Gastric cancer is one of the most common malignant tumors of the digestive system and is currently the second most prevalent tumor in China. The treatment options for advanced gastric cancer are still very limited and the treatment needs are far from being met, and the median survival of patients with locally advanced and metastatic disease is generally only 9 to 12 months. Targeted therapy may further improve the efficacy of advanced gastric cancer based on traditional chemotherapy. The only internationally approved targeted therapy for advanced gastric cancer is trastuzumab, which acts on the HFR2 target.
With the development of proteomics and genomics, tumor treatment is rapidly developing in the direction of individualized and precise treatment. In addition to HER2, the top I therapeutic targets in gastric cancer include HGF/MET pathway, PARP target and PD-1/PD-LI target immunotherapy, and this lecture will review the related research and progress.
I. MET targets
MET is a tyrosine kinase receptor, which plays a key role in the growth, invasion and metastasis of many solid tumors. When the ligand HGF binds to MET, the HGF/MET signaling pathway is activated and undergoes autophosphorylation to recruit downstream bridging proteins such as Gab-1, Grb-2, Shc and c-Cbl, followed by activation of PI3K, ERK l/2, PLC-Cbl through a series of phosphorylation reactions. ERK l/2, PLC-^y, STAT and FAK and other important signaling molecules and corresponding signaling pathways through a series of phosphorylation reactions, thereby regulating the proliferation, migration and invasive ability of tumor cells.
Overexpression of MET can be observed in most solid tumor tissues and correlates with poorer prognosis. Studies have shown that 26-74% of cases of gastric cancer are associated with MET overexpression and 2-23% of cases have gene amplification. Similarly, elevated serum HGF levels at diagnosis in gastric cancer patients correlate with disease stage, and HGF levels decrease after tumor resection. In a meta-analysis of the correlation between MET expression and amplification and prognosis of gastric cancer, the risk ratios of death in patients with high MET expression and amplification were 2.42 (95% confidence interval: (1.66-3.54) and 2.82 (95% confidence interval: 1.86-4.27), respectively, suggesting that high MET expression and amplification are poor prognostic factors for gastric cancer.
Since MET is the intersection of many pathways leading to tumor formation and metastasis, it is relatively easy to target MET to interfere with many pathways simultaneously. Once the abnormally activated HGF/MET signaling pathway in tumor cells is blocked, tumor cells will show a series of changes such as cell morphology, slowed proliferation, reduced tumorigenicity, and decreased invasion ability. Thus, MET has become an extremely promising new target for anti-tumor metastasis therapy, and is one of the most promising targets for gastric cancer treatment.
There are two major classes of HGF/MET signaling pathway inhibitors: large-molecule monoclonal antibodies targeting the MET receptor or ligand HGF, such as onartuzumab (MetMab) and Rilotumumab; and small-molecule tyrosine kinase inhibitors, such as AMG 337, INC280 and Volitinib. MetMab is a single-arm antibody that acts on MET, and its initial phase II study (OAM4558g) showed preliminary efficacy in MET-positive lung cancer in a subgroup analysis, but this year ASCO published the results of an interim analysis of MetTlung, a phase III study evaluating MetMab in combination with erlotinib versus erlotinib in patients with MET-positive advanced NSCLC, with unsatisfactory results, and Roche stopped further development of MetMab. further development of MetMab. However, due to differences in MET-positive screening methods, tumor species differences, and the study design itself, confidence in the study of MET pathway inhibitors in other tumors has not been lost.
The current data on MET inhibitors in gastric cancer are mainly from Rilotumumab and AMG 337, a fully human anti-HGF monoclonal antibody that inhibits MET pathway activation by preventing HGF from binding to its receptor MET. o The Rilotumumab20060317 study is a study in advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction, in which subjects were randomized to receive either ECX chemotherapy or ECX in combination with rilotumumab.
Although there was a prolongation of OS time in the overall population in the rilotumumab combination group versus chemotherapy alone (10.6 months vs. 8.9 months), the difference was not significant. Immunohistochemical (IHC) testing of the MET status of the tumor tissue revealed a median overall survival (OS) of 10.6 months (80% CI 9.2, 12.0) in the MET-positive patients in the rilotumumab-treated group compared to 5.7 months (80% CI 4.7, 10.2) in the placebo group, with a median OS difference of 4.9 months. Positive MET expression may be an important predictive marker of efficacy for rilotumumab. However, the sample size was too small, so based on the results of this phase II study ‘ and focusing on the differences in standard treatment between the East and West, a randomized controlled phase III study was subsequently conducted in Eastern and Western populations to investigate the role of rilotumumab in combination with the respective standard chemotherapy first-line treatment for patients with advanced gastric cancer with MET overexpression.
AMG 337 is a highly selective and potent small molecule inhibitor of MET that acts by all known mechanisms of MET activation except for mutations at certain binding sites. AMG 337 inhibits cell proliferation in vitro and blocks MET-dependent pathways in vivo to inhibit the growth of transplanted tumors. ASCO presented the results of the first human study of AMG337 as an oral presentation, which included data from patients with gastric cancer.
Among 10 patients with MET-amplified advanced gastric or gastroesophageal junction cancer who failed repeated therapy, 5 achieved objective remission, with a 50% remission rate, including one patient in remission for more than 2 years, suggesting the promising use of MET small molecule inhibitors in the MET-amplified gastric cancer population. A phase II single-arm study of MET-amplified gastric cancer failing standard therapy is also underway in both Eastern and Western populations. Other small molecule inhibitors of MET, such as Volitinib, have also completed phase I dose-escalation trials and have shown good efficacy in other solid tumors in the MET-hyperamplified population, and trials in gastric cancer are actively under preparation.
There are still many important questions to be answered in the current MET-targeted therapy research. One of the most critical ones is how to select biomarkers to select the most suitable patients for MET-targeted therapy according to the principle of personalized treatment, and at the same time to distinguish between large-molecule monoclonal antibodies and small-molecule inhibitors.
The previous large-molecule monoclonal antibody MetMab lung cancer study and the current Rilotumumab gastric cancer study both used IHC as an important method to select patients with MET overexpression; while the phase I/II studies of AMG 337 and INC280, Volitinib and other small-molecule inhibitors of MET used FISH or FISH combined with IHC to select patients with MET-positive tumors. It is believed that after more studies are published, there will be a clear answer to this question, including what is the appropriate threshold for IHC overexpression and FISH amplification.
II. PAPR Targets
PolyADP-ribose polymerase (PAPR) has important roles in maintaining the structural integrity of chromosomes, participating in DNA replication and transcription, and maintaining genomic stability. Therefore, PARP inhibitors can inhibit the repair of DNA damage in tumor cells and enhance the sensitivity of tumor cell DNA to damage factors. In recent years, PARP inhibitors have received more and more attention in tumor therapy research.
The current research on PARP inhibitors includes two main aspects: the synthetic lethal effect of PARP inhibitors alone in tumors with defective reticulocyte recombination repair (including BRCA l.2 mutation); and the enhancement of chemotherapy and radiotherapy as chemosensitizing agents. Because BRCA mutations are more common in breast and ovarian cancers, PARP inhibitors have been extensively studied in breast and ovarian cancers. Although a completed phase III clinical study of PAPR inhibitors in progressive triple-negative breast cancer did not yield satisfactory results, research on PARP inhibitors has not stopped, and perhaps with the development of molecular biology techniques, more suitable populations for PAP inhibitors will be screened for individualized tumor treatment.
PARP inhibitors have also begun to be explored in gastric cancer. Last year, ASCO reported a phase II study of Olaparib, an oral PARP inhibitor, in patients with gastric cancer treated with Olaparib in combination with paclitaxel versus paclitaxel alone in second line, and the results are shown in Table 1. A subgroup analysis was performed for patients with low ATM expression by IHC. OS was longer in the combination therapy group, but PFS was not statistically different. Neutropenia was greater in the combination therapy group (56% vs. 39%).
Based on the encouraging results from the Olaparib phase II study, a phase III study led by Professor Bang is underway to define the therapeutic role of Olaparib in combination with paclitaxel versus paclitaxe in the second-line treatment of advanced gastric cancer.
PD-1/PD-L1 signaling pathway inhibitors
Tumor immunotherapy is to purposely remove the cancerous cells by activating the immune cells in the body. With the advantages of high specificity, long duration of action and minimal side effects, this treatment has been considered as the ultimate means to cure tumors. However, it is only in recent years that this dream may have begun to be realized with the emergence of antibodies targeting immune test sites and autologous T-cell therapies expressing chimeric antigen receptors (CARs). Science magazine listed tumor immunotherapy as a major scientific breakthrough in 2013.
Among these, the most recent to attract attention are antibodies targeting the lmmune Checkpoint programmed death-1 (PD-1) and its ligand (PD-L1). As a newly identified member of the B7/CD28 immunoglobulin supergene family, PD-1 has been shown to negatively regulate the immune response by inhibiting the activation and proliferation of T cells and plays an important role in regulating immune tolerance, microbial infection and tumor immune escape.
The activation of T cells is finely regulated by a “dual-signaling” pathway. One activation signal is the binding of MHc (major histocompatibility complex) and TcR (T cell receptor), and the other is signaling from co-stimulatory molecules (OX40, 4-1BB) and co-inhibitory molecules such as PD-L1/PD-1. Thus, monoclonal antibodies targeting PD.1/PD.L1 can block the negative effect of PD-l/PD-L1 on T cells, and T cells are freed from the suppression of arsenical tumor cells and are reactivated to recognize and kill tumor cells, thus exerting anti-tumor effects.
There are several companies developing monoclonal antibodies against PD-1 and PD-L1, and the competition is very fierce. Currently, Nivolumah and Pembrolizumab for PD-1 and MPDL3280A and MEDI-47360 for PD-L1 are in Phase III clinical trials, while combination therapy trials with CTLA-4 and PD-1 monoclonal antibodies are also underway with promising results. The release of clinical trial data for immune test site inhibitor monoclonal antibodies has been a notable highlight at ASCO annual meetings for the past three years. Multiple immune test point antibodies are expected to become available in the next few years, and the indications will be expanded to include other tumor types.
While PD-1/PD-LI antibodies have been focused on melanoma and non-small cell lung cancer, and encouraging results have been achieved, the results of the Phase I MEDI-47361 extension study presented at this year’s ASCO Annual Meeting offer a glimpse of PD-I/PD-L1 antibodies for the treatment of colon cancer. The vast majority (92%) of patients in the human arm were patients with advanced tumors who had received more than one systemic therapy, and 16 patients with gastroesophageal cancer could be evaluated for oncologic response, including 4 who achieved objective remission, for a remission rate of 25%.
Several PD-1/PD-L1 antibodies currently have plans to enroll gastric cancer in their Phase I studies, with the largest enrollment of gastric cancer patients being MSB0010718C, which is planned to enroll 150 gastric or combined gastroesophageal cancers in the dose expansion phase of the Phase I study. Therefore, more gastric cancer data will be published in the next few years.
Tumor immunotherapy as a new therapeutic concept brings new thoughts on both clinical trial protocol design and safety assessment of this new drug class. First of all, it is the issue of efficacy assessment of solid tumors. In clinical trials of immune test point monoclonal antibodies, some patients’ tumors become larger in size in the first few months, and the efficacy of the drug can only gradually appear after a few months, and then the tumor size gradually becomes smaller and is controlled in the longer term.
So the clinical trial protocol design for this new drug class needs to take into account these new changes to test the efficacy of the new drug with the most optimal regimen, clinical assessment endpoints and statistical methods. The second key unanswered question is how to use biomarkers to select the most appropriate patients for tumor immunotherapy based on the principle of personalized treatment, as the overall patient population in clinical trials of immunologic point-of-care monoclonal antibodies did not have high remission rates. Finally, tumor immunotherapy, while avoiding the toxicity of some traditional oncology drugs, poses new safety challenges, as immune test point monoclonal antibodies can cause serious adverse reactions related to the autoimmune system (e.g., colitis and pituitary inflammation) and even death.
Overall, targeted therapies for gastric cancer are also moving forward with twists and turns. Targeted drug development for HGF/MET pathway, PARP target and PD-1/PD-L1 signaling pathway and other targets, as well as continuous improvement of biomarker detection means, will bring new breakthroughs for individualized treatment of gastric cancer beyond HER2.