
CAPOX Capecitabine and oxaliplatin
TIM-3 T cell immunoglobulin and mucin domain 3
CAR Chimeric antigen receptor
TKIs Tyrosine kinase inhibitors
CCNE1 Cyclin E1
TMB Tumor mutational burden
CF Cisplatin and fluorouracil
VEGF Vascular endothelial growth factor
CFDA China Food and Drug Administration
VISTA V-domain Ig suppressor of T cell activation
CI Confidence interval
XP Capecitabine and cisplatin
CLDN18.2 Claudin18.2
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(Grant No. 82203678 to Y.H.), the Science and Technology Program of Guang‑ 18. Ajani JA, et al. Gastric cancer, version 2, 2022, NCCN clinical practice
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