Recent Advances in the Treatment of Stomach (Gastric) Cancer

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Recent Advances in the Treatment of Stomach (Gastric) Cancer

Recent Advances in the Treatment of Stomach (Gastric) Cancer. Stomach cancer presents a significant global health challenge.

In 2020, there were 1,089,103 new cases and 768,793 deaths, making it the fifth most common cancer and the fourth leading cause of cancer-related deaths worldwide.

The epidemiology of stomach cancer varies by gender and geographical region, with men having twice the incidence of women, and higher rates in East Asia and Eastern Europe. Additionally, stomach cancer can be classified into two anatomic subtypes and involves distinct histologic and molecular subtypes.

Patients with advanced stomach cancer and gastroesophageal junction cancer (GOJC) have a poor prognosis, with a 5-year relative survival rate of only 6%.

While chemotherapy and surgical approaches have improved, the prognosis for these patients remains challenging.

In advanced stomach cancer, only drugs like trastuzumab and certain immune checkpoint inhibitors such as nivolumab and pembrolizumab, along with chemotherapy, have consistently demonstrated efficacy, primarily in HER2-positive and PD-L1-positive tumors.

Currently, numerous drugs targeting the intrinsic characteristics of stomach cancer are being tested in phase II and III clinical trials, some showing promise in improving the prognosis and survival of stomach cancer patients.

The molecular characteristics of stomach cancer indicate significant heterogeneity among patients, contributing to the failure of several phase II and III clinical trials. Moreover, up to 36% of stomach cancers exhibit intratumoral heterogeneity, with inconsistencies between primary tumors and metastatic lesions.

Even within tumor samples from the same patient, there is temporal heterogeneity, often associated with resistance mechanisms, when comparing the situation before and after targeted treatment.

Recent Advances in the Treatment of Stomach (Gastric) Cancer

In terms of anti-HER2 therapy, while the anti-HER2 antibody trastuzumab has shown benefits in HER2-positive patients in first-line therapy, subsequent phase II and III trial results have been less promising.

The JACOB trial, comparing chemotherapy plus trastuzumab to chemotherapy plus trastuzumab and pertuzumab, ultimately did not show a significant improvement in overall survival.

Other anti-HER2 drugs like lapatinib and T-DM1 also performed poorly in second-line therapy for HER2-positive stomach cancer.

Progress has been made with HER2-targeted therapy in locally resectable stomach cancer, such as the NEOHX trial, which demonstrated the activity of HER2 blockade.

Additionally, the PETRARCA trial evaluated the efficacy of trastuzumab and pertuzumab in combination with standard FLOT chemotherapy, showing significantly improved rates of pathological complete response and negative lymph nodes.

However, some of the failures in anti-HER2 treatment trials are attributed to the complexity of HER2 scoring, as well as resistance mechanisms to HER2-targeted therapy, including loss of PTEN, activation mutations in PIK3CA, FGFR2 fusion, and amplifications of CCNE1 or EGFR.

To address these challenges, new types of antibody-drug conjugates (ADCs) and more effective antibodies are in development, such as trastuzumab deruxtecan, which has bystander effects capable of destroying surrounding cells, potentially valuable given the tumor heterogeneity.

Results from the DESTINY-Gastric01 trial showed significant efficacy of trastuzumab deruxtecan in HER2-positive stomach cancer, offering hope for future treatments.

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed the landscape of stomach cancer treatment.

Stomach cancer includes subtypes with moderate to high tumor mutational burden (TMB), such as MSI-H tumors or EBV-related cancers, which are especially sensitive to immunotherapy.

Some anti-PD-1 drugs have shown promising results when used in combination with standard chemotherapy in first-line treatment, such as nivolumab and pembrolizumab.

However, the efficacy across different trials may depend on the type of chemotherapy selected, and there is still uncertainty regarding the optimal treatment line for ICIs.

Recent data suggest substantial overlap between HER2 and PD-L1 positivity, supporting dual treatment strategies with anti-HER2 and anti-PD-L1, and combination testing of multi-kinase inhibitors with ICIs is ongoing, including regorafenib with nivolumab or lenvatinib with pembrolizumab, showing potential synergy.

Anti-angiogenic therapy has also found some application in stomach cancer, with drugs like ramucirumab and apatinib. However, the efficacy of these treatments appears to be limited in first-line therapy.

Regarding targeted therapy, while some targets have not proven to be more effective, new promising targets like FGFR2 and CLDN18.2 have emerged. New drugs like bemarituzumab, derazantinib, and zolbetuximab have shown activity against these targets, and further clinical trials are underway.

In summary, the treatment of stomach cancer is evolving towards personalized approaches that take into account the molecular characteristics, spatial, and temporal tumor heterogeneity of patients, with the goal of improving survival rates and quality of life.

In the face of this complex disease, integrating clinical and molecular data will help tailor the best treatment strategies.