Advances in gastric cancer treatment in 2024: Key breakthroughs and emerging trends

Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide (1). Despite advancements in early detection, surgical techniques, and drug therapies, the prognosis for patients with advanced GC remains poor. This underscores the urgent need for continued research and innovation in treatment strategies (2). In 2024, significant progress has been made across various treatment modalities for GC, including immunotherapy, molecular targeted therapies, antibody-drug conjugates (ADCs), and function-preserving surgeries. These breakthroughs are paving the way for more effective and personalized approaches to GC treatment. This research highlight summarizes key advancements and emerging trends in GC treatment over the past year.

Immunotherapy

Immunotherapy has emerged as one of the most transformative treatment approaches in various cancers, including GC. In 2024, immunotherapy of GC has shown good potential, and it has gradually moved from late first-line treatment to perioperative treatment, and new dual-target immunotherapy drugs have also achieved satisfactory efficacy in late first-line treatment.

Cadonilimab (AK104), a bispecific antibody targeting both programmed cell death 1 (PD-1) and CTLA-4, achieved promising results in the phase 1b/2 COMPASSION-04 trial. When combined with chemotherapy as a first-line treatment for human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma, it showed a median overall survival (OS) of 17.48 months across all patients. Benefits increased with programmed cell death ligand 1 (PD-L1) expression, with a median OS of 20.32 months for patients with combined positive score (CPS) ≥5 and 17.64 months for those with CPS<1 (3). Similarly, SHR-1701, a bispecific antibody targeting PD-L1 and transforming growth factor beta receptor II (TGF-βIIR), demonstrated the efficacy in a phase III trial presented at the 2024 European Society for Medical Oncology (ESMO) Congress. Among HER2-negative advanced GC patients with PD-L1 CPS≥5, combining SHR-1701 with CAPOX significantly improved median OS [16.8 vs. 10.4 months, hazard ratio (HR)=0.53, P<0.0001]. The intent-to-treat (ITT) population also saw the OS benefits (15.8 vs. 11.2 months, HR=0.66, P<0.0001) (4).

Significantly, updated 4-year follow-up data from the CheckMate-649 trial presented at 2024 American Society of Clinical Oncology (ASCO) Congress further highlighted the long-term survival benefits of nivolumab plus chemotherapy (5,6). The study updated the latest results from the Chinese subpopulation with a median follow-up of 49.2 months, showing that in the PD-L1 CPS≥5 group, the nivolumab plus chemotherapy arm had a 4-year OS rate of 25%, compared to only 11% for chemotherapy alone (6). Similarly, the phase III KEYNOTE-811 trial has previously demonstrated the efficacy of combining pembrolizumab, trastuzumab, and chemotherapy in patients with unresectable HER2-positive advanced GC, particularly those with PD-L1 CPS≥1. At the 2024 ESMO Congress, the final OS results were presented. In the ITT population, the pembrolizumab group achieved a median OS of 20.0 months, surpassing the control group (16.9 months; HR=0.80, P=0.0040). Median progression-free survival (PFS) was 10.0 months in the pembrolizumab group compared to 8.1 months in the control group (HR=0.73). The overall response rate (ORR) was notably higher in the pembrolizumab group at 72.6%, vs. 60.1% in the control group, with a median duration of response of 11.3 months compared to 9.5 months. Among patients with PD-L1 CPS≥1, the observed benefits were even more pronounced, aligning with the trends seen in the overall population (7).

In perioperative immunotherapy, studies suggest that adding immunotherapy may enhance pathological complete response (pCR) rates, although survival benefits remain uncertain. At 2024 ASCO Congress, the ECOG-ACRIN EA2174 trial showed no improvement in pCR rates when nivolumab was added to neoadjuvant treatment (carboplatin, paclitaxel, and radiation) for resectable esophageal and gastroesophageal junction adenocarcinoma (8). Furthermore, the KEYNOTE-585 study previously reported an improved pCR rate of 10.9%, but event-free survival (EFS) did not reach statistical significance. At this year’s ASCO Congress, a post-hoc analysis was conducted to evaluate pCR, major pathological response (mPR), and tumor downstaging as surrogate endpoints. The analysis revealed that the pembrolizumab plus chemotherapy group achieved a pCR rate improvement of approximately 10.9% compared to the chemotherapy group. The mPR rate increased by less than 10%, accompanied by an 11% improvement in both tumor and lymph node downstaging. However, the findings suggest that in patients with untreated locally advanced resectable gastric or gastroesophageal junction adenocarcinoma, this regimen may not necessarily translate into EFS benefits (9). Further long-term follow-up and subsequent studies are needed to assess the effectiveness of this strategy. Nonetheless, several small-sample studies on perioperative immunotherapy for GC were presented this year, including tislelizumab combined with chemotherapy and avelumab combined with chemoradiotherapy. Although these studies had limited sample sizes, they still observed promising prospects for immune combination therapy in the perioperative setting for GC.

Molecular targeted therapies

In 2024, significant advancements in targeted therapies have been achieved, particularly in HER2-positive and CLDN18.2-positive GC, as well as in the development of antibody-drug conjugates (ADCs). These breakthroughs have enriched the therapeutic arsenal and expanded the eligible patient population, marking an important step forward in the treatment of advanced and metastatic GC.

HER2 amplification is present in approximately 6%−35% of GC, and the use of HER2-targeted therapies, such as trastuzumab, had demonstrated significant therapeutic efficacy and established a cornerstone in the treatment of HER2-positive GC (10). In 2024, the results of several clinical trials have reinforced the role of HER2-targeted agents in improving OS and PFS in HER2-positive GC patients. The DESTINY-Gastric01 trial demonstrated the superiority of trastuzumab deruxtecan (T-DXd) over chemotherapy, solidifying its role as a first-line treatment (11). Based on this, the DESTINY-Gastric06 study was launched. The results were presented at the 2024 ESMO Asia Congress, and confirmed the efficacy of T-DXd, leading to its approval in China (12). Besides, in patients with ERBB2 extrachromosomal DNA (ecDNA) amplification, a recent ASCO presentation indicated that these patients benefit significantly from HER2-targeted therapies (13). Additionally, KN026 is a novel HER2-targeted bispecific antibody. Research results indicate that, in patients with HER2-positive advanced GC who have failed first-line treatment with trastuzumab-based regimens, the combination of KN026 and chemotherapy has shown encouraging efficacy. Its phase III clinical trial is currently ongoing, with promising prospects for the future (14).

Advances in CLDN18.2-targeted therapies have also marked a turning point. Previous interim and updated analyses have demonstrated improvements in both PFS and OS with zolbetuximab in combination with chemotherapy as a first-line treatment for patients with HER2-negative, CLDN18.2-positive advanced GC in the SPOTLIGHT and GLOW studies. The final pooled OS results from these studies were presented at the 2024 ESMO Congress. The pooled analysis revealed that zolbetuximab significantly improved PFS (9.2 vs. 8.2 months, HR=0.71) and OS (16.4 vs. 13.7 months, HR=0.77) compared to the control group (15). In addition, the TranStar102 study, a multicenter, open-label, multi-cohort phase I/IIa trial conducted in China, recently confirmed the favorable safety profile and durable antitumor activity of osemitamab, another CLDN18.2-targeting monoclonal antibody, in combination with nivolumab and chemotherapy as a first-line treatment for advanced GC. Notably, for patients with high or moderate CLDN18.2 expression, no correlation was found with PD-L1 CPS levels (16). Furthermore, chimeric antigen receptor T-cell immunotherapy (CAR-T), ADCs and bispecific antibodies targeting CLDN18.2 are showing promising therapeutic potential (17).

Beyond HER2 and CLDN18.2, targeted therapies for FGFR2b, c-Met, and EGFR are advancing precision oncology approaches, promising a new era of personalized treatment.

Function-preserving surgery

In surgical management, there is a growing focus on preserving gastric function to improve long-term quality of life (18). The Senorita study, a multicenter phase III trial, compared laparoscopic standard gastrectomy (LSG) with laparoscopic sentinel lymph node navigation surgery (LSNNS) in terms of tumor safety and postoperative quality of life. While LSNNS did not meet the primary endpoint for 3-year DFS, salvage surgery resulted in comparable 3-year OS (19). Subsequent analysis indicated that gastric-preserving surgery resulted in better long-term quality of life and nutritional outcomes compared to standard gastrectomy, with no statistical difference in 5-year OS and disease-free survival (20,21). These findings suggest that LSNNS may be a viable treatment option for certain GC patients. Other techniques, such as robotic surgery, anti-reflux procedures for proximal gastrectomy, and combined endoscopic-laparoscopic surgery, are being explored in small-sample studies, demonstrating potential for less invasive yet effective surgical options.

Conclusions

In 2024, GC treatment has seen remarkable progress, particularly in molecular targeted therapies, immunotherapy, and function-preserving surgeries. Traditional anti-PD-1 antibodies like pembrolizumab and nivolumab continue to show strong efficacy, while novel dual-target agents such as cadonilimab and SHR-1701 offer new therapeutic options. Emerging data suggest that perioperative immunotherapy may enhance pCR rates, though long-term benefits remain under investigation. Meanwhile, advancements in HER2 and CLDN18.2-targeted therapies highlight the promise of precision oncology. Lastly, function-preserving surgical techniques are reshaping the approach to early-stage GC, prioritizing patient quality of life. These breakthroughs underscore a paradigm shift towards personalized, targeted, and less invasive treatments, offering new hope for improved survival and quality of life across all stages of GC.