Current gastric cancer treatment methods and new developments

Stomach cancer is one of the most common types of cancer worldwide, ranking fifth in cancer diagnoses and fourth
in cancer-related deaths worldwide.
Despite tremendous advances in diagnosis and treatment strategies and significant improvements in patient survival, many patients are diagnosed with advanced stages of gastric cancer as they are often asymptomatic until they progress to malignant stages, resulting in a poor prognosis and high recurrence rates
.
Advances in modern molecular technology have revealed the important role
of EGFR/HER2, P53, PI3K, immune checkpoint pathways, and cell adhesion signaling pathways in the occurrence, progression, metastasis, and treatment response of gastric cancer.
These biomarkers and molecular classifications open the way
to more accurate diagnosis and treatment of gastric cancer patients.

Since the first successful gastrectomy in the 80s of the 19th century, in the long-term battle against gastric cancer, diagnostic and treatment strategies have made great progress, and patient survival has also improved significantly
.
A variety of targeted drugs and immune checkpoint inhibitors have been approved for gastric cancer treatment (Figure 1).

In the research of gastric cancer, new signaling pathways and therapeutic targets have received more and more attention and new drug development
.
This article gives a brief introduction
to the current treatment of gastric cancer and the new progress of treatment in recent years.

Figure 1.
Timeline of key findings and treatment progression for gastric cancer

Current treatments for stomach cancer

The treatment and prognosis of gastric cancer depends heavily on the stage of the tumor and is typically evaluated
using the American Joint Commission on Cancer (AJCC) tumor-lymph node-metastasis (TNM) system.
This system describes the degree of tumor invasion of the layers of the stomach wall (class T), the spread of the tumor to nearby lymph nodes (class N), and the migration of cancer cells to other organs (class M).

Surgery is the mainstay of treatment for all stages of
stomach cancer.
Even with advances in chemotherapy, radiation therapy, targeted therapy, immunotherapy, and other treatments, surgery is currently the only cure for
stomach cancer.
The ultimate goal of surgery is to complete a radical resection, meaning that the associated local lymph nodes are eliminated and the cut edge is tumor-free
.
The two most common surgical modalities are oesophageal-small bowel anastomosis
after distal gastrectomy and total gastrectomy.
For patients preparing for surgery, the type of surgery depends on the different stages of clinical tumor node-metastasis (TNM) (Figure 2).

Depending on the patient's physical condition, patients who cannot undergo surgery require individualized care
.
However, studies have shown that perioperative treatment, including preoperative neoadjuvant therapy and postoperative adjuvant chemotherapy, can effectively improve the 5-year survival rate
of gastric cancer patients.

Fig.
2.
Current status of gastric cancer treatment based on stage

For stage I gastric cancer, endoscopic resection, including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), has been shown to be a successful treatment for early-stage gastric cancer and is therefore preferred unless there are significant risk factors, such as lymph node metastasis
.
For patients who do not meet EMR or ESD criteria, gastrectomy with D1 or D2 lymph node dissection
can be performed by laparotomy or laparoscopic surgery.

Stage II gastric cancer is usually performed laparoscopic gastrectomy plus lymph node dissection
.
According to the findings of the large prospective studies JCOG0912 and KLASS01, laparoscopic surgery has been shown to be safe
compared to conventional open surgery.
To improve tumor response rates, XELOX (oxaliplatin plus capecitabine) or S-1 monotherapy
is required postoperatively.
Several clinical trials have shown that adding radiotherapy does not improve overall survival (OS) after gastrectomy, so postoperative radiotherapy
is not recommended.

For stage III advanced gastric cancer, the results of two phase III clinical trials CLASS01 and KLASS02 showed that laparoscopic distal gastrectomy combined with D2 lymph node dissection was safer than traditional open surgery, with less intraoperative bleeding, faster recovery of gastrointestinal function, reduced length of hospital stay, and no significant difference in
long-term survival.
Preoperative neoadjuvant chemotherapy or chemoradiotherapy, and postoperative adjuvant chemotherapy is important
in patients with advanced gastric cancer.
Preoperative neoadjuvant chemotherapy can be used in a variety of regimens, including SOX regimen (oxaliplatin + S-1), XELOX (oxaliplatin + capecitabine), FOLFOX (leucovorin + fluorouracil + oxaliplatin), FLOT (fluorouracil + calcium leucovorin + oxaliplatin + docetaxel).

DT45~50.
4Gy and platinum or paclitaxel are used for preoperative neoadjuvant chemoradiotherapy
.
POSTOPERATIVE ADJUVANT CHEMOTHERAPY IS XELOX OR SOX
.

For stage IV gastric cancer, only systemic anti-tumor drugs can currently be used to prolong a patient's life, as surgery is no longer an option
due to organ metastasis of cancer cells.
Chemotherapy drugs, molecularly targeted therapies and immune checkpoint inhibitors are currently the most widely used systemic anti-tumor drugs
.
Trastuzumab (anti-HER2 drug) and Ramucirumab (anti-angiogenic drug) are two commonly used molecularly targeted drugs
.
In addition, immune checkpoint inhibitors PD-1 monoclonal antibodies, such as nivolumab, can be used to treat refractory cancers
.
According to a phase III clinical study, patients treated with nivolumab had a higher
rate of OS compared with patients who received placebo and supportive therapy alone.

In addition, supportive care is crucial in the treatment of advanced stomach cancer as it can significantly improve the nutritional and psychological state of patients and their survival time
.

Research progress in targeted therapy and immunotherapy for gastric cancer

At present, the development of new drugs for gastric cancer is mainly focused on
targeted therapy and immunotherapy.
Although evidence suggests that many different genes and signaling pathways play a key role in the development and progression of stomach cancer, only a fraction are
available with drugs.
Current drug targets focus on EGFR/HER2 and c-MET pathways associated with cell growth, immune checkpoint pathways associated with immune evasion, and cell adhesion and cell connection signaling pathways associated with invasion and metastasis (Figure 3).

The most successful target in stomach cancer is HER2, which transmits growth signals that induce cell proliferation, motility, and invasion
.
The development of immune checkpoint inhibitors, primarily PD-1 antibodies, has changed the treatment
regimen for stomach cancer.
Other drug targets available in gastric cancer are growth factor receptors such as EGFR, VEGFR, c-MET, and FGFR2, and enzymes involved in epigenetic regulation, such as DNMT and HDAC
.
In addition, a small number of membrane proteins that are overexpressed in gastric cancer cells, including Claudin 18.
2, Trop2, and Mucin 17 (MUC17), are also targets for strategies such as antibodies, ADCs, bispecific antibodies, or CAR-T
.
These drugs are in rapid clinical development and may change the landscape
of stomach cancer treatment in the coming years.

Figure 3.
The main signal transduction pathway of gastric cancer

• HER2 - targeted therapy

Drugs against HER2, including antibodies, ADCs, and small molecule tyrosine kinase inhibitors, are being developed for cancer treatment
.
Trastuzumab is the first drug to be developed to target HER2 and could improve outcomes
in women with HER2-positive breast cancer.
In gastric cancer, adding Trastuzumab to standard chemotherapy for HER2-positive gastric cancer may increase patient survival
.

More recently, among the anti-HER2 monoclonal antibodies under development, Margetuximab has emerged as a promising drug
for the treatment of HER2-positive stomach cancer.
Margetuximab has similar HER2 binding and antiproliferative effects to trastuzumab, while its engineered Fc domain enhances immune system involvement
.
In the Phase Ib/II trial in HER2-positive patients with advanced gastric cancer, 95 HER2+ gastric cancer patients with advanced standard therapy received margetuximab in combination with pembrolizumab with acceptable drug toxicity of 18.
4% and DCR of 53%, supporting a synergistic effect
between anti-HER2 therapy and immunomodulatory therapy.
In June 2020, Margetuximab received FDA approval as an orphan drug
for gastroesophageal cancer.

Although HER2 antibodies were widely used, treatment failed to maintain control of the tumor, eventually developing resistance
.
In order to further enhance the cytotoxic effect of HER2 antibodies, HER2 ADC
was developed.
Trastuzumab deruxtecan (T-Dxd, DS-8201a) is a novel ADC drug consisting of
trastuzumab, a cleavage of tetrapeptide linkers, and a cytotoxic topoisomerase I inhibitor.
Recently, the DS-8201a has achieved positive results
.
The most relevant feature is the "bystander-killing effect," which includes internalization of Trastuzumab deruxtecan mediated by HER2-positive cells, release into the cytoplasm, and subsequent transfer to adjacent HER2-negative cells
.
Thus, trastuzumab can overcome the heterogeneity
of HER2 expression in gastric cancer.
DS-8201 has a higher drug-antibody ratio (approximately 8vs3-4) compared to T-DM1, which is associated with
a higher cytotoxic payload on HER2-positive cancer cells.
In addition, due to the high permeability of the membrane, its high cytotoxic effect can also be prolonged
.
In the Destination-Gastric01 Phase II trial study, 187 patients with advanced gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma were assigned to DS-8201 or chemotherapy of physician-selected (paclitaxel or irinotecan)
after having received at least two prior treatments, including trastuzumab.
Surprisingly, patients using DS-8201a experienced significant improvements
in both ORR (42.
9% versus 12.
5%) and mOS (12.
5 months versus 8.
4 months).
In patients with low expression of HER2+/ISH, the ORR, DCR, mPFS and mOS were 26.
3% (5/19), 89.
5% (17/19), 4.
4 months and 7.
8 months
, respectively.
In patients with HER-2 IHCl+, the ORR was 9.
5% (2/21), the DCR was 71.
4% (15/21), the mPFS was 2.
8 months, and the mOS was 8.
5 months
.
These results suggest that DS-8201a also has clinical benefits
in previously treated patients with gastric cancer with low HER2 expression or GEJ cancer.
These amazing achievements prompted the FDA to approve DS-8201a on January 15, 2021, for patients
with locally advanced or metastatic HER2-positive gastric cancer or GEJ adenocarcinoma who had previously received trastuzumab therapy.

Ditamab vedotin (RC48-ADC) is another novel anti-HER2 ADC drug consisting of
an anti-HER-2 monoclonal antibody, a cleavable linker, and MMAE 。 In a single-arm, open-label, multicenter pivotal phase II clinical study in patients with HER2-positive locally advanced or metastatic gastric cancer, RC48 showed excellent efficacy in 127 patients with advanced gastric cancer who had received HER2 overexpression in the past 2 lines or more of systemic chemotherapy, with an ORR of 24.
4%, a DCR of 42%, mPFS of 4.
1 months, and mOS of 7.
6 months, and the survival status of patients was almost equivalent
to that of second-line therapy 。 On June 9, 2021, Remegen's HER2-targeted ADC drug vedicitumab (RC48) was approved for marketing in China for the treatment of patients with HER2 overexpression locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least 2 systemic chemotherapy, breaking the situation that there are no original domestic new drugs in the field of ADC drugs, which is a
milestone.

ZW25 developed by Zymeworks is a novel bispecific antibody that binds simultaneously to two nonoverlapping epitopes of HER2: extracellular region IV and extracellular region II
.
At the January 2021 ASCO-GI meeting, Zymeworks announced the Phase I clinical results of GEA patients who had received at least second-line therapy (including trastuzumab) with ZW25 alone or in combination with chemotherapy, and the results showed that the ORR was 33%, SD was 27%, PD was 39%, and DCR was 61%
in patients treated with ZW25 alone 。 ZW25 combined chemotherapy was more effective, achieving a confirmed ORR of 54%, including one CR patient, with an SD of 25%, a PD of 21%, and a DCR of 79%.

Median duration of response: 8.
9 months VS 6.
0 months, mPFS 5.
6 months VS 3.
6 months
.

Small molecule tyrosine kinase inhibitors targeting HER2 are also under
development.
Lapatinib, the first dual inhibitor of EGFR and HER2, was approved by the U.
S.
FDA in 2007 for combined chemotherapy in breast cancer
with HER2 overexpression.
In the phase III TRIO-013/LOGiC trial, lapatinib was combined with chemotherapy for HER2-positive gastric and esophageal cancers and unfortunately did not increase OS
.

• EGFR-targeted therapy

Like HER2, EGFR also plays a key role
in various cancer types.
Unlike HER2, EGFR is activated
primarily by mutation rather than gene amplification.
Mutations in the EGFR gene, including point mutations and exon 20 insertion, are the driver mutations
for NSCLC.
However, EGFR mutations in other tumor types, including stomach cancer, are much
rarer.
Cetuximab is a monoclonal antibody against EGFR that is effective
in the treatment of colorectal cancer.
However, the addition of cetuximab to standard chemotherapy in phase III trials did not show any improvement in survival in patients with gastric cancer
.
However, the study did not select EGFR expression, which may have contributed to
its failure.
In an earlier study, researchers identified 19 patients with EGFR-amplified gastroesophageal cancer in
363 screening patients.
The addition of Cetuximab to chemotherapy in this small subset of patients resulted in a high tumor response rate
.
Therefore, anti-EGFR may be effective in carefully selected patients with gastric cancer with high expression of EGFR, which requires more clinical trials to demonstrate this preliminary result
.

• VEGF/VEGFR targeted therapy

In the treatment of stomach cancer, attempts have been made to block angiogenesis, but the results have varied
.
Angiogenesis is mainly regulated
by VEGF/VEGFR signaling.
Strategies to block angiogenic signals include neutralizing VEGF with antibodies, blocking VEGF receptors with antibodies, and inhibiting angiogenic signals
with small molecule tyrosine kinase inhibitors.
Unfortunately, studies targeting VEGF in stomach cancer have not been successful
.
In the phase III AVAGAST study, the anti-VEGF antibody bevacizumab combined with chemotherapy failed to improve the patient's OS
.
However, bevacizumab treatment increased progression-free survival and overall response rates
.

Positive effects
have been achieved against VEGFR in gastric cancer.
In the phase III trial, VEGFR2 antibody ramucirorumab monotherapy had survival benefits
in patients with gastric or gastroesophageal junction cancers.
Apatinib is a selective VEGFR2 small molecule tyrosine kinase inhibitor
approved in China.
In phase III clinical trials, Apatinib monotherapy has shown that Apatinib monotherapy can increase OS in
patients with gastric cancer.
Lenvatinib and Regorafenib are multikinase inhibitors
with anti-VEGFR activity.
These drugs are currently being tested
in early clinical trials with immune checkpoint inhibitors in patients with stomach cancer.
Some positive preliminary results have been observed, and the final efficacy needs to be confirmed
in larger clinical trials.

• C-MET targeted therapy

Rilotumumab is a monoclonal antibody
against c-Met.
In phase II trials, Rilotumumab showed some antitumor effect
in gastric and gastroesophageal cancers.
Unfortunately, in the pivotal phase III RILOMET-1 trial, the addition of rilotumumab to chemotherapy failed to improve the prognosis
of gastric and gastroesophageal cancer.
At present, the research of c-MET inhibitor drugs mainly focuses on
tyrosine kinase inhibitors.
Savolitinib is a selective c-MET tyrosine kinase inhibitor approved in China for the treatment of patients with metastatic NSCLC with MET exon 14-skipping
alterations.
In the VIKTORY trial, Savolitinib had an overall response rate of 50% (10/20) to MET amplified patients, showing great potential
.

• Targeted therapy for FGFRs

There are two main strategies for targeting FGFRs: using TKIs or antibodies
.
AZD4547 (ABSK091) is an inhibitor
of FGFR1/2/3.
The phase II SHIRE trial compared AZD4547 and paclitaxel as second-line treatment
for metastatic gastric cancer with FGFR2 amplification.
Unfortunately, the trial did not show improvement
.

Bemarituzumab is the first antibody
to selectively bind to FGFR2b, block ligand binding and have ADCC.
The Phase II FIGHT trial tested the efficacy
of Bemarituzumab in first-line treatment of patients with metastatic gastric and gastroesophageal cancer.
Adding Bemarituzumab to chemotherapy resulted in a 2-month improvement in progression-free survival (PFS), but failed to prolong OS
.

• Claudin18.
  2 Targeted therapy

Currently, there are multiple strategies to target Claudin 18.
2, including monoclonal antibodies, bispecific antibodies, CAR-T, and ADCs
.
Zolbetuximab (IMAB362) is a Claudin18.
2-targeting antibody
.
The FAST study included patients with
advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma.
Adding Zolbetuximab to chemotherapy improves PFS and OS, and side effects are
manageable.
Zolbetuximab is currently undergoing phase III trials (NCT03653507, NCT03504397).

Zolbetuximab's initial success drew more attention to Claudin 18.
2, particularly CAR-T
.
CT041 is a Claudin18.
2-targeted CAR-T drug
.
In phase I clinical trials, CT041 showed an acceptable safety profile and encouraging ORR
.
These preliminary results suggest that CT041 is likely to have a good effect
in the treatment of gastric cancer.

• Trop2-targeted therapy

Sacituzumab goitecan is an ADC drug approved by the US FDA in 2020 for the third-line treatment
of metastatic TNBC.
Clinical trials are underway to expand the use
of Sacituzumab goitecan in a variety of solid tumors, including stomach cancer.

• Immune checkpoint-targeted therapy and other immunotherapies

Immunotherapy is a breakthrough
in cancer treatment over the past decade.
Immunotherapy for stomach cancer has also made very rapid progress
.
Tumor immunotherapy mainly includes checkpoint inhibitors, adoptive immune cell therapy and tumor vaccines
.
Checkpoint inhibitors have been approved for the treatment of various types of
solid tumors.
Immune cell therapies and cancer vaccines are still under clinical research
in entities.

According to TCGA classification, gastric cancer of MSI or EBV+ subtypes has high immunogenicity and high expression of immune checkpoints, and is a good candidate for tumor immunotherapy
.
At present, PD-1 inhibitors have been successfully used in the treatment
of gastric cancer.
The phase III study evaluated the efficacy of the PD-1 inhibitor nivolumab in repetitive treatment of advanced gastric and gastroesophageal junction (G/GEJ) cancer, and based on 2-year follow-up, OS was significantly prolonged
in the nivolumab group regardless of tumor PDL1 expression.
In the Phase III Keynote-062 trial, the PD-1 inhibitor pembrolizumab, alone or in combination with chemotherapy, was tested as a first-line treatment for advanced gastric cancer
.
This trial found that pembrolizumab was not inferior to chemotherapy and observed fewer
adverse effects.
PD-1 inhibitors may also benefit HER2-positive stomach cancer
.
In the Phase III Keynote-811 study, pembrolizumab was added to standard Trastuzumab plus chemotherapy for HER2-positive gastric or gastroesophageal junction cancers
.
According to the interim analysis, the addition of pembrolizumab significantly reduced tumor size and significantly increased
ORR.

CTLA-4 is another important checkpoint
.
Unfortunately, CTLA-4 checkpoint inhibitors have not been successful
in gastric cancer.
New strategies
for combining PD-1 and CTLA-4 inhibitors have been tried.
Cadonilimab (AK104) is the first PD-1/CTLA-4 bispecific antibody
developed by Akeso.
In 2022, it was approved by the China Medical Products Administration for the treatment of patients with recurrent or metastatic cervical cancer who
have previously failed platinum-based chemotherapy.
In a Phase Ib/II study, AK104 was used in combination with chemotherapy for first-line treatment of G/GEJ cancer (NCT03852251).

AK104 shows good activity and controlled safety
.
A Phase III study of AK104 in combination with chemotherapy as a first-line treatment for G/GEJ cancer is ongoing (NCT05008783).

Adoptive immune cell therapy is another rapidly developing area
of immunotherapy.
CAR-T therapy is the core of
adoptive immune cell therapy.
CAR-T therapy is very effective in treating hematopoietic tumors, and so far, several CAR-T therapies
have been approved worldwide.
However, CAR-T therapy is still difficult in treating solid tumors, and no CAR-T therapy has been approved for solid tumors
.
As mentioned earlier, Claudin18.
2 targeted CAR-T is being tested in patients with gastric cancer, and preliminary results have shown very good efficacy
.
Oncology vaccines are still in early clinical development, and their potential in cancer treatment needs to be further validated
.

Editor's summary

In recent years, the treatment of gastric cancer has developed rapidly, and some new targeted drugs and immune checkpoint drugs have been approved for the treatment of gastric cancer, greatly improving the survival benefits
of gastric cancer patients.
However, the drugs currently available in clinical practice are still limited, and more innovations are still needed in the future to accelerate the development of
gastric cancer drugs.

References

1.
Signaling pathways and therapeutic interventions in gastric cancer.

2.
State-of-the-Art of monoclonal antibodies for the treatment of gastric cancer.