| Line of treatment and tumor types | Grade I recommendations | Grade II recommendations | Grade III recommendations |
|---|---|---|---|
| First‐line treatment | |||
| HER2 positive (IHC 3+ or IHC 2+ and FISH +) | Trastuzumab combined with oxaliplatin/cisplatin + 5‐FU/capecitabine h (Evidence 1A) | Trastuzumab combined with oxaliplatin/cisplatin + S‐1 h (Evidence 2B) |
|
| HER2 negative | PD‐L1 CPS ≥ 5, FOLFOX/XELOX combined with nivolumab k (Evidence 1A) | SOX combined with nivolumab | |
| PD‐L1 CPS < 5 or undetectable, FOLFOX/XELOX combined with nivolumab k (Evidence 1B) | Single‐agent fluoropyrimidines (5‐FU/capecitabine/S‐1) or paclitaxel/docetaxel b, c (Evidence 2B) for patients with poor physical conditions and other clinical situations. | ||
| Oxaliplatin/cisplatin + fluoropyrimidines (5‐FU/ capecitabine/S‐1) b‐e (Evidence 1A) | Three‐drug combination regimens, i.e., DCF and mDCF (Evidence 1B) for patients in good physical conditions and with large tumor burden b | PD‐L1 CPS ≥ 1, pembrolizumab monotherapy l (Evidence 2B). | |
| Paclitaxel/docetaxel + fluoropyrimidines (5‐FU/ capecitabine/S‐1) b‐d (Evidence 2A) | |||
| MSI‐H/dMMR, regardless of HER2 status | Pembrolizumab m (Evidence 2B) | Nivolumab + ipilimumab m (Evidence 2B) | |
| Nivolumab combined with FOLFOX/XELOX m (Evidence 2B) | |||
| Pembrolizumab combined with PF m (Evidence 2B) | |||
| Other immune checkpoint inhibitors m (Evidence 3) | |||
| Chemotherapy alone m (Evidence 3) | |||
| Second‐line treatment | |||
| HER2 positive (IHC 3+ or IHC 2+ and FISH +) | If trastuzumab has been previously used:
|
For those who failed with platinum therapy and did not receive trastuzumab, trastuzumab in combination with paclitaxel is recommended h (Evidence 2a) |
If trastuzumab has not been previously used, trastuzumab in combination with second‐line chemotherapy regimens other than anthracycline is recommended. (Evidence 3) Refer to the second‐line chemotherapy drug selection for HER2‐negative gastric cancer. Encourage participation in clinical trial. |
| HER2 negative |
|
Two‐drug chemotherapy, according to the previous regimens: | If there is no previous platinum treatment failure, oxaliplatin‐ or cisplatin‐based regimens can be considered (Evidence 3). |
| MSI‐H/dMMR, regardless of HER2 status |
Envafolimab (Evidence 2A)* Tislelizumab (Evidence 2A)* |
Pembrolizumab (Evidence 2B)* | If previously used PD‐1/PD‐L1 monotherapy, select second‐line treatment based on HER2 status n (Evidence 3) |
| Third‐line treatment | |||
| HER2 positive (IHC 3+ or 2+) |
Disitamab vedotin i (Evidence 2A) Apatinib j (Evidence 1A) Nivolumab monotherapy o (Evidence 1A)* |
Select monotherapy chemotherapy based on past anti‐tumor drug use and referring to second‐line Recommended regimens g (Evidence 3) | |
| HER2 negative |
Afatinib j (Evidence 1A) |
Encourage participation in clinical trials. | |
Abbreviations: HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; FISH, fluorescent in situ hybridization; dMMR, deficient DNA MMR; MSI‐H, microsatellite instability‐high; 5FU, 5‐fluorouracil; PD‐L1, programmed death ligand‐l; PD‐1, programmed death protein‐1; CPS, Combined Positive Score; ELOX, capecitabine (Xeloda) and oxaliplatin (Eloxatin); FOLFOX, folinic acid (leucovorin), 5‐FU, and oxaliplatin; mDCF, modified docetaxel, cisplatin and 5‐FU; PF, cisplatin plus 5‐FU;
PD‐1/PD‐L1 monoclonal antibodies have not been previously used.
Notes
The overall prognosis of advanced gastric cancer remains poor. The development of chemotherapeutic drugs stepped into a bottleneck period. The selection of targeted drugs remains limited. The current efficacy of immunotherapy alone was unsatisfactory. In the era of precision medicine, considering the high heterogeneity of gastric cancer, the dilemma of precision therapy and the exploration of new anti‐tumor drugs, patients with advanced gastric cancer should be encouraged to participate in clinical trials.
Fluoropyrimidines, platinums and taxanes are the main chemotherapeutic drugs for gastric cancer. First‐line chemotherapeutic regimens are generally dual‐ or triple‐drugs regimen which is based on fluoropyrimidines in combination with platinum and/or taxanes [153, 154, 155, 156, 157, 158, 159, 160, 161, 162]. In China, the dual‐drug regimen consisting of fluoropyrimidine and platinum is recommended, and oxaliplatin is preferred over cisplatin, based on Chinese real‐world data and better tolerability [157, 161]. In the phase III SOX‐GC clinical trial [161], the efficacy of SOX and SP as first‐line treatment in diffuse or mixed advanced gastric/EGJ adenocarcinoma was compared. The results showed that compared with the SP regimen, the SOX regimen was associated with improved efficacy, survival and tolerance, and was then recommended as the first choice of treatment for non‐intestinal type gastric cancer. Paclitaxel combined with fluorouracil has shown sufficient efficacy and safety in clinical research and practice [158]. Although the three‐drug DCF regimen has attained its endpoint in phase III clinical trials, its high toxicity limits its clinical application [159]. The modified docetaxel plus cisplatin plus 5‐FU (mDCF) [160] and paclitaxel plus oxaliplatin and 5‐FU (POF) regimens [163] were shown to be more effective and tolerable than the two‐drug regimens in randomized trials. However, a phase III study found that the addition of docetaxel to cisplatin and S‐1 did not improve the OS in chemotherapy‐naïve, unresectable or recurrent gastric cancer [164]. The choice of chemotherapy regimen should be based on the patient's age, physical condition, accompanying diseases, previous treatment, patient's willingness, economic status, possible clinical practice bias, and drug accessibility.
There is no sufficient evidence to recommend chemotherapeutic drugs based on the prediction of chemotherapeutic response according to the Lauren classification, molecular classification, in vitro drug susceptibility test, xenograft transplantation model, xenobiotic metabolism, or metabolomics. Patients suspected of fluoropyrimidine‐associated metabolic disorders are advised to undergo a dihydropyrimidine dehydrogenase deficiency (DPD) test [165], and those suspected of irinotecan‐associated metabolic disorders can undergo the UGT1A1 gene polymorphism testing [166].
The standard treatment for late‐stage gastric cancer usually lasts 4‐6 months, and these patients should be regularly followed‐up after disease control. A phase III randomized controlled trial revealed that sequential therapy, involving the combination of paclitaxel and capecitabine for 4 cycles followed by single‐agent capecitabine, did not result in an extension of overall survival compared to six cycles of cisplatin combined with capecitabine but significantly improved quality of life and decreased treatment‐related adverse events [158]. This study marked a milestone as the first large‐scale prospective clinical investigation into maintenance therapy for gastric cancer. Findings from the phase III JAVELIN G100 study showed that in first‐line treatment, continuing avelumab monotherapy maintenance after achieving disease control with chemotherapy extended OS in the PD‐L1 CPS ≥ 1 subgroup but did not yield the same benefit in the overall population [167]. With the advent of immunotherapy and targeted therapy in first‐line treatment, sequential maintenance therapy following chemotherapy has become a common choice in clinical practice. Studies such as KEYNOTE‐062, CheckMate 649 and various Chinese phase III clinical trials have explored various maintenance therapy patterns, with the most common being single‐agent immunotherapy/targeted therapy, followed by combinations of these agents with capecitabine or combinations of targeted and immune agents. Presently, the optimal maintenance therapy approach for first‐line treatment of advanced gastric cancer remains undetermined.
Studies have shown that two‐drug regimens for reducing dosage were better than single‐drug regimens for elderly or frail patients [168, 169]. In the GO2 study [156], elderly or frail patients were randomly assigned to the following three dose levels: A: oxaliplatin 130 mg/m2 + capecitabine 625 mg/m2 (twice daily on days 1‐21, every 3 weeks); B: 80% dosage of Level A; C: 60% dosage of Level A. The results showed that, compared to Level A and B doses, patients with Level C doses not only had non‐inferior outcomes in terms of PFS but also had better overall treatment utility (overall therapeutic efficacy, toxicity, and quality of life).
Currently, the second‐line chemotherapy in phase III clinical trials is based on single‐drug treatment, but there are small‐sample phase II studies that show that for patients with PS = 0‐1, two‐drug chemotherapy regimens are safe and can bring improved tumor control [170, 171]. Therefore, for patients with good physical condition, after fully weighing the pros and cons of treatment, combined chemotherapy can be considered. The Japanese ABSOLUTE phase III clinical trial showed that weekly nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) was not inferior to weekly solvent‐based paclitaxel in terms of OS [172]. Neutropenia and loss of appetite were more common in the nab‐paclitaxel group, but the rate of hypersensitivity was lower.
Clinical studies regarding third‐line treatment for advanced gastric cancer, although comprised of a limited number of patients, did not find significant benefit from chemotherapy in this group of patients. Although the phase III TAGS study showed that trifluridine/tipiracil (TAS‐102) provided a survival benefit in third‐line treatment, no Chinese patients were included in the study [173]. The risks and benefits of treatment should be carefully weighed depending on the patients’ physical condition, underlying diseases, tumor‐related symptoms, and risk of complications.
ToGA trial [174] showed that, compared with chemotherapy alone, trastuzumab combined with first‐line chemotherapy was associated with improved efficacy and survival in HER2‐overexpressed, treatment‐naïve, advanced or metastatic gastric cancer patients. Several phase II clinical studies have evaluated the combination of trastuzumab and other chemotherapeutic regimens and shown good efficacy and safety [175, 176]. The EVIDENCE study was designed to evaluate the efficacy, safety, treatment model, and clinical outcomes of trastuzumab in Chinese HER2‐positive metastatic gastric cancer patients. It included 1,600 patients and further confirmed the efficacy and good safety of trastuzumab in the Chinese population. Among the first‐line combined chemotherapeutic regimens, XELOX had the best outcome with an OS of 34.6 months [177]. For HER2‐positive advanced gastric cancer patients without prior use of trastuzumab, paclitaxel combined with trastuzumab was found to be effective and safe in a phase II clinical study [175]. However, for HER2‐positive advanced gastric cancer patients who have previously failed to receive first‐line treatment with trastuzumab, recent Chinese or international phase II and retrospective studies showed controversy over the value of trastuzumab as cross‐line therapy, lacking high‐level evidence‐based medical evidence [175]. The 2020 “Chinese expert consensus on drug analogues” approved the clinical substitution of drug analogues. In August 2020, the National Medical Products Administration (NMPA) of China approved the indications of trastuzumab analog HLX02 for HER2‐positive breast cancer and the combination of capecitabine/5‐FU and cisplatin for newly diagnosed, metastatic, HER2‐positive gastric cancer. Immunotherapy has become an important exploration direction for the combined treatment of HER2 positive advanced gastric cancer. Several Phase II studies have shown that for HER2‐positive advanced gastric cancer patients, first‐line treatment with chemotherapy, trastuzumab and PD‐1 monoclonal antibody achieved a high overall response rate (ORR) and significantly prolonged PFS than previous survival data [178]. Phase III KEYNOTE‐811 clinical trial [179] involved 434 previously untreated patients with advanced HER2‐positive gastric cancer. A mid‐term analysis of 264 enrolled patients showed that compared to the control group treated with trastuzumab and chemotherapy, the further combination of pembrolizumab resulted in a significantly higher response rate (74.4% vs 51.9%; P = 0.00006). In May 2021, the FDA accelerated the approval of pembrolizumab combined with trastuzumab and fluoropyrimidine and platinum chemotherapy as first‐line treatment for unresectable locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma patients.
Other HER2‐targeted drugs included pertuzumab (anti‐HER2 monoclonal antibody (mAb), JACOB study) [180], lapatinib (small molecule tyrosine kinase inhibitor; LOGIC study and TyTAN study) [181, 182], Disitamab vedotin (ADC and C008 studies [183]) and trastuzumab deruxtecan (T‐DXd) (ADC, DESTINY‐Gastric01 and 02 studies [184, 185]). The phase III study of trastuzumab emtansine (T‐DM1) in second‐line treatment of gastric cancer showed negative results [186]. The phase II multicenter C008 study showed that Disitamab vedotin used in advanced gastric cancer patients with HER2 positive expression (IHC 2+ or 3+) who had previously received ≥2 lines of therapy achieved an ORR of 24.4% and a median OS of 7.6 months [183] . In June 2021, China NMPA conditionally approved Disitamab vedotin for HER2‐positive expressing advanced or metastatic gastric cancer (including EGJ adenocarcinoma) patients who had previously received ≥2 lines of therapy. Phase II study DESTINY‐Gastric01 compared the efficacy of T‐DXd with chemotherapy in HER2‐positive advanced gastric cancer patients who had previously failed trastuzumab‐based treatment and revealed that T‐DXd group had a higher ORR (51% vs. 14%, P < 0.001) and a longer median OS (12.5 months vs. 8.4 months; HR: 0.59) compared with chemotherapy [184]. T‐DXd has also shown good results in the second‐line treatment of gastric cancer. The DESTINY‐Gastric02 study included 79 HER2‐positive gastric cancer patients who had failed first‐line trastuzumab‐containing regimens. T‐DXd monotherapy, achieving a response rate of 41.8% and a PFS of 5.6 months [185]. However, this study did not include the Asian population. In January 2021, the U.S. FDA approved T‐DXd for use in advanced or metastatic HER2‐positive gastric or EGJ adenocarcinoma patients who had previously received trastuzumab‐based treatment.
Anti‐angiogenic drugs for advanced gastric cancer included ramucirumab (anti‐VEGFR2 monoclonal antibody) and methanesulfonic acid apatinib (VEGFR‐2 small‐molecule tyrosine kinase inhibitor). For metastatic EGJ/gastric adenocarcinoma that progressed after first‐line platinum and/or fluorouracil‐based chemotherapy, REGARD study [187] showed that ramucirumab monotherapyas second‐line treatment, compared with placebo, could prolong mOS (5.2 vs. 3.8 months, P = 0.047). RAINBOW study [188] showed that compared with paclitaxel alone, ramucirumab combined with paclitaxel as second‐line could prolong mOS (9.63 vs. 7.36 months, P = 0.0169) and had tolerable adverse reactions. Moreover, this combination therapy was associated with manageable adverse reactions. RAINBOW‐Asia phase III study [189] (90% of patients from China) showed that the PFS of patients in the combination of ramoxizumab and paclitaxel group was significantly longer than that of the paclitaxel group (4.14 months vs 3.15 months) and showed a median OS benefit consistent with results from the global key registered clinical trial RAINBOW (HR: 0.963). The patients generally tolerated the treatment well, and no new safety concerns were observed. A phase III clinical study [190] enrolled 273 patients who had failed second‐line or above treatment. The results showed that the apatinib group, compared with the placebo group, could prolong the mPFS (2.6 vs. 1.8 months, P < 0.001) and increase the disease control rate (42.05% vs. 8.79%, P < 0.001). Apatinib was approved for third‐line or above treatment in patients with advanced gastric or EGJ adenocarcinoma.
In the phase III clinical trial ORIENT‐16 [191], 650 patients with treatment naïve advanced gastric cancer were enrolled, and the study compared sintilimab plus XELOX chemotherapy with a placebo plus XELOX chemotherapy. For patients with PD‐L1 CPS ≥ 5, the combination of sintilimab with XELOX significantly improved both PFS (7.7 months vs. 5.8 months, HR: 0.628, P = 0.0002) and OS (18.4 months vs. 12.9 months, HR: 0.660, P = 0.0023). The ORR also increased from 48.4% to 58.2%. In the intention to treat (ITT) population, PFS and OS were improved by 1.4 months and 2.9 months, respectively. However, no survival benefits were observed for patients with PD‐L1 CPS < 5. The CheckMate 649 study demonstrated statistically significant survival benefits in the ITT population, including 626 patients with a PD‐L1 CPS score < 5 [192]. Two meta‐analyses also supported the lack of survival improvement in advanced gastric cancer patients with PD‐L1 negative or low expression [193, 194]. Considering the clinical practice in China, it is recommended that for patients with PD‐L1 CPS < 5 or when PD‐L1 testing is not available, the combination of XELOX/FOLFOX with nivolumab or XELOX with sintilimab may be considered, especially in cases whose tumor burden is substantial, the patient's performance status is good, there's a need to quickly reduce tumor burden and alleviate symptoms, or when second‐line treatment options are limited, and there are no contraindications to immune checkpoint inhibitors. The RATIONALE 305 study is a global phase III clinical trial that compared the effectiveness and safety of trastuzumab deruxtecan in combination with platinum‐based chemotherapy versus placebo in combination with platinum‐based chemotherapy as a first‐line treatment for locally advanced, unresectable or metastatic gastric or EGJ adenocarcinoma patients [195]. The study's results demonstrated a substantial improvement in median OS among patients who were PD‐L1 positive (TAP score ≥ 5%) in the combination group compared to the control group (17.2 months vs. 12.6 months, HR: 0.74, 95% CI: 0.59‐0.94), which represents a significant 26% reduction in the risk of death. Remarkably, the survival benefit of trastuzumab deruxtecan in combination with chemotherapy was consistent across various patient subgroups, including different age groups, ECOG performance status, gender, race, chemotherapy regimen selection, and the presence of peritoneal metastasis. The combination group also exhibited a marked extension in PFS (7.2 months vs. 5.9 months, HR: 0.67; 95% CI: 0.55‐0.83), indicating a 33% reduction in the risk of disease progression. As a result, trastuzumab deruxtecan in combination with chemotherapy may become a standard first‐line treatment option for advanced gastric cancer patients who are PD‐L1 positive. The ATTRACTION‐4 study enrolled 724 patients and compared SOX/XELOX plus nivolumab with SOX/XELOX plus a placebo using primary endpoints PFS and OS [196]. The findings revealed that the combination of chemotherapy and immunotherapy significantly prolonged PFS (10.45 months vs. 8.34 months, HR: 0.68, P = 0.0007) and elevated the ORR from 47.8% to 57.5%. While the difference in OS (17.45 months vs. 17.15 months, HR: 0.9, P = 0.26) did not reach statistical significance, this may be attributed to the influence of subsequent treatments. Nevertheless, considering that SOX is a widely accepted first‐line chemotherapy regimen in China with established efficacy and safety, SOX in combination with nivolumab, has been included as a Grade III recommendation.
In the phase III KEYNOTE‐062 study [197], among patients with gastric/EGJ cancer with a PD‐L1 CPS score of ≥1, pembrolizumab was found to be non‐inferior to chemotherapy, demonstrating median overall survivals of 10.6 months vs. 11.1 months. Additionally, in the CPS ≥10 subgroup, the pembrolizumab group demonstrated a significant advantage over the chemotherapy group (HR: 0.69). Data from the Asian subgroup revealed that pembrolizumab monotherapy led to a longer OS benefit compared to chemotherapy, with OS of 22.7 months vs. 13.8 months for patients with CPS ≥1 and 28.5 months vs. 14.8 months for patients with CPS ≥10. Pembrolizumab monotherapy also showed superior PFS and ORR in Asian patients compared to the overall population. Therefore, in patients with gastric cancer and a CPS score of ≥1, pembrolizumab monotherapy may be considered when first‐line chemotherapy combined with immunotherapy is not suitable.
dMMR/MSI‐H gastric cancer accounts for approximately 6% of advanced gastric cancer cases [198]. It exhibits significant differences in molecular subtyping characteristics, biological behavior, drug sensitivity, tumor microenvironment, treatment modalities and prognosis compared to pMMR/MSS patients [199]. Its main features include a favorable prognosis, insensitivity to chemotherapy and good response to immunotherapy. Therefore, in this update, it is classified separately for comprehensive management. However, due to the low incidence, there is a lack of large‐sample high‐level evidence in evidence‐based medicine for dMMR/MSI‐H gastric cancer patients, who are often included as non‐predefined subgroups in prospective studies. For example, the KEYNOTE‐062 and CheckMate‐649 studies included 50 and 55 patients with dMMR/MSI‐H gastric cancer, respectively. Hence, there is currently no Grade I recommendation for first‐line treatment for this patient group. Participation in clinical research is encouraged [192, 197]. In the dMMR/MSI‐H gastric cancer subgroup of the KEYNOTE‐062 study, 14, 17, and 19 patients received pembrolizumab monotherapy, pembrolizumab combined with chemotherapy, and chemotherapy alone, respectively. The ORRs and 24‐month survival rates were as follows: pembrolizumab monotherapy 57.1%/71%, pembrolizumab combined with chemotherapy 36.8%/26%, and chemotherapy alone 64.7%/65% [197]. These findings suggest that in first‐line treatment, immunotherapy as monotherapy and immunotherapy combined with chemotherapy are superior to chemotherapy alone. The long‐term survival benefits of immunotherapy monotherapy are more evident and can be considered as Grade II recommendations. Based on clinical practice in China and considering patient affordability, other immune checkpoint inhibitors that are already approved in China can also be considered as Grade III recommendations. Immune combination therapy (pembrolizumab combined with FP or nivolumab combined with FOLFOX/XELOX) is recommended as Grade III, but only when there are contraindications or unavailability of immune checkpoint inhibitors, should chemotherapy alone be considered. In the MSI‐H subgroup of the CheckMate 649 study, dual immunotherapy (nivolumab combined with ipilimumab) compared to chemotherapy had ORRs of 70% and 57%, respectively. OS was significantly extended (not reached vs. 10 months, HR: 0.28), with a 72% reduction in the risk of death in the dual immunotherapy group. The combination therapy group had ORR and OS of 55% and 38.7 months, respectively. Although the dual immunotherapy group was prematurely terminated due to safety concerns, subsequent studies such as CheckMate 142 confirmed the good safety profile of adjusted doses (nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg) [192, 200]. Therefore, adjusted‐dose dual immunotherapy can be considered as Grade III recommendation for first‐line treatment of dMMR/MSI‐H gastric cancer.
In a prospective multicenter phase II clinical study that included patients with advanced solid tumors, including gastric cancer, who had failed standard treatment, a total of 18 patients with gastric cancer were enrolled. Among them, 33.3% had undergone third or higher line of treatments. These patients were given envafolimab, and the ORR, disease control rate (DCR), duration of response (DoR) for ≥ 12 months, 12‐month PFS, and 12‐month OS were 44.4%, 83.3%, 100.0%, 58.0%, and 83.3%, respectively. However, the PFS and OS were not reached. Compared to the KEYNOTE‐016 study, this study was conducted in a larger sample of Chinese patients and demonstrated good safety. Envolizumab has received conditional approval for the indication of advanced dMMR/MSI‐H solid tumors through a priority review process. Therefore, in the second‐line treatment population who have not previously received PD‐1/PD‐L1 monoclonal antibody inhibitors, it can be considered as a Grade I recommendation [201]. In a phase II study, RATIONALE‐209 [202], which included 80 patients with locally advanced unresectable or metastatic MSI‐H/dMMR solid tumors, monotherapy with toripalimab was used. Among the 9 patients with gastric cancer/EGJ), 1 achieved CR and 4 achieved progressive response (PR), resulting in an ORR of 55.6%, with good safety. On March 11, 2022, the China NMPA approved the use of toripalimab for locally advanced unresectable or metastatic MSI‐H/dMMR solid tumors after failing previous treatments [202]. For patients who have received ICI therapy as first‐line treatment, second‐line treatment is recommended based on HER2 status. A prospective clinical study comprising 68 patients with MSI‐H/dMMR advanced malignancies who had failed standard treatment gave them serplulimab, and the patients demonstrated an ORR of 39.7%, a 12‐month DoR of 92.1%, and a 12‐month OS of 74.5% [203]. Among the 3 gastric cancer patients who had received second‐line treatment, with a median follow‐up time of 7.16 months, 1 achieved PR and had an ORR of 33.3%. Due to the limited sample size, more clinical data accumulation is needed for MSI‐H gastric cancer patients who have failed standard treatment and are treated with serplulimab.
Based on the ATTRACTION‐2 study [204], nivolumab monotherapy was approved for third‐line treatment of advanced gastric cancer. However, with the publication of first‐line studies like CheckMate 649, which have reshaped the landscape of first‐line immunotherapy for gastric cancer, there are few applicable scenarios in clinical practice for third‐line treatment. It should only be considered cautiously in patients who have not received PD‐1/PD‐L1 monoclonal antibody therapy in the first and second lines after evaluating the patient's physical condition, potential risk of hyperprogression, and adverse reactions. Merck announced the voluntary withdrawal of an accelerated approval indication for Keytruda in the United States for the treatment of PD‐L1‐positive locally advanced or metastatic gastric and EGJ adenocarcinoma that has progressed after second‐line or later‐line therapy. Therefore, it is removed from the recommendations for third‐line treatment of gastric cancer.
A phase II clinical study from South Korea comprising patients with treatment‐resistant gastric/EGJ adenocarcinoma reported that among the 61 patients, 6 were positive for EBV infection and had an ORR of 100%, suggesting that EBV infection might be a potential biomarker for predicting potential PD‐1 monoclonal antibody therapy response. However, two observational studies in the Chinese population showed that the efficacy of ICIs in EBV‐positive gastric cancer patients who have failed first‐line treatment is 33.3% [205, 206]. Therefore, whether EBV infection is an accurate key biomarker requires further validation in prospective studies.
Claudin18.2 is moderately to highly expressed in approximately 40% of gastric cancer patients. In the phase III randomized SPOTLIGHT study [207], the patients with advanced gastric/esophagogastric junction cancer who were claudin18.2‐positive and HER2‐negative received zolbetuximab, a Claudin18.2 monoclonal antibody, combined with mFOLFOX6 as a first‐line treatment compared to modified FOLFOX6 chemotherapy alone. The median PFS (10.61 months vs. 8.67 months, HR: 0.751, P = 0.0066) and OS (18.23 months vs. 15.54 months, HR: 0.750, P = 0.0053) improved. In a phase I study initiated by researchers, 28 Claudin18.2‐positive gastric cancer patients who had failed standard treatment received Chimeric antigen receptor (CAR)‐T cell therapy and achieved an ORR of 57.1%. Among 18 patients who had previously failed second‐line treatment, the ORR was as high as 61.1%, with median PFS and OS of 5.4 months and 9.5 months, respectively [208]. In another phase Ib study involving 14 Claudin18.2‐positive gastric cancer patients who had failed second‐line treatment, an ORR of 57.1% with median PFS and OS of 5.6 months and 10.8 months were observed [209]. These results showed significant improvements compared to existing third‐line treatments. Confirmatory studies are currently being conducted for validation.