Grade I recommendations	Grade II recommendations	Grade III recommendations
Apatinibj (Evidence 1A)	Pembrolizumab monotherapy for PD‐L1 CPS ≥ 1 patientsk (Evidence 1B)	According to the previous drug use, refer to the second‐line recommendations for selection of single drug chemotherapyg (Evidence 3)
Nivolumab monotherapyk (Evidence 1A)

Abbreviations: PD‐L1 CPS, programmed death ligand‐1 combined positive score;

Notes

^aThe overall prognosis of advanced gastric cancer is poor. Traditional chemotherapy drugs remain among the last evidence‐based treatments available as the choice of targeted drugs remains limited and the efficacy of immunotherapy alone has not been satisfactory. Thus, considering the heterogeneity of gastric cancer, these patients are encouraged to participate in clinical trials for the advancement of precision medicine.

^bFluoropyrimidine, platinum, and taxanes are the main therapeutic drugs for late‐stage gastric cancer. Usually, first‐line regimens are based on fluoropyrimidine combined with platinum and/or taxanes to constitute a two‐ or three‐drug regimen [122, 128‐¹³⁶]. In China, the two‐drug therapy consisting of fluoropyrimidine and platinum is recommended, and oxaliplatin is preferred over platinum‐based on Chinese real‐world data and better‐observed tolerability [130, 134]. In the phase III SOX‐GC clinical trial [134], 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 a certain extent of improved efficacy, survival, and tolerance. Further, the rates of grade ≥3 adverse events, such as neutropenia, anemia, nausea, vomiting, nausea, vomiting, anorexia (except neurosensory toxicity), were significantly lower in the SOX group than in the SP group. Therefore, the SOX regimen is 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 [131]. Although the three‐drug DCF regimen has attained its endpoint in phase III clinical trials, its high toxicity limits its clinical application [132]. The modified docetaxel plus cisplatin plus 5‐FU (mDCF) [133] and paclitaxel plus FOLFOX (POF) regimens [137] 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 [138]. A phase II study showed that the efficacy and survival rate of docetaxel plus oxaliplatin plus 5‐FU (TEF) was superior to docetaxel plus oxaliplatin (TE) or docetaxel plus oxaliplatin plus capecitabine (TEX) regimens [139]. 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.

^cThere 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 [140], and those suspected of irinotecan‐associated metabolic disorders can undergo the UGT1A1 gene polymorphism testing [141].

^dThe 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 study showed that first‐line chemotherapy with paclitaxel plus capecitabine therapy followed by capecitabine for maintenance (PACX) was not associated with improved median progression‐free survival (mPFS) and mOS, compared to the XP regimen, but significantly improved quality of life and decreased treatment‐related adverse events [131].

^eStudies have shown that two‐drug regimens were better than single‐drug regimens for elderly or frail patients [142, 143]. In the GO2 study [136], 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 dose, patients with Level C dose 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).

^fCurrently, the results of studies for second‐line chemotherapy comparing the efficacy of single‐drug treatment showed that for patients with Eastern Cooperative Oncology Group performance score (ECOG PS) 0‐1, two‐drug chemotherapy was safe and was associated with better tumor control, although the investigated cohort size was relatively small [144, 145]. 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 [146]. Neutropenia and loss of appetite were more common in the nab‐paclitaxel group, but the rate of hypersensitivity was lower.

^gClinical studies regarding third‐line treatment for late‐stage gastric cancer, although comprised of a limited number of patients, and did not find significant benefit from chemotherapy in this group of patients. 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.

^hThe ToGA trial [26] showed that, compared with chemotherapy alone, trastuzumab combined with first‐line chemotherapy was associated with improved efficacy and survival in HER2‐overexpressed, treatment‐naïve, late‐stage gastric cancer patients. A number of phase II clinical studies have evaluated the combination of trastuzumab and other chemotherapy regimens, showing good efficacy and safety [147, 148]. The EVIDENCE study [149] was designed to evaluate the efficacy, safety, treatment mode, and clinical outcomes of trastuzumab in Chinese HER2‐positive, metastatic gastric cancer patients. Its findings showed that, compared to chemotherapy alone, trastuzumab was associated with improved OS and PFS in Chinese HER2+ metastatic gastric cancer patients, was well tolerated and effective when combined with a range of other therapies in a real‐world setting. In the case of combined chemotherapy using the XELOX regimen, the best efficacy of trastuzumab demonstrated an OS of 34.6 months [150]. For HER2‐positive late‐stage gastric cancer patients with no prior use of trastuzumab, paclitaxel combined with trastuzumab was found to be effective and safe in a Chinese phase II clinical study [147]. However, after failure with trastuzumab, recent evidence from phase II clinical trials and retrospective analyses suggested different significance for trastuzumab cross‐line application, and more evidence is required [147]. 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 that the indications of trastuzumab analogue HLX02 for HER2‐positive breast cancer and the combination of capecitabine/5‐FU and cisplatin for newly diagnosed, metastatic, HER2‐positive gastric cancer.

ⁱNo positive response from other HER2‐targeted drugs, including pertuzumab (anti‐HER2 mAb, JACOB study) [151], lapatinib (small molecule tyrosine kinase inhibitor; LOGIC and TyTAN study) [152, 153], and antibody‐drug conjugate (ADC) TDM‐1 (drug coupled anti‐HER2 mAb) [154], as second‐line treatment of metastatic gastric cancer in phase II clinical study was observed. The use of ADCs targeting HER2 remains promising.

^jRamucirumab (anti‐VEGFR2 mAb) and apatinib mesylate (VEGFR2 small‐molecule tyrosine kinase inhibitor) are the common anti‐angiogenic drugs for late‐stage gastric cancer patients. For metastatic gastric/EGJ adenocarcinoma that progressed after first‐line platinum‐ and/or fluorouracil‐based chemotherapy, the REGARD study [155] showed that ramucirumab monotherapy, compared with placebo, as second‐line treatment could prolong the mOS (5.2 vs. 3.8 months, P = 0.047). The RAINBOW study [156] showed that compared with paclitaxel alone, second‐line ramucirumab combined with paclitaxel could prolong mOS (9.63 vs. 7.36 months, P = 0.0169) and had tolerable adverse reactions, which led to the approval of ramucirumab alone or in combination with paclitaxel by the U.S FDA as a second‐line treatment for late‐stage gastric cancer. A phase III clinical study [157] which enrolled 273 patients who had treatment failure after using second‐line/subsequent‐lines chemotherapeutic regimens showed that apatinib, compared with the placebo, 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 mesylate is approved for third‐ or higher lines of treatment in patients with advanced gastric or EGJ adenocarcinoma. The CSCO Anti‐tumor Drug Safety management Expert Committee suggests the use of the “Expert Consensus on Clinical Application of Apatinib Mesylate" guidelines to assist clinicians regarding the application and safety of apatinib [158].

^kBased on the results of prospective clinical studies, immune checkpoint inhibitors have been approved for the third‐line treatment of gastric cancer worldwide. In regard to the treatment of Asian populations, results of the ATTRACTION‐2 study [159] showed that the risk of death in patients with recurrent or metastatic gastric or EGJ adenocarcinoma when treated with nivolumab as the third‐line treatment was significantly lower than that of placebo. The 1‐year OS rates of the two groups were 26.2% and 10.9%, respectively. In 2020, the updated 3‐year follow‐up data in ASCO‐GI showed continued survival benefits for patients treated in the nivolumab group [160]. In March 2020, the NMPA of China approved the use of nivolumab for patients with advanced or recurrent gastric/EGJ adenocarcinoma who had received two or more systemic treatment regimens. The results of the KEYNOTE‐059 study [161] showed that pembrolizumab as a third‐line treatment for recurrent or metastatic adenocarcinoma of gastric/EGJ cancer with PD‐L1 CPS ≥ 1 had an OS of 6 months and overall response rate (ORR) of 12%. At present, the use of PD‐1 antibodies in Chinese clinical research of advanced gastric cancer who failed with standard chemotherapy have demonstrated an ORR of 10%‐20% and controllable safety.

^lFor second‐line treatment using immunotherapy in gastric cancer, a clinical trial that enrolled 11 types of dMMR/MSI‐H malignant tumors including gastric cancer that failed conventional treatment showed that treatment with pembrolizumab could be beneficial and was associated with an ORR of 53% and CR of 21% [162]. Results of the KEYNOTE‐061 study [31] showed that compared with paclitaxel, the second‐line treatment with pembrolizumab did not significantly prolong the OS of patients with PD‐L1 CPS ≥ 1, although follow‐up analysis showed that the TMB and PD‐L1 CPS scores were related to pembrolizumab benefit, but pembrolizumab had a better safety profile than paclitaxel. The status of immunosuppressive agents in the treatment of late‐stage gastric cancer has not been confirmed, and it is not recommended to use immunosuppressive agents alone or as combination in routine practice. Patients are encouraged to participate in relevant clinical studies.

^mImmunotherapy strategy for gastric cancer includes PD‐1 mAb or combination with chemotherapy. For combination therapy, there are three phase III randomized controlled trials that compared PD‐1 mAb combined with chemotherapy or chemotherapy alone. Results of the KEYNOTE‐062 phase III clinical study [163] showed that for patients with PD‐L1 CPS ≥ 1, pembrolizumab combined with chemotherapy (capecitabine or 5‐FU + cisplatin) was not associated with significant OS improvements compared to chemotherapy alone. The CheckMate‐649 study [164] showed that for patients with PD‐L1 CPS ≥ 5, the mOS of nivolumab combined chemotherapy (FOLFOX or XELOX) was longer than that of chemotherapy alone (mOS: 14.4 vs. 11.1 months, hazard ratio (HR) = 0.71, P < 0.0001); significant survival benefit was also observed in the secondary endpoint group which consisted of OS in all randomized patients and those with a PD‐L1 CPS of 1 or greater. Further, combination therapy demonstrated PFS benefit in patients with CPS ≥ 1 and in all randomized patients, and statistical significance in patients with CPS ≥5 (mPFS = 7.7 vs. 6.0 months, HR = 0.68, P < 0.0001). Thus, nivolumab combined with FOLFOX/XELOX is recommended for late‐stage gastric cancer with PD‐L1 CPS ≥ 5. The ATTRACTION‐4 clinical trial [165], a phase II/III multicenter randomized clinical trial, evaluated the efficacy and safety of nivolumab plus chemotherapy (SOX/XELOX) versus chemotherapy as first‐line treatment in patients with HER2‐negative, advanced or recurrent gastric/EGJ cancer. The study findings showed that mPFS of the nivolumab plus chemotherapy group was significantly superior to chemotherapy alone (10.5 vs. 8.3 months, HR = 0.68, P = 0.0007). Further, the ORR and duration of response (DoR) of the nivolumab plus chemotherapy group was significantly higher than that of the chemotherapy group (ORR, 57.5% vs. 47.8%, P = 0.0088). However, it should be noted that the mOS of the two groups was similar (17.45 vs. 17.15 months, HR = 0.90), and in regard to ethnicity, only ∼5% of the participants were from Taiwan, China. For patients with unknown PD‐L1 status, conventional therapy combined with PD‐1 mAb is not recommended.

ⁿFor first‐line use of single‐drug immunotherapy in gastric cancer, the KEYNOTE‐059 study showed that for patients with PD‐L1 CPS ≥ 1, pembrolizumab was associated with an ORR of 26%, DCR of 36%, mPFS of 3.3 months, and mOS of 20.7 months [161]. The phase III KEYNOTE‐062 study showed that for patients with PD‐L1 CPS ≥ 1, the OS of pembrolizumab was not inferior to chemotherapy (10.6 vs. 11.1 months), but crossing of their survival curves was observed, and the risk of progression should be considered [163]. It was suggested that pembrolizumab should be considered only in patients with chemotherapy contraindications or who refused chemotherapy, and careful monitoring of their performance status and nutritional function should be implemented. In MSI‐H subgroup, the ORR of the pembrolizumab group was 57.1% (versus chemotherapy, 36.8%) and the mOS was not reached (NR) in both pembrolizumab arms; for comparison, pembrolizumab versus chemotherapy, mOS was NR (95% CI, 10.7 months‐NR) versus 8.5 months (95% CI, 5.3‐20.8 months), respectively, and mOS was NR (95% CI, 3.6 months‐NR) with pembrolizumab plus chemotherapy compared to 8.5 months (95% CI, 5.3‐20.8 months) with chemotherapy. In addition, Asian subgroup analysis showed that pembrolizumab monotherapy was associated with superior survival advantages than chemotherapy, with an OS of 22.7 vs. 13.8 for patients with CPS ≥1 and 28.5 vs. 14.8 for patients with CPS <1. Due to the lack of sufficient data on the risk of over‐progression with pembrolizumab monotherapy, first‐line use of single‐drug immunotherapy is not recommended for patients with PD‐L1 CPS ≥1 but can be considered if chemotherapy contraindications exist. For MSI‐H patients, pembrolizumab monotherapy has shown obvious survival benefit compared with chemotherapy alone, and thus, chemotherapy alone is not recommended in this group of patients.

^oAt present, dMMR/MSI‐H is recognized as a predictor for the efficacy of immunotherapy in gastric cancer [162]. The U.S FDA has approved pembrolizumab and nivolumab as second‐ or third‐line treatment for all patients with solid tumors with MSI‐H or dMMR. Apart from the above clinical studies in which PD‐L1 CPS score was used as a screening criterion, results from the KEYNOTE‐061 study [31] showed that for patients with PD‐L1 CPS ≥1, 5, and 10, compared with paclitaxel alone, pembrolizumab was associated with an extended OS of 0.8, 1.9, and 2.4 months, respectively, showing an association between PD‐L1 CPS score and treatment response, which was also confirmed in the CheckMate649 study [164]. The KEYNOTE‐061 study [31] also showed that in patients with high TMB, pembrolizumab was associated with superior ORR, PFS, and OS than paclitaxel. In a Chinese phase II study using toripalimab for the treatment of refractory gastric cancer, the ORR (33.3% vs. 7.1%, P = 0.017) and OS (14.6 vs. 4.0 months, P = 0.038) of patients with high TMB (≥ 12 muts/Mb) were also found to be significantly better than those of patients with low TMB (<12 muts/Mb) [166].

^pIn a prospective phase II clinical trial from Korea [167] which enrolled 61 metastatic gastric cancer patients treated with pembrolizumab as salvage treatment, in patients with MSI‐H or EBV‐positive tumors, dramatic responses to pembrolizumab were observed (ORR 85.7% in MSI‐H metastatic gastric cancer and ORR 100% in EBV‐positive metastatic gastric cancer). Thus, EBV positivity in gastric cancer could be associated with positive response to PD‐1 antibody therapy. However, two observational studies in the Chinese population showed that the effective rate of EBV‐positive gastric cancer patients receiving immunosuppressive agents was 33.3% [168, 169]. Therefore, whether EBV infection could be used as a key marker for immunotherapy still needs to be confirmed in prospective studies.

^qSeveral phase II studies have shown that combined therapy using anti‐HER2 drugs combined with PD‐1 antibody or antiangiogenic inhibitor combined with PD‐1 antibody could be a potential treatment strategy in HER2‐positive gastric cancer patients; i.e., pembrolizumab plus trastuzumab in combination with XELOX for first‐line treatment of late‐stage gastric cancer (NCT0365326, CTR20182551) [170], and camrelizumab combined with XELOX followed by camrelizumab and apatinib as first‐line therapy for advanced or metastatic gastric or gastroesophageal junction cancer [171]. Such regimens are still currently being investigated in stage III clinical trials (NCT03813784, CTR20200660) and are not recommended for routine clinical practice.