What are the therapeutic candidates targeting c-Met?

Introduction to c-Met

c‑Met, also known as the hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase that plays a pivotal role in embryonic development, tissue regeneration, and wound healing. Under physiological conditions, c‑Met engages with its sole high‐affinity ligand, hepatocyte growth factor (HGF), to modulate several key cellular processes such as proliferation, differentiation, motility, and survival. The receptor’s activation – beginning with HGF binding, followed by dimerization and autophosphorylation of critical tyrosine residues – triggers cascades involving the MAPK, PI3K/Akt, STAT, and other downstream signaling networks. This basal understanding makes c‑Met not only a critical regulator under normal circumstances but also an attractive therapeutic target when dysregulation occurs.

Biological Role of c-Met

Biologically, c‑Met functions as a master regulator of cellular activities. Its activation leads to the recruitment of multifunctional adaptor proteins such as Gab1, which in turn propagate signals that stimulate changes in cell shape, promote motility, and encourage angiogenesis by altering gene expression. This receptor’s inherent ability to induce epithelial-to-mesenchymal transition (EMT) further underscores its role during both embryonic development and pathological conditions like cancer. Importantly, in the normal setting, c‑Met’s role is tightly controlled; however, overexpression, mutation, or amplification can lead to persistent activation, resulting in oncogenic transformation.

c-Met in Disease Pathogenesis

Aberrant c‑Met signaling is a recurrent event in many human cancers, including lung, gastric, colorectal, renal, and head and neck cancers. In these malignancies, c‑Met is frequently overexpressed or genetically altered via mutations, gene amplification, or exon 14-skipping events that eliminate regulatory sites, allowing unchecked signaling. The consequence is enhanced tumor cell proliferation, invasion, metastasis, and resistance to apoptosis. Additionally, c‑Met activation contributes to the formation and maintenance of cancer stem cells and may cause resistance to other targeted therapies (for example, EGFR inhibitors in non-small cell lung cancer). In essence, while the receptor’s normal functions are vital for tissue repair and homeostasis, its dysregulation drives disease pathogenesis by promoting a tumorigenic microenvironment and enabling disease progression.

Therapeutic Candidates Targeting c-Met

Given the central role c‑Met plays in tumor biology and metastasis, intensive research efforts have been directed toward developing therapeutic candidates that target this receptor. These candidates fall into several categories, each with a distinctive mechanism of action and clinical development pathway.

Small Molecules

Small molecule inhibitors represent one of the most intensively studied classes of agents targeting c‑Met. Their key advantage lies in their ability to penetrate the cell membrane and directly bind to the intracellular tyrosine kinase domain, thereby inhibiting the receptor’s catalytic activity.

• Crizotinib was among the first c‑Met inhibitors to be approved; while originally discovered for its ALK inhibitory activity, crizotinib has demonstrated efficacy in tumors harboring MET amplifications or exon 14 skipping mutations.
• Cabozantinib, a multi-kinase inhibitor, targets c‑Met along with VEGFR2 and other kinases. Its dual inhibition is believed to not only reduce tumor cell proliferation but also impair tumor angiogenesis, making it effective in multiple malignancies.
• Capmatinib is another orally available, highly selective c‑Met inhibitor that has been specifically evaluated for non‑small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations. Capmatinib has shown promising response rates and is widely considered a valid option in targeted therapy.
• Tepotinib and Savolitinib have also entered the clinical arena as selective c‑Met inhibitors. Tepotinib, in particular, has received approval based on its significant activity in MET-driven NSCLC. Savolitinib, developed and evaluated in various trials (for example, in gastric cancers and NSCLC), has been reported to have a manageable safety profile and promising efficacy data.
• Merestinib, another orally available inhibitor, has been described in the literature with promising preclinical and early clinical trial results; it has a broader kinase inhibitory profile which may be advantageous in tumors with complex signaling alterations.
• Novel compounds such as APL‑101 (also known as TQ-B3101) have emerged from recent research as potent c‑Met inhibitors. APL‑101 is currently being evaluated in global and China-based Phase 1/2 studies with an emphasis on NSCLC and other solid tumors featuring MET amplification or mutations.
• Numerous additional small molecule inhibitors have been synthesized and evaluated using structure-based drug design approaches. For example, some groups have developed quinoline and pyrimidine derivatives with a strong binding affinity for the c‑Met kinase domain. These compounds, designed based on the structural features of earlier inhibitors like BMS‑777607, underscore the continuous evolution in medicinal chemistry efforts to generate potent and selective inhibitors.
• Beyond these, research studies have also described inhibitors bearing novel scaffolds such as 3‑carboxypiperidin‑2‑one and pyrazolo[3,4‑b]pyridine derivatives – each designed to optimize binding affinity, pharmacokinetics, and safety profiles, all of which constitute promising candidates from early preclinical investigations.

Monoclonal Antibodies

Monoclonal antibodies (mAbs) targeting c‑Met offer an alternative modality that typically interferes with the receptor’s activation by preventing the binding of HGF or by inducing receptor internalization and degradation.

• Onartuzumab is one of the well-known anti‑c‑Met monovalent antibodies developed to antagonize c‑Met activation. Because bivalent antibodies may inadvertently trigger receptor activation through dimerization, onartuzumab was engineered as a monovalent fragment to avoid such agonistic effects. Although early clinical trials yielded mixed results, it remains a benchmark for antibody-based approaches.
• Emibetuzumab represents another mAb that targets c‑Met by binding to its extracellular domain. Emibetuzumab not only blocks ligand binding but may also induce receptor down‑regulation, thereby dampening the downstream oncogenic signals. Clinical trials have evaluated its potential in combination with other agents to address resistance mechanisms.
• ARGX‑111 is a newer candidate that functions by binding and neutralizing c‑Met activity while also harnessing the immune system through enhanced antibody-dependent cellular cytotoxicity (ADCC) effects. Its bispecific nature, in some studies, has shown promising synergistic activity.
• In addition to conventional mAbs, several bispecific antibodies have been developed which target c‑Met in combination with other receptors. For example, bispecific antibodies designed to target both c‑Met and PD‑1 aim to couple direct inhibition of the c‑Met signaling cascade with an immunotherapeutic effect, potentially overcoming immune evasion as well as intrinsic oncogenic signaling.
• Antibody‑drug conjugates (ADCs) directed against c‑Met are also being explored. These agents couple a cytotoxic payload to a c‑Met targeting antibody, ensuring selective delivery of the drug to c‑Met positive tumor cells. Recent preclinical data have highlighted the potential of c‑Met‑targeted ADCs, demonstrating enhanced internalization and potent efficacy in animal models.

Other Therapeutic Modalities

In addition to small molecules and mAbs, several other therapeutic modalities are under investigation for c‑Met targeting.

• Bispecific T‑cell engagers (BiTEs) and chimeric antigen receptor (CAR)‑T cells are emerging as immune‑mediated approaches for targeting c‑Met. These agents are designed to redirect T‑cells to recognize and kill tumor cells expressing high levels of c‑Met. Early studies with c‑Met‑targeted CAR‑T cells have shown promising tumor infiltration and antitumor activity in preclinical models.
• Radioligand therapy approaches are being developed that combine c‑Met targeting with the delivery of radioactive isotopes. Such agents have the potential for both diagnostic imaging and therapeutic intervention through targeted radiation delivery, as demonstrated in PET‑based imaging studies that incorporate c‑Met–selective peptides.
• Peptide‑based inhibitors and ligand traps are also emerging. These agents often mimic the structure of HGF or key binding determinants to interfere with c‑Met activation. While still in early development, they provide additional avenues to modulate c‑Met signaling without the complexities of full antibody production.

Mechanism of Action

Understanding the mechanism of action is central to appreciating how the various therapeutic candidates exert their effects upon c‑Met signaling.

Inhibition of c‑Met Signaling Pathways

Therapeutic candidates targeting c‑Met operate through several key mechanisms:

• Small Molecules – These agents typically bind to the ATP‑binding pocket within the intracellular tyrosine kinase domain of c‑Met. By competing with ATP, they inhibit the autophosphorylation events required for receptor activation. This blockade prevents the recruitment of adapter proteins such as Gab1, which would otherwise transmit downstream signals through the MAPK, PI3K/Akt, and STAT pathways that control critical cellular processes like proliferation and survival.
• Monoclonal Antibodies – mAbs generally act extracellularly. By binding to specific epitopes on the receptor’s extracellular domain, they prevent HGF from engaging its receptor, thereby blocking dimerization and subsequent activation. Some antibodies are engineered to induce receptor internalization and degradation, reducing the overall receptor density on the cell surface and further dampening downstream signaling.
• Bispecific Antibodies and ADCs – In addition to blocking ligand binding, bispecific antibodies can recruit T‑cells to tumor cells, initiating immune‑mediated cytotoxicity. ADCs, in contrast, combine receptor targeting with the intracellular delivery of cytotoxic drugs, thus killing cells that overexpress c‑Met.
• Other modalities – CAR‑T cells are modified to express receptors that specifically recognize c‑Met, thereby triggering T‑cell activation and subsequent tumor cell lysis upon encountering c‑Met‑positive cells. Radioligand therapies, on the other hand, deliver ionizing radiation directly to the tumor as a result of c‑Met binding, causing DNA damage and apoptotic cell death.

Impact on Cancer and Other Diseases

The inhibition of c‑Met signaling has broad therapeutic implications:

• In cancer, blocking c‑Met disrupts a critical pathway that drives tumor growth, metastasis, and resistance to therapy. By inhibiting c‑Met, these drugs can impair cell proliferation, reduce angiogenesis, and even reverse EMT, which is directly linked to invasive behavior.
• Furthermore, c‑Met inhibitors may sensitize tumors to other therapies. For instance, combining c‑Met inhibitors with EGFR inhibitors has been shown to overcome resistance mechanisms in NSCLC.
• Beyond oncology, c‑Met modulation is being explored in other conditions where aberrant tissue repair and fibrosis play a role. For instance, in regenerative medicine or fibrotic diseases, transient modulation of c‑Met activity might aid in balanced tissue repair.
• Additionally, some therapeutic candidates have been shown to affect the tumor microenvironment, reducing the secretion of growth factors and cytokines that aid in tumor progression and immune suppression.

Clinical Development and Trials

Numerous clinical trials have been conducted or are ongoing to evaluate the safety and efficacy of therapeutic candidates targeting c‑Met. The clinical development pathway varies across differing molecules and strategies.

Current Clinical Trials

• Several Phase II and Phase III trials have investigated small molecule inhibitors such as capmatinib, tepotinib, and savolitinib, particularly in NSCLC patients with MET exon 14 skipping mutations or MET amplification. These studies focus on endpoints such as objective response rate, progression‑free survival, and overall response rate.
• For example, capmatinib has been studied extensively in NSCLC, and its clinical trials have provided robust data on its safety, pharmacokinetics, and efficacy in a molecularly selected patient population.
• In parallel, clinical trials are investigating APL‑101 in both global and China-based studies, with indications including NSCLC, brain tumors with MET alterations, and other solid tumors.
• Monoclonal antibodies like onartuzumab have been evaluated in trials combining them with EGFR inhibitors in NSCLC, although outcomes have been mixed. The failure of onartuzumab to meet endpoints in certain studies underscores the complexities involved with patient selection and antibody design.
• Trials combining c‑Met‑targeted agents with other therapies—for instance, bispecific antibodies that target both c‑Met and PD‑1—are also underway. These innovative approaches aim to integrate targeted therapy with immunotherapy in order to improve response rates and overcome resistance mechanisms.
• Other modalities such as CAR‑T cells targeting c‑Met have reached early-phase clinical investigations. Although most data are preclinical at this point, these strategies show promise in harnessing the immune system to attack c‑Met‑overexpressing tumors.

Efficacy and Safety Data

• The safety profile of small molecules such as capmatinib, tepotinib, and savolitinib has generally been acceptable, with manageable toxicities. However, long-term observations are needed to determine whether resistance mechanisms or late‐onset adverse events occur.
• Data from clinical trials of capmatinib have reported significant efficacy in a selected subset of NSCLC patients, with improvements in progression‑free survival and overall response when compared to historical controls.
• Cabozantinib, although it targets multiple kinases, provides an example of a broader spectrum approach that can be beneficial in patients with advanced disease, yet it requires careful management of adverse effects due to its multi‑target activity.
• Monoclonal antibody studies have been more challenging. For instance, onartuzumab’s development was hampered by difficulties in achieving a clear clinical benefit in unselected populations, partly due to issues with agonistic activity at higher doses.
• Early-phase trials utilizing bispecific antibodies and ADCs are encouraging as they combine direct inhibition of c‑Met signaling with mechanisms that enhance the immune response or selectively deliver cytotoxic agents.
• Overall, clinical trial data supports the concept that patient selection based on molecular diagnostics (e.g., MET amplification, exon 14 skipping mutations) is paramount to achieving the intended efficacy with c‑Met inhibitors.
• Safety data across modalities tend to highlight common class effects such as peripheral edema, gastrointestinal disturbances, and fatigue. In contrast, antibody-based therapies sometimes generate infusion-related reactions that require careful management.

Future Prospects and Challenges

The development of c‑Met–targeted therapies continues to evolve. Several emerging trends and challenges need to be addressed before these therapies can achieve their full potential.

Emerging Therapies

• New small molecule inhibitors continue to be developed with increasingly selective and potent binding to the c‑Met kinase domain. Advances in medicinal chemistry, including structure‑based design, have led to compounds that can overcome resistance mutations around the active site.
• Innovative antibody formats, such as bispecific agents, one‑armed antibodies, and ADCs, are emerging as promising candidates. These novel formats can combine the benefits of receptor blockade with immunomodulation or targeted cytotoxic drug delivery, addressing multiple facets of tumor cell biology simultaneously.
• Cell‑based immunotherapies (such as c‑Met–directed CAR‑T cells) are at the frontier of research. Utilizing the high expression of c‑Met in certain tumors to direct personalized immunotherapies represents a cutting‑edge approach that may benefit patients with refractory cancers.
• Radioligand therapies and molecular imaging agents targeting c‑Met are also an area of active investigation. Such agents could not only serve diagnostic purposes but also deliver localized radiation to tumor sites, thereby bridging the gap between diagnosis and therapeutic intervention.
• Furthermore, combination therapies that integrate c‑Met inhibitors with other targeted agents (e.g., EGFR inhibitors, VEGFR inhibitors) and immune checkpoint inhibitors are being actively explored. Such strategies are designed to neutralize compensatory pathways and overcome acquired resistance.

Challenges in Targeting c-Met

Despite significant progress, several challenges must be overcome:

• Patient Selection: A major hurdle has been the reliable stratification of patients who are most likely to benefit from c‑Met inhibitors. Variability in c‑Met expression, the presence of MET amplification or mutations, and differences in assay methodologies (immunohistochemistry, FISH, NGS) have introduced challenges in clinical trial design and interpretation of outcomes.
• Resistance Mechanisms: As observed with many targeted therapies, resistance to c‑Met inhibition is a recurrent problem. Secondary mutations within the kinase domain, activation of bypass signaling pathways, and compensatory receptor tyrosine kinase signaling can limit long‑term efficacy. Ongoing research is directed at understanding these mechanisms and developing next‑generation inhibitors to overcome them.
• Optimal Combination Strategies: Determining which agents to combine with c‑Met inhibitors remains a critical question. Effective combinations must balance efficacy with safety while avoiding overlapping toxicities. This is particularly important given that many patients will require prolonged treatment regimens.
• Adverse Effects: While the safety profiles of many c‑Met inhibitors have been acceptable, managing class-specific toxicities such as peripheral edema, gastrointestinal symptoms, and potential infusion-related reactions in antibody therapies continues to require refinement.
• Regulatory Pathways and Biomarker Validation: The development and approval of these agents depend significantly on robust biomarkers that can predict response and monitor efficacy in clinical settings. The harmonization of biomarker assays and criteria across trials is an ongoing challenge.
• Cost and Accessibility: Novel therapies – particularly advanced immunotherapies and ADCs – are often expensive, and ensuring broad access to these treatments remains an important concern for healthcare systems worldwide.

Conclusion

In summary, therapeutic candidates targeting c‑Met encompass a broad and evolving spectrum of agents ranging from small molecule inhibitors to monoclonal antibodies, bispecific formats, ADCs, and emerging cell‑based therapies. The biological rationale for targeting c‑Met is built on its central role in normal physiology as well as its aberrant activation in diverse cancers, where it drives proliferation, metastasis, and therapeutic resistance.

Small molecules such as crizotinib, cabozantinib, capmatinib, tepotinib, savolitinib, merestinib, and the investigational candidate APL‑101 have shown considerable promise by inhibiting the ATP-binding domain of c‑Met, thereby blocking downstream signaling pathways. Monoclonal antibodies, including onartuzumab, emibetuzumab, and ARGX‑111, operate through extracellular blockade of the receptor, while next‑generation antibody formats such as bispecific antibodies and ADCs are being developed to not only suppress c‑Met signaling but also to stimulate immune attack or deliver targeted cytotoxic agents. Other therapeutic modalities such as CAR‑T cells and radioligand therapies further expand the potential impact of c‑Met targeting strategies, particularly in overcoming resistance and treating refractory disease.

Mechanistically, these agents act primarily by interfering with c‑Met activation and its downstream signaling cascades (MAPK, PI3K/Akt, STAT), ultimately inhibiting tumor growth, migration, angiogenesis, and resistance to apoptosis. Clinically, numerous trials focusing on molecularly defined patient populations have produced promising efficacy and safety data, although challenges remain regarding optimal patient selection, resistance, and combination strategies. Emerging therapies continue to push the boundaries of what is achievable with c‑Met–targeted treatments. Yet the challenges inherent in biomarker refinement, resistance management, and cost‐effective delivery of complex therapies continue to shape the future prospects of this field.

In conclusion, c‑Met represents one of the most attractive and challenging targets in oncology. The diversity of therapeutic candidates—from small molecules and monoclonal antibodies to innovative immunotherapies and beyond—illustrates the multifaceted approach required to fully exploit c‑Met as a therapeutic target. Continued refinement of molecular diagnostics, combination regimens, and next‑generation inhibitory strategies will be essential to overcome current limitations and deliver durable, effective therapies to patients with c‑Met–driven malignancies. The evolving clinical landscape and ongoing research efforts provide a strong rationale for optimism while underscoring that strategic, patient‑tailored approaches and further innovation are needed to fully achieve the potential of c‑Met targeting in cancer and other diseases.