Editor's Note: In recent years, advancements in immunotherapy and targeted therapy have significantly contributed to a more personalized and precise approach to the treatment of advanced gastric cancer. As the year comes to a close, Oncology Frontier is honored to invite Dr. Qian Dong from Liaoning Cancer Hospital to provide a comprehensive review of the major advancements and developments in the field of advanced gastric cancer treatment in 2024. This review aims to reflect on past achievements, explore future directions, and offer valuable insights and strategic recommendations for further progress in treating advanced gastric cancer.Progress in First-Line Treatment of Advanced Gastric Cancer
Targeted Therapy + Chemotherapy ± Immunotherapy: Advances and Breakthroughs
CLDN18.2
The SPOTLIGHT and GLOW studies are global, multicenter, randomized, double-blind, placebo-controlled phase III clinical trials that included 1,072 patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma who were CLDN18.2-positive and HER2-negative. Patients received Zolbetuximab combined with chemotherapy or a placebo combined with chemotherapy. The chemotherapy regimen in the SPOTLIGHT study was mFOLFOX6, while the GLOW study used CAPOX. The primary endpoint was progression-free survival (PFS), with overall survival (OS) as a key secondary endpoint.
In September 2024, The New England Journal of Medicine published the final survival and safety results from the combined analysis of the SPOTLIGHT and GLOW phase III studies. The pooled results demonstrated that Zolbetuximab combined with chemotherapy significantly improved PFS compared to placebo combined with chemotherapy (9.2 vs. 8.2 months), reducing the risk of disease progression by 29%, thereby meeting the primary endpoint. Regarding the key secondary endpoint, Zolbetuximab combined with chemotherapy significantly extended OS (16.4 vs. 13.7 months), reducing the risk of death by 23%. No new safety signals were observed in this pooled analysis.
ASKB589 Combined with CAPOX and PD-1 Inhibitors
A phase Ib/II study evaluated the safety, tolerability, dose-limiting toxicity, maximum tolerated dose, and recommended phase III dose of ASKB589 combined with CAPOX and a PD-1 inhibitor as a first-line treatment for locally advanced, recurrent, and metastatic G/GEJ adenocarcinoma.
As of December 20, 2023, 62 patients with CLDN18.2-positive tumors met the inclusion criteria and received ASKB589 combined with CAPOX and a PD-1 inhibitor. Nine patients were enrolled in the dose-escalation phase (ASKB589 at 6 mg/kg [n=3] and 10 mg/kg [n=6]), and 53 patients were enrolled in the dose-expansion phase at 6 mg/kg. Among 45 patients with measurable target lesions and moderate-to-high CLDN18.2 expression who underwent at least one post-treatment tumor evaluation during the dose-expansion phase, 80.0% achieved partial response, and 20.0% achieved stable disease, resulting in a disease control rate of 100%. As of the cutoff date, 41 of 53 patients (77.3%) remained on treatment.
HER2-Positive Therapies
DG-03 Study
The DG-03 phase II study evaluated the efficacy of the anti-HER2 antibody-drug conjugate (ADC) Trastuzumab Deruxtecan (T-DXd) combined with FP chemotherapy and a PD-1 inhibitor in the first-line treatment of advanced or metastatic HER2-positive esophageal or G/GEJ adenocarcinoma. A total of 307 HER2-positive patients worldwide were enrolled, receiving six different treatment regimens. The specific protocols and efficacy/safety data are summarized in Table 1.
The study observed an objective response rate (ORR) of 49% for T-DXd monotherapy, which increased to 78% when combined with fluoropyrimidine-based chemotherapy. The combination of T-DXd with 5-FU/capecitabine achieved the longest median progression-free survival (PFS) of 20 months.
RC48 Combined with Tislelizumab and S-1
At the 2024 ASCO Annual Meeting, a phase II clinical trial evaluating the anti-HER2 ADC Vidicitumab (RC48) combined with Tislelizumab and S-1 as a first-line treatment for HER2-positive advanced G/GEJ adenocarcinoma reported promising results. The primary endpoint, ORR, was 94.3%, while the disease control rate (DCR) reached 98.1%. Although median PFS and overall survival (OS) have not yet been reached, the 1-year PFS rate was 71.8%, and the 1-year OS rate was 97.6%. These results represent unprecedented outcomes in this field, and the final results are highly anticipated.
Zanidatamab (HER2 Bispecific Antibody) + Chemotherapy
At the 2024 ESMO Annual Meeting, a phase II study evaluated the efficacy and safety of Zanidatamab combined with chemotherapy (CAPOX, FP, or mFOLFOX6) as a first-line treatment for HER2-positive advanced or metastatic gastroesophageal adenocarcinomas (GEAs). The study reported an ORR of 84%, a median PFS of 15.2 months, and manageable safety profiles.
Immunotherapy Combined with Chemotherapy: Standard First-Line Regimens
HER2-Negative Patients
GEMSTONE-303 Study
The GEMSTONE-303 phase III study assessed the efficacy of Sugemalimab combined with CAPOX compared to CAPOX alone in the first-line treatment of unresectable locally advanced or metastatic G/GEJ adenocarcinoma. The primary endpoints were PFS and OS in patients with PD-L1 CPS ≥5%. The study achieved dual-positive results for OS and PFS, with median OS reaching 15.64 months in patients with PD-L1 CPS ≥5% and 17.81 months in patients with CPS ≥10%. ORR in the combination group was 68.6% (an improvement of 15.9%), with ORR reaching 71.4% (an increase of 23%) in patients with high PD-L1 expression. Safety was favorable.
KEYNOTE-859 Study
KEYNOTE-859 is a global randomized, double-blind, phase III trial evaluating the efficacy and safety of Pembrolizumab combined with chemotherapy as a first-line treatment for HER2-negative advanced G/GEJ adenocarcinoma. The results demonstrated significant improvements in OS and PFS in the Pembrolizumab combination group, with an ORR of 51.3% and a CR rate of 9.5%. Patients with high PD-L1 expression (CPS ≥1) derived greater benefits.
CheckMate 649 Study
CheckMate 649 is a global phase III trial evaluating Nivolumab combined with chemotherapy versus chemotherapy alone in previously untreated patients with HER2-negative advanced or metastatic gastric cancer, GEJC, or esophageal adenocarcinoma. The Chinese subgroup included 208 patients randomized to receive either Nivolumab + chemotherapy (n=99) or chemotherapy alone (n=109) with a minimum follow-up of 49.2 months. Results showed significant clinical benefits in the Nivolumab + chemotherapy group, with median OS (14.3 vs. 10.3 months) and PFS (8.3 vs. 5.6 months). In patients with CPS ≥5, median OS (15.5 vs. 9.6 months) and PFS (8.5 vs. 4.3 months) in the combination group exceeded those in the control group, alongside a higher ORR (68% vs. 48%). OS and PFS benefits were also observed in patients with CPS ≥1 and in the overall population.
IKF-AIO-Moonlight Study
The IKF-AIO-Moonlight phase II study evaluated the efficacy and safety of a modified FOLFOX regimen ± Nivolumab and Ipilimumab versus the FLOT regimen + Nivolumab as a first-line treatment for advanced or metastatic G/GEJ adenocarcinoma. Results indicated that the parallel administration of dual checkpoint inhibitors with chemotherapy was associated with increased toxicity but no additional efficacy. Sequential immunotherapy following chemotherapy failed to meet expectations, though the FLOT + Nivolumab regimen was feasible and appeared to improve outcomes.
NIVOFGFR2 Study
NIVOFGFR2 is a single-arm, multicenter phase II clinical trial evaluating Nivolumab combined with CAPEOX in untreated FGFR2-positive, PD-L1-positive advanced gastric cancer. Interim analysis indicated that the combination demonstrated certain efficacy and manageable safety in this patient population, with follow-up ongoing.
HER2-Positive Patients
KEYNOTE-811 Study
The phase III KEYNOTE-811 trial assessed the efficacy and safety of Trastuzumab + chemotherapy ± Pembrolizumab in HER2-positive unresectable or metastatic G/GEJ adenocarcinoma. With a median follow-up of 50.2 months, the Pembrolizumab combination group demonstrated significantly superior median OS compared to the placebo group (20.0 vs. 16.8 months, P=0.0040). Among patients with PD-L1 CPS ≥1, the median OS extended to 20.1 months in the Pembrolizumab group versus 15.7 months in the control group. Additionally, median PFS (10.0 vs. 8.1 months) and ORR (72.6% vs. 60.1%) were notably higher in the Pembrolizumab group. However, grade ≥3 treatment-related adverse events occurred in 59% of the Pembrolizumab group, slightly higher than the 51% in the placebo group, warranting attention.
HLX22 (Modified Humanized Monoclonal Antibody) + HLX02 (Trastuzumab Biosimilar) + CAPOX
At the 2024 ASCO GI Conference, a phase II clinical study conducted in China was presented, evaluating the efficacy and safety of HLX22 combined with HLX02 and CAPOX as a first-line treatment for HER2-positive locally advanced or metastatic gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Patients were randomized (1:1:1) into three groups: Group A received HLX22 (25 mg/kg) + HLX02 + CAPOX, Group B received HLX22 (15 mg/kg) + HLX02 + CAPOX, and Group C received a placebo + HLX02 + CAPOX, with treatment cycles repeated every three weeks.
Analysis of the primary efficacy indicators revealed median PFS values of 15.1 months for Group A, not reached for Group B, and 8.2 months for Group C. Confirmed ORRs were 77.8%, 82.4%, and 88.9%, respectively, while the median duration of response (DOR) was 12.4 months for Group A, not reached for Group B, and 6.8 months for Group C. Median OS has not yet been reached in any group. Other efficacy indicators (Table 2) and safety profiles were deemed manageable. Researchers concluded that HLX22 combined with HLX02 and CAPOX improved disease response and survival benefits in first-line treatment for HER2-positive gastric cancer.
As phase III trials continue and their results solidify, the landscape of first-line treatment for advanced gastric cancer is expected to become more stratified based on the confirmed efficacy of various targeted therapies. For HER2-positive gastric cancer with PD-L1 CPS ≥1, chemotherapy combined with anti-HER2 and PD-1 monoclonal antibodies forms the foundation of treatment. For those with PD-L1 CPS <1, chemotherapy with anti-HER2 therapy remains the mainstay. Exploration of ADCs and bispecific HER2 antibodies offers hope for further efficacy improvements.
In HER2-negative populations, the imminent availability of CLDN18.2 monoclonal antibodies will enable treatment decisions based on PD-L1 and/or CLDN18.2 expression levels. Precision subgroup selection will require further exploration, such as understanding co-expression or differential expression of PD-L1 and CLDN18.2, or identifying novel biomarkers to guide combinations of chemotherapy with CLDN18.2 or PD-1/PD-L1 monoclonal antibodies. Additionally, innovative therapies targeting TGF-β/PD-L1 and FGFR inhibitors are under investigation.
The future holds promise for more precise and diversified first-line treatments for advanced gastric cancer, with continued improvements in patient survival outcomes.
Advances in Second-Line Treatment for Advanced Gastric Cancer
Targeted Therapy + Chemotherapy or Immunotherapy
FRUTIGA Study
The phase III FRUTIGA trial evaluated the efficacy of fruquintinib combined with paclitaxel as a second-line treatment for G/GEJ adenocarcinoma. A total of 703 patients were enrolled, with 699 receiving treatment. Results showed that the fruquintinib-paclitaxel group significantly improved median PFS compared to the placebo-paclitaxel group, with consistent PFS benefits across all subgroups. However, no significant improvement in OS was observed. Secondary endpoints, including ORR, DCR, and DOR, demonstrated statistically and clinically meaningful improvements. Safety profiles were consistent with previous studies, with no new safety signals identified.
DG-06 Study
The DG-06 phase II trial, conducted in China, assessed the safety and efficacy of trastuzumab deruxtecan (T-DXd) in HER2-positive locally advanced or metastatic G/GEJ adenocarcinoma patients who had undergone at least two prior chemotherapy regimens. Results were consistent with global data from the DG-01 trial. Among 73 patients with a median follow-up of 8.0 months, investigator-assessed ORR was 35.6%, while independent central review reported an ORR of 28.8%. DCR was 79.5%, with IHC3+ and IHC2+/ISH+ patients showing ORRs of 32.1% and 20.0%, respectively.
Multi-Target Immunotherapy + Anti-Angiogenic Agents + Chemotherapy
AK109-201 Study
The AK109-201 phase Ib/II trial explored cadonilimab combined with prolizumab (AK109) and paclitaxel as a second-line treatment for advanced G/GEJ adenocarcinoma in patients with prior failure of immunotherapy and chemotherapy. The trial consisted of a safety lead-in phase and an expansion phase, with patients randomized 1:1 into two cohorts: cadonilimab + prolizumab + paclitaxel (Cohort 1) or placebo + prolizumab + paclitaxel (Cohort 2). Cohort 1 demonstrated superior safety and efficacy, with an ORR of 48.0% compared to 39.3% in Cohort 2. This regimen may represent a potential strategy to overcome resistance to immunotherapy. A phase III trial is underway.
Chemotherapy-Based Strategies
DOC-GC Study
The DOC-GC phase III trial compared docetaxel + oxaliplatin + capecitabine/5-FU (DOC/F) sequential docetaxel versus CAPOX/mFOLFOX-7 in the treatment of advanced gastric cancer. Results indicated no differences in response rates or quality of life (QOL) between the two groups. Fewer patients received second-line treatment than expected, with a higher proportion receiving second-line therapy in the CAPOX/mFOLFOX group (38.7% vs. 26.7%). While adding docetaxel benefited some patients, it did not significantly alter oncological endpoints or patient outcomes, and the incidence of grade 3/4 TRAEs increased.
The Future of Precision Medicine in Advanced Gastric Cancer
Precision medicine is increasingly becoming the cornerstone of advanced gastric cancer treatment. Studies presented at the 2024 ASCO GI Conference showcased the potential of artificial intelligence (AI) and biomarkers in refining therapeutic strategies.
One study utilized AI to analyze single-cell features from whole-slide H&E-stained images (WSIs) to predict immunotherapy response and survival outcomes. Spatial features describing interactions between lymphocytes and neutrophils correlated strongly with PFS in the training cohort, a finding validated in an independent external cohort. The multivariable model incorporating spatial features demonstrated superior predictive accuracy for ORR.
Another notable study, SCRUM-Japan, analyzed gastrointestinal cancer patients to evaluate outcomes in biomarker-matched clinical trials. Results revealed an ORR of 27.8% for biomarker-matched therapies, with the highest response rates observed in ADC therapies (48.8%) and HER2-targeted trials (46%). Biomarker-matched therapies also significantly prolonged OS compared to unmatched treatments.
In summary, precision medicine leverages molecular characteristics to deliver personalized treatments. Advances in HER2-positive therapies, CLDN18.2-targeting agents, and combination immunotherapy herald a new era of tailored strategies. The integration of AI and biomarker-driven approaches will further optimize gastric cancer treatment, ensuring greater precision and improved patient outcomes.
Dr. Qian Dong
Chief Physician, Master’s Supervisor Liaoning Cancer Hospital Deputy Director, Second Department of Gastroenterology Youth Committee Member, Chinese Research Hospital Association’s Digestive Tract Tumor Professional Committee Member, CSCO Anticancer Drug Safety Committee Deputy Director, Youth Committee of Beijing Cancer Prevention Society’s Gastric Cancer Prevention Division Deputy Director, Tumor Immunology and Immunotherapy Professional Committee, Liaoning Society for Cell Biology Deputy Director, Tumor Precision Medicine and Big Data Management Professional Committee, Liaoning Society for Cell Biology
