Editor’s Note: In recent years, breakthroughs in new drugs and therapeutic targets for gastrointestinal tumors have brought renewed hope for patients. At the 2024 European Society for Medical Oncology Asia Congress (ESMO ASIA 2024), Professor Kohei Shitara from Japan’s National Cancer Center Hospital delivered an insightful presentation on emerging targeted therapies for gastrointestinal tumors. During the conference, Oncology Frontier invited Professor Shitara to review the progress and challenges in the development of new therapeutic targets for gastrointestinal tumors.Key Oncogenic Targets in Focus
FGFR2
Approximately 3%–5% of gastric cancer patients exhibit FGFR2 overexpression or amplification, which is associated with tumor dissemination and poor prognosis. Studies on FGFR2 inhibitors have shown mixed results:
- The Shine study comparing AZD4547 with paclitaxel (PTX) reported no statistically significant difference in progression-free survival (PFS) between the two groups.
- Futibatinib demonstrated an objective response rate (ORR) of 18% in gastric cancer patients with FGFR2 amplification (copy number >10).
- Infigratinib achieved an ORR of 25% in FGFR-positive gastric cancer patients.
Challenges remain with resistance to FGFR-targeted therapies, often attributed to off-target effects or bypass mechanisms, which shorten the duration of response (DoR).
Extrachromosomal DNA (ecDNA)
Circular DNA found outside chromosomes carries oncogenes and can emerge from chromosomal breakage or bridge-fusion cycles. These contribute to tumor resistance through genetic heterogeneity, rapid genomic alterations driven by super-enhancers, and amplification of resistance genes.
Studies have shown increased HER2 ecDNA copy numbers in HER2-positive tumors, with chemotherapy combined with HER2-targeted therapy extending PFS. Emerging therapeutic directions include:
- Enhancing replicative stress and DNA damage using fluorouracil or oxaliplatin to disrupt ecDNA flexibility.
- Ongoing trials, such as NCT05827614, are evaluating CHK1 inhibitors to target replicative stress.
- PARP and DNA-PK inhibitors are under investigation for their potential to disrupt ecDNA structural integrity.
FGFR2b
FGFR2b, an epithelial splice variant of FGFR2, is expressed in approximately 30% of gastric cancers. The anti-FGFR2b monoclonal antibody bemarituzumab has shown promising results, achieving an ORR of 18% as monotherapy. Compared to TKIs, bemarituzumab causes fewer electrolyte disturbances but presents reversible corneal toxicity.
In the FIGHT trial, the combination of bemarituzumab with FOLFOX6 was compared to placebo in gastric and gastroesophageal junction adenocarcinomas. Improvements were observed in median PFS (9.5 vs. 7.4 months; HR 0.72) and median OS (19.2 vs. 13.5 months; HR 0.77). Ongoing trials, including two Phase III studies (NCT05052801 and NCT05111626) and a basket trial, aim to further evaluate its efficacy. Research on resistance to bemarituzumab has focused on FGFR2c expression and epithelial-mesenchymal transition (EMT), as increased FGFR2c correlates with poor OS.
EGFR
In esophageal squamous cell carcinoma (ESCC), EGFR1 is primarily abnormal, whereas in gastric cancer, EGFR2 predominates. EGFR-TKI combined with PD-1 inhibitors has shown initial efficacy. Chemotherapy with EGFR inhibitors has demonstrated activity in colorectal cancer patients enriched for MET, EGFR, HER2, and fusion mutations, but results were negative in gastric and esophageal cancers. Subgroups with EGFR amplification or high expression, or those with minimal RAS/RAF mutations, showed potential benefits.
Amivantamab, a bispecific antibody targeting EGFR and MET, showed initial efficacy in colorectal cancer patients after anti-EGFR treatment, with adverse events including infusion reactions, skin toxicity, and hypoalbuminemia. In gastric and esophageal cancers, amivantamab combined with chemotherapy exhibited high activity in patients with high target expression.
MET
ABBV-400 (telisotuzumab adizutecan), a MET-targeting antibody-drug conjugate (ADC), showed preliminary efficacy in MET-amplified gastric and colorectal cancer in Phase I studies.
Other Gene Amplifications in Gastric Cancer (WES)
- CCNE1 amplification: Investigational therapies include CDK2 inhibitor INCB123667 and Wee1 inhibitor adavosertib.
- MYC amplification: Investigational therapy includes MYC inhibitor OMO-103.
- KRAS amplification: Investigational therapy includes BI 3706674.
MTAP Deletion
MTAP deletion increases tumor reliance on the MAT2A/PRMT5 axis and is commonly associated with CDKN2A co-deletion on chromosome 9p21. Found in approximately 10%–15% of tumors, including pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), ESCC, and gastric cancer, MTAP-deficient tumors are sensitive to PRMT5 and MAT2A inhibitors.
TP53
The TP53 Y220C mutation, located in the DNA-binding domain, is present in approximately 3% of ovarian cancers and 0.5%–1.5% of gastrointestinal cancers (PDAC or gastric cancer). The investigational drug Rezatapopt (PC14586) reactivates TP53 transcriptional activity. In the PYNNACLE study, PC14586 achieved a 30% ORR and a 7-month DoR in patients with wild-type RAS tumors. Adverse events included nausea, vomiting, diarrhea, and elevated creatinine.
Advances in Non-Oncogenic Targets for Gastrointestinal Tumor Therapies
Claudin Family
The Claudin family, a group of tight junction membrane proteins, plays roles in defense and permeability regulation. Under normal conditions, Claudin18.1 is highly expressed in lung tissue, while Claudin18.2 is expressed in gastric mucosa. In gastric cancer and gastroesophageal junction tumors, Claudin18.2 is consistently expressed and ectopically expressed in other malignancies like pancreatic cancer.
The first monoclonal antibody targeting Claudin18.2, Zolbetuximab, has been successfully marketed. This pure IgG1 monoclonal antibody does not exhibit direct blocking activity; its efficacy depends on antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In the SPOTLIGHT and GLOW studies, patients with ≥75% Claudin18.2 expression (IHC 2+ or 3+) showed significant improvements in progression-free survival (PFS) and overall survival (OS) with Zolbetuximab combined with chemotherapy. Researchers are planning further randomized controlled trials.
More than 30 Claudin18.2-targeted drugs are in clinical trials, including enhanced monoclonal antibodies, antibody-drug conjugates (ADCs), bispecific antibodies, and CAR-T therapies.
- Osemitamab (TST001 or ASKB589): A high-affinity Claudin18.2 monoclonal antibody. In early solid tumor studies, it achieved an overall response rate (ORR) of 67% when combined with CAPOX and 80% when combined with CAPOX and anti-PD-1 therapy.
- CT041: A Claudin18.2-targeted CAR-T therapy showed an ORR of 39% in Claudin18.2-positive gastrointestinal tumors, including 55% in gastric cancer and 20% in pancreatic ductal adenocarcinoma. Cytokine release syndrome (CRS) occurred in 97% of patients, though mostly grade 1–2, with no grade 3 CRS.
- C-CAR031: A CAR-T therapy targeting phosphatidylinositol proteoglycan-3 (GPC3), demonstrated an ORR of 50% in hepatocellular carcinoma patients, with a median duration of response (DoR) of 7.4 months. CRS occurred in 92% of patients, with 4% experiencing grade 3 CRS.
Additional drugs include Claudin18.2/CD3 bispecific T-cell engagers (BiTEs) that connect tumor cells with immune T cells, boosting recognition and destruction of cancer cells. In one study, gastric cancer patients had an ORR of 31%, while pancreatic ductal adenocarcinoma patients showed an ORR of 11.1%. Notable side effects included CRS and gastrointestinal toxicity. Other agents, such as Givastomig (Claudin18.2/4-1BB bispecific antibody) and Q1802 (Claudin18.2/PD-L1 bispecific antibody), have entered early human trials.
Claudin18.2 ADCs in development include CMG901 (an antibody conjugated to microtubule inhibitor MMAE), SHR-A1904 (conjugated to topo1 inhibitor), and IBI343 (conjugated to exatecan). These have entered Phase II or III trials. Different cutoff levels and markers such as MMR, HER2, FGFR2b, CPS, and immune markers like PD-1, CD4, CD8, and CTLA4 are being explored to optimize treatment efficacy.
TROP-2
TROP-2 is a glycoprotein overexpressed in various tumors. Sacituzumab tirumotecan (Sac-TMT), an ADC targeting TROP-2, has completed Phase I trials. TROP-2 expression serves as a biomarker, with its membrane-to-cytoplasmic ratio indicating prognosis. Lower ratios are associated with better outcomes.
CEA
CEACAM5, a surface glycoprotein involved in cell adhesion and differentiation, is highly expressed in colorectal, gastric, and non-small cell lung cancers. ADCs targeting this protein include Tusamitamab ravtansine (SAR408701) and M9140.
B7-H3
B7-H3 is a transmembrane glycoprotein in the B7 family of immune checkpoint molecules. ADCs such as DS7300 (I-DXd) and YL201 are being developed against this target.
Tissue Factor (TF)
TF is highly expressed in cervical cancer and targeted by the ADC Tisotumab, which is already approved. Resistance to ADCs is an emerging issue, leading to studies on combination therapies with immune checkpoint inhibitors, receptor tyrosine kinase (RTK) inhibitors, Wee1 inhibitors, and EZH1/2 inhibitors. Bispecific ADCs and ADC–ADC combinations are also under investigation.
Insights from Researchers
Significant advancements are being made in gastrointestinal tumor research, with HER2, KRAS, and tissue factor emerging as promising targets. The ADC trastuzumab deruxtecan (T-DXd) has demonstrated clear anti-tumor activity for HER2-targeted therapy. KRAS inhibitors show significant efficacy in pancreatic cancer, while tissue factor-targeted therapies have potential in colorectal cancer and beyond.
Emerging therapies targeting Claudin18.2, such as Zolbetuximab, CAR-T cells, and ADCs, hold great promise for gastric and gastroesophageal cancers. Additionally, HER2 amplification, even in the absence of overexpression, can serve as a target in ongoing trials. MTAP deletion, seen in 10%–15% of PDAC, BTC, ESCC, and gastric cancers, is another exciting target, with PRMT5 and MAT2A inhibitors showing sensitivity in these tumors. TROP-2, CCR families, B7-H3, and TF are also being validated as innovative therapeutic targets.
In conclusion, these breakthroughs in upper gastrointestinal cancer targets offer promising directions for improving patient outcomes and advancing precision medicine.
