Recent advances in palliative systemic therapy for locally advanced unresectable or metastatic gastric cancer: a narrative review

Systematic therapy for advanced gastric cancer

Article information

J Korean Med Assoc. 2025;68(12):802-808

Publication date (electronic) : 2025 December 10

doi : https://doi.org/10.5124/jkma.25.0114

Minkyu Jung, MD, PhD

Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

Corresponding author: Minkyu Jung E-mail: minkjung@yuhs.ac

Received 2025 August 25; Accepted 2025 October 24.

Abstract

Purpose

Systemic therapy remains the cornerstone of managing advanced gastric cancer (AGC). For patients with unresectable or metastatic AGC, it is essential for extending survival and alleviating symptoms.

Current Concepts

Cytotoxic chemotherapy, historically centered on fluoropyrimidines, platinum agents, taxanes, and irinotecan, continues to form the treatment foundation. More recently, targeted agents and immune checkpoint inhibitors (ICIs) have reshaped therapeutic strategies. Combination regimens incorporating nivolumab, pembrolizumab, or tislelizumab with chemotherapy have improved outcomes in HER2-negative AGC, particularly among patients with programmed cell death-ligand 1–positive or microsatellite instability-high/deficient mismatch repair tumors. Zolbetuximab, which targets CLDN18.2, has also shown clinically meaningful benefit in CLDN18.2-positive disease. In HER2-positive AGC, trastuzumab remains the therapeutic backbone, with findings from the KEYNOTE-811 trial supporting the addition of pembrolizumab to trastuzumab-based chemotherapy. In the second-line setting, ramucirumab plus paclitaxel is preferred, and trastuzumab deruxtecan provides benefit in previously treated HER2-positive patients. Later-line options include trifluridine/tipiracil, nivolumab, and trastuzumab deruxtecan.

Discussion and Conclusion

The treatment landscape for AGC is rapidly evolving toward biomarker-driven precision oncology. Incorporating ICIs, targeted agents, and optimized treatment strategies has transformed management and enabled more individualized, effective, and less invasive therapeutic approaches.

Keywords: Biomarkers; Immune checkpoint inhibitors; Immunotherapy; Precision medicine; Stomach neoplasms

Introduction

Background

Gastric cancer remains a major global malignancy with high incidence and mortality; its burden is especially substantial in East Asia, including Korea. While early-stage disease may potentially be cured with endoscopic resection or radical surgery, treatment outcomes in locally advanced, unresectable, or metastatic disease depend primarily on systemic chemotherapy. Over recent decades, cytotoxic chemotherapy based on fluoropyrimidines, platinum agents, taxanes, and irinotecan has remained central. Subsequently, the development of HER2-targeted therapy and immune checkpoint inhibitors (ICIs) has rapidly shifted the therapeutic paradigm. More recently, biomarker-driven approaches such as programmed cell death-1 (PD-1) inhibitors combined with chemotherapy, CLDN18.2-targeted agents, and antibody-drug conjugates (ADCs) have entered clinical practice, emphasizing the importance of precision strategies tailored to molecular subtypes. Nonetheless, several challenges persist, including heterogeneity in treatment response, toxicity concerns, and insufficient evidence regarding the optimal sequencing or combination of available treatments.

Purpose

This narrative review summarizes recent evidence supporting systemic therapy options for advanced gastric cancer and provides a balanced evaluation of cytotoxic chemotherapy, targeted therapy, and immunotherapy. In alignment with Korean Gastric Cancer Association guidelines, it also offers practical recommendations for patient selection and drug choice applicable in routine clinical care [1].

First-Line Palliative Systemic Therapy for HER2-Negative Disease

Nivolumab, a PD-1 ICI, was the first ICI to demonstrate benefit when combined with cytotoxic chemotherapy as first-line treatment for HER2-negative, locally advanced, unresectable, or metastatic gastric cancer. The CheckMate-649 trial showed that the addition of nivolumab to capecitabine or 5-fluorouracil (5-FU) plus oxaliplatin significantly improved overall survival (OS) compared with chemotherapy alone (median OS, 13.8 vs. 11.6 months; hazard ratio [HR], 0.80; 99.3% confidence interval [CI], 0.68–0.94; P=0.0002) [2]. The benefit was greater in patients with a programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥5 (median OS, 14.4 vs. 11.1 months; HR, 0.71; 98.4% CI, 0.59–0.86; P<0.01) [2]. The ATTRACTION-4 trial, conducted in Japan, Korea, and Taiwan, also evaluated nivolumab plus chemotherapy (capecitabine or S-1 plus oxaliplatin) as first-line treatment in HER2-negative gastric cancer, demonstrating significantly improved progression-free survival (PFS) (median PFS 10.5 vs. 8.3 months; HR, 0.68; 95% CI, 0.51–0.90; P<0.01), although OS improvement was not observed [3].

Pembrolizumab has also been studied in combination with chemotherapy as first-line therapy. In the KEYNOTE-062 trial, pembrolizumab plus chemotherapy (5-FU or capecitabine plus cisplatin) did not show superiority over chemotherapy alone in OS among HER2-negative, PD-L1 CPS ≥1 patients (median OS, 12.5 vs. 11.1 months; HR, 0.85; 95% CI, 0.70–1.03; P=0.05) [4]. However, the KEYNOTE-859 trial demonstrated that pembrolizumab added to 5-FU/cisplatin (FP) or CAPOX significantly improved OS in first-line palliative systemic therapy. In the intention-to-treat population, median OS was 12.9 months with pembrolizumab plus chemotherapy versus 11.5 months with chemotherapy alone (HR, 0.78; 95% CI, 0.70–0.87; P<0.01). Greater benefit was observed in PD-L1 CPS ≥1 patients (median OS, 13.0 vs. 11.4 months; HR, 0.74; 95% CI, 0.65–0.84) and CPS ≥10 patients (15.7 vs. 11.8 months; HR, 0.65; 95% CI, 0.53–0.79) [5]. Another PD-1 inhibitor, tislelizumab, showed improved OS compared with chemotherapy alone in the global phase III RATIONALE-305 trial (median OS, 15.0 vs. 12.9 months; HR, 0.80; P=0.001), with greater benefit in patients with PD-L1 tumor area positivity ≥5 [6].

A meta-analysis confirmed that combining anti-PD-1 antibodies with chemotherapy was superior to chemotherapy alone in OS (HR, 0.81; 95% CI, 0.76–0.86), PFS (HR, 0.78; 95% CI, 0.73–0.83), objective response rate (ORR), and disease control rate (DCR). Based on this evidence, nivolumab plus chemotherapy (CAPOX or FOLFOX), pembrolizumab plus chemotherapy (FP or CAPOX), and tislelizumab plus chemotherapy (FP or CAPOX) are approved as first-line palliative systemic therapies in Korea. Although microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors are uncommon, subgroup analyses consistently show additional OS benefits with anti-PD-1 therapy [7].

Zolbetuximab, a monoclonal antibody targeting CLDN18.2, significantly improved OS and PFS when combined with mFOLFOX6 or CAPOX in two global phase III trials, SPOTLIGHT and GLOW (OS, 18.2 vs. 15.6 months; HR, 0.78; P<0.01/OS, 14.3 vs. 12.2 months; HR, 0.77; PFS, 8.2 vs. 6.8 months; HR, 0.69; P<0.001) in CLDN18.2-positive patients [8,9]. Based on these results, zolbetuximab plus chemotherapy (mFOLFOX6 or CAPOX) is now approved and used in Korea for patients with CLDN18.2-positive, HER2-negative advanced gastric cancer.

First-Line Palliative Systemic Therapy for HER2-Positive Disease

The clinical efficacy of trastuzumab, a monoclonal antibody targeting HER2, was first demonstrated in the global phase III ToGA trial. In patients with HER2-positive gastric cancer, adding trastuzumab to fluoropyrimidine/cisplatin-based first-line chemotherapy significantly improved OS [10]. Specifically, combining trastuzumab with capecitabine or 5-FU and cisplatin resulted in a longer median OS compared with chemotherapy alone (13.8 vs. 11.1 months; HR, 0.74; 95% CI, 0.60–0.91; P=0.0046). The survival benefit was greater in patients with high HER2 protein expression (immunohistochemistry [IHC] 3+ or IHC 2+ with in situ hybridization positivity), with median OS of 16.0 vs. 11.8 months (HR, 0.65; 95% CI, 0.51–0.83; P<0.01). PFS was also significantly prolonged in the trastuzumab arm (6.7 vs. 5.5 months; HR, 0.71; 95 % CI, 0.59–0.85; P=0.036). ORR and DCR were higher with trastuzumab (ORR, 47% vs. 35%; odds ratio [OR], 1.70; 95% CI, 1.22–2.38; P=0.002; DCR, 75% vs. 70%; OR, 1.66; 95% CI, 1.14–2.41; P=0.008).

The tyrosine kinase inhibitor (TKI) lapatinib (an epidermal growth factor receptor [EGFR]/HER2 TKI) was evaluated in the LOGiC trial in combination with CAPOX but did not improve OS in patients with HER2-amplified gastric cancer (median OS, 12.2 vs. 10.5 months; HR, 0.91; 95% CI, 0.73–1.12; P=0.349) [11]. To assess the potential benefit of dual HER2 blockade, the JACOB trial added pertuzumab, a monoclonal antibody that inhibits HER2/HER4 heterodimerization, to trastuzumab plus chemotherapy. Although PFS improved (median, 8.5 vs. 7.2 months; HR, 0.73; 95% CI, 0.62–0.85; P<0.01), the primary endpoint of OS did not reach statistical significance (17.5 vs. 14.2 months; HR, 0.84; 95% CI, 0.71–1.00; P=0.057) [12].

The strategy of combining ICIs with standard chemotherapy, which has demonstrated survival benefit in HER2-negative gastric cancer, has been extended to HER2-positive disease. The randomized phase III KEYNOTE-811 trial compared pembrolizumab plus trastuzumab combined with standard chemotherapy (5-FU or capecitabine plus platinum) versus trastuzumab with chemotherapy alone [13]. In the intention-to-treat population, adding pembrolizumab improved PFS (median, 10.0 vs. 8.1 months; HR, 0.73; 95% CI, 0.61–0.87; P=0.0005). OS showed a trend toward improvement (median, 20.0 vs. 16.8 months; HR, 0.84; 95% CI, 0.70–1.01; P=0.06), with greater benefit observed among patients with PD-L1 CPS ≥1. In this subgroup, PFS was 10.9 vs. 7.3 months (HR, 0.72; 95% CI, 0.60–0.87; P<0.01) and OS was 20.1 vs. 15.7 months (HR, 0.79; 95% CI, 0.66–0.95; P=0.006). ORR was significantly higher with pembrolizumab (72.6% vs. 60.1%; OR, 1.76; 95% CI, 1.28–2.42; P<0.001), and DCR also tended to be improved (91.7% vs. 87.4%; OR, 1.60; 95% CI, 0.98–2.63; P=0.06). Based on these findings, pembrolizumab added to trastuzumab plus chemotherapy is recommended for HER2-positive patients with PD-L1 CPS ≥1.

Second-Line Palliative Systemic Therapy

Randomized controlled trials and meta-analyses have clearly shown that second-line palliative chemotherapy with irinotecan or taxanes provides survival benefits compared with best supportive care (BSC) alone in patients with locally advanced unresectable or metastatic gastric cancer [14–19]. Phase III trials demonstrated that weekly paclitaxel achieved outcomes comparable to those of biweekly irinotecan [18,19]. Ramucirumab, a monoclonal antibody targeting vascular endothelia growth factor receptor-2 (VEGFR-2), significantly prolonged OS and PFS compared with placebo in the REGARD trial [20]. The RAINBOW trial further showed that adding ramucirumab to weekly paclitaxel significantly improved OS (median, 9.6 vs. 7.4 months; HR, 0.807; 95% CI, 0.68–0.97; P=0.017) and PFS (median, 4.4 vs. 2.9 months; HR, 0.635; 95% CI, 0.53–0.76; P<0.0001) compared with paclitaxel plus placebo [21]. Together, these findings support ramucirumab plus paclitaxel as the preferred second-line treatment.

Among ICIs, pembrolizumab did not demonstrate a significant survival advantage over paclitaxel in unselected gastric cancer populations [22–24], but showed meaningful efficacy in molecularly defined subgroups such as MSI-H, dMMR, and tumor mutational burden-high (≥10 mutations/megabase) disease [25,26]. In Korea, pembrolizumab is approved for patients with unresectable or metastatic solid tumors (including gastric cancer) who are MSI-H or dMMR, have progressed following prior treatment, and lack alternative therapeutic options.

Trastuzumab deruxtecan (T-DXd), an HER2-targeted ADC containing a topoisomerase I inhibitor payload, has received U.S. Food and Drug Administration approval for HER2-positive gastric cancer previously treated with trastuzumab-based therapy. Evidence supporting T-DXd as a second-line therapy has primarily come from Western populations [27]. The recently reported global phase III DESTINY-Gastric04 trial, which included Asian patients, compared T-DXd with ramucirumab plus paclitaxel, the standard second-line regimen, in HER2-positive gastric cancer. The trial demonstrated significant improvements in the primary endpoint OS (14.7 vs. 11.4 months; HR, 0.7; 95% CI, 0.55–0.90; P=0.004) and PFS (HR, 0.74; 95% CI, 0.59–0.92) [28]. These results support T-DXd as an effective second-line treatment option for HER2-positive gastric cancer.

Third-Line Palliative Systemic Therapy

For patients who maintain adequate performance status after completing second-line treatment, third-line palliative systemic therapy is recommended. Among cytotoxic agents, docetaxel or irinotecan is considered appropriate. A randomized phase III trial demonstrated that docetaxel or irinotecan improved OS compared with BSC (median, 5.3 vs. 3.8 months; HR, 0.66; 95% CI, 0.49–0.89; P=0.007) [14]. Multiple phase III and retrospective studies evaluating taxane- or irinotecan-based third-line chemotherapy have reported consistent findings [29–31]. The phase III trial of trifluridine/tipiracil (TAS-102) showed an OS benefit over placebo in gastric cancer patients who had received at least two prior systemic therapies (median, 5.7 vs. 3.6 months; HR, 0.69; 95% CI, 0.56–0.85; P=0.00058) [32]. Nivolumab demonstrated an OS benefit over placebo in patients who had failed two or more prior systemic therapies in the ATTRACTION-2 phase III trial conducted in Japan, Korea, and Taiwan (median OS, 5.3 vs. 4.1 months; HR, 0.63; 95% CI, 0.51–0.78; P<0.0001) [33]. A two-year follow-up analysis confirmed long-term survival benefits irrespective of PD-L1 expression [34]. Therefore, nivolumab is recommended as third-line therapy for patients without prior exposure to ICIs.

The DESTINY-Gastric01 phase II trial (conducted in Korea and Japan) compared T-DXd with physician’s choice chemotherapy (irinotecan or paclitaxel) in HER2-positive patients who had received at least two prior systemic therapies, including trastuzumab [35]. T-DXd significantly improved ORR (51% vs. 14%, P<0.001) and OS (median, 12.5 vs. 8.4 months; HR, 0.59; 95% CI, 0.39–0.88; P=0.01). Based on these results, T-DXd is approved as second-line or later therapy in the United States and as third-line or later therapy in Korea.

Conclusion

In advanced gastric cancer, treatment has progressed beyond conventional cytotoxic chemotherapy to include molecularly targeted and immune-based approaches. For HER2-positive disease, trastuzumab combined with chemotherapy remains the standard backbone, and adding pembrolizumab to trastuzumab-based chemotherapy has further improved response rates and survival, particularly in patients with PD-L1 CPS ≥1. The ADC T-DXd has demonstrated meaningful efficacy in both the second- and third-line settings, expanding therapeutic options for refractory disease.

For HER2-negative tumors, zolbetuximab plus cytotoxic chemotherapy has emerged as a new first-line option for CLDN18.2-positive gastric cancer. ICIs—including nivolumab, pembrolizumab, and tislelizumab—are also widely used in PD-L1–positive disease and have shown substantial survival benefit, especially in tumors with high PD-L1 expression. In addition, next-generation agents such as CLDN18.2-targeted ADCs are in active development. Collectively, these advances continue to broaden the therapeutic landscape and are expected to contribute to further improvements in survival outcomes for patients with advanced gastric cancer.

Notes

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Data Availability

Not applicable.

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