What's the latest update on the ongoing clinical trials related to c-Met?

Understanding c-Met

Role of c-Met in Cancer
c-Met, also known as the hepatocyte growth factor receptor (HGFR), plays a pivotal role in regulating cell growth, migration, survival, and angiogenesis. Aberrant activation of c-Met—whether by mutation, gene amplification, overexpression, or ligand (HGF) binding—has been linked to tumorigenesis in various cancers including non‐small cell lung cancer (NSCLC), gastric cancer, hepatocellular carcinoma, and others. Its dysregulation leads to enhanced invasive capabilities, metastatic spread, and often correlates with poor clinical outcomes. Through its downstream signaling pathways such as PI3K/Akt/mTOR, RAS/MAPK, and STAT, c-Met contributes significantly to cancer progression and resistance to conventional therapies.

c-Met as a Therapeutic Target
Given its central role in cancer biology, c-Met is an attractive target for therapeutic intervention. Several small-molecule inhibitors, monoclonal antibodies, and novel antibody–drug conjugates (ADCs) have been developed to interrupt c-Met signaling. Agents such as TPX-0022 have shown promising preclinical profiles—with high potency and selectivity in targeting both c-Met and additional kinases like CSF1R and c-Src—which in turn may overcome multifactorial resistance mechanisms. Moreover, emerging approaches involving c-Met–targeting CAR-T cells and combination strategies with other targeted agents further underscore the enthusiasm for mitigating c-Met–driven oncogenic processes.

Current Clinical Trials

Overview of Ongoing Trials
The clinical landscape for c-Met–targeted therapies has evolved considerably over the past few years. There are now several ongoing clinical trials—ranging from early-phase to phase III studies—that are investigating the safety, tolerability, pharmacokinetics, and efficacy of novel c-Met inhibitors and therapeutic antibodies. For example, a phase I/II study (NCT03993873) is evaluating TPX-0022 in patients with advanced NSCLC and gastric cancer harboring MET genetic alterations. Furthermore, biomarkers-based trials are increasingly being incorporated to better identify patient subpopulations most likely to benefit from c-Met inhibition, using methodologies that include fluorescence imaging, circulating tumor cell capture, next-generation sequencing (NGS), and immunohistochemistry (IHC). This integrated approach in trial design is critical given the molecular heterogeneity observed in c-Met–driven tumors.

Key Trials and Their Objectives
Among the pivotal ongoing studies, several stand out:

- TPX-0022 Phase I/II Trial:
Designed to assess safety, tolerability, pharmacokinetics, and preliminary efficacy in cancers with MET gene alterations, this trial is focusing on two indications—advanced NSCLC and gastric cancer. The study incorporates robust biomarker stratification to target MET amplification, exon 14 skipping mutations, and overexpression. Initial results have been encouraging, suggesting that TPX-0022 might overcome resistance mechanisms seen with first-generation c-Met inhibitors.

- SPARTA Study for Vebreltinib (APL-101):
Another critical trial in the c-Met inhibitor space is the SPARTA study, which is a phase II trial evaluating vebreltinib—a potent and selective oral c-Met inhibitor. The study enrolls various cohorts including c-Met naïve MET exon 14 skipping NSCLC subjects, MET amplification–positive NSCLC, and histology-agnostic cancers harboring MET gene fusions. Notably, the trial also explores combination strategies with EGFR inhibitors to address acquired resistance mechanisms in EGFR-mutant patients. With over 240 subjects enrolled across all cohorts, this study is expected to provide comprehensive data on the efficacy and safety of vebreltinib in different patient subgroups.

- Biomarker-Centric Trials:
In addition to therapeutic agent studies, there are clinical trials designed primarily to validate biomarkers for predicting treatment responses to c-Met inhibitors. For instance, studies evaluating the feasibility of capturing circulating tumor cells (CTCs) using c-Met targeted probes have been initiated to enhance patient stratification and real-time monitoring of treatment efficacy. Such studies are critical to move from a “one-size-fits-all” approach into precision oncology for c-Met–driven tumors.

Trial Methodologies

Study Designs and Phases
Ongoing clinical trials for c-Met targeting therapies predominantly incorporate early-phase (I/II) designs with adaptive features that allow for escalation based on safety and preliminary efficacy signals. For example, the TPX-0022 phase I/II study is structured to first determine the maximum tolerated dose (MTD) and then expand into specific cohorts based on MET alterations. These studies are generally open-label, often using a dose-escalation format followed by dose-expansion cohorts. In more advanced settings, randomized controlled designs are being considered to compare the new agent against the standard-of-care therapies or to assess these compounds in combination with other targeted agents (e.g., anti-EGFR therapies).

Additionally, many of the studies have become increasingly biomarker-driven. There is a strong emphasis on genomic profiling using NGS and IHC-based approaches to select patients with MET amplification, exon 14 skipping mutations, or overexpression. Adaptive trial designs are in development to allow modifications, such as cohort expansion or discontinuation, depending on interim efficacy and safety data. This strategy not only speeds up the drug development process but also ensures that the right population receives a potentially efficacious therapy.

Biomarkers and Endpoints
Biomarkers play a crucial role in the evaluation of c-Met inhibitors in clinical trials. The identification and monitoring of predictive markers—such as MET gene amplification, exon 14 skipping mutations, protein overexpression, and circulating tumor cells—are integrated into trial endpoints. Primary endpoints typically include objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), while secondary endpoints may assess quality-of-life measures, pharmacokinetics, and safety profiles.

For instance, in the TPX-0022 trial, patient selection is largely dependent on the status of MET alterations, ensuring that the treatment population is enriched for those most likely to benefit. Additionally, some studies incorporate functional imaging and tissue-based assessments (using techniques like PET with MET-targeted probes) as exploratory endpoints to better understand the biodistribution and receptor occupancy of the investigational drug. This level of detailed biomarker integration is imperative in identifying early signals of efficacy and a better understanding of resistance mechanisms.

Recent Findings and Implications

Interim Results and Updates
Recent interim analyses from ongoing trials have yielded promising updates. In the TPX-0022 phase I/II trial, early signals indicate that the agent is well tolerated and demonstrates promising activity in patients with MET-driven NSCLC and gastric cancer. The pharmacokinetic profile appears favorable, and initial tumor responses have been observed in cohorts with confirmed MET alterations. Although it is early in the trial, these results suggest that compact multicyclic scaffold–based inhibitors like TPX-0022 might provide a viable option over the more established linear inhibitors, with potential benefits in terms of metabolic stability and oral bioavailability.

On the other hand, the SPARTA study evaluating vebreltinib (APL-101) in NSCLC cohorts has been progressing steadily. Interim data from this trial have shown that the drug is active in multiple cohorts, including patients with c-Met naive MET exon 14 mutations, MET amplification, and those with MET gene fusions. These preliminary signals have established the possibility that vebreltinib could not only serve as monotherapy in selected patient populations but also as a component of combination regimens designed to overcome resistance, particularly in EGFR-mutant patients with secondary MET amplification.

Furthermore, biomarker-focused trials, such as those assessing circulating tumor cells (CTCs) using c-Met–targeted probes, are beginning to show that dynamic changes in c-Met expression can be monitored noninvasively. This innovation could allow clinicians to track treatment response in real time, thereby offering insights into the evolution of resistance during the therapy course.

Potential Impact on Treatment Strategies
The early positive results from these ongoing trials have several important clinical implications. First, they support the notion that a biomarker-driven approach to patient selection significantly improves the clinical benefit of c-Met inhibitors. By confining treatment to patients with demonstrable MET alterations (such as MET amplification or exon 14 skipping), these studies increase the likelihood of achieving meaningful clinical responses.

Second, the promising safety profiles and preliminary efficacy results encourage further exploration of combination regimens. For instance, combining c-Met inhibitors with other targeted therapies (such as EGFR inhibitors) is emerging as a strategy to combat acquired resistance—an issue observed in patients treated with monotherapy. Finally, the integration of advanced imaging and molecular monitoring into clinical trials is expected to refine treatment algorithms further. As emerging data validate the use of PET and other modalities to quantify c-Met activity in vivo, treatment regimens might be tailored in real time to maximize therapeutic outcomes.

Future Directions

Challenges in Targeting c-Met
Despite these promising updates, several challenges remain in the clinical development of c-Met–targeted therapies. One major hurdle is the inherent complexity of the c-Met signaling pathway and the multiple mechanisms by which tumors develop resistance. Acquired resistance through secondary mutations in the MET kinase domain, bypass signaling via other receptor tyrosine kinases, and the heterogeneity of MET alterations across different tumor types complicate treatment strategies. Moreover, patient selection remains critical; inconsistent or suboptimal detection methods for MET alterations can lead to the inclusion of patients unlikely to respond, thereby diluting trial outcomes.

Furthermore, safety concerns such as potential off-target effects—especially when c-Met inhibitors are combined with other agents (as seen in trials combining immunotherapies and targeted agents)—warrant vigilant monitoring. There is also the risk of on-target toxicity in normal tissues that express low levels of c-Met, emphasizing the need for highly specific inhibitors with favorable therapeutic windows.

Emerging Research and Innovations
In response to these challenges, emerging research is focusing on next-generation c-Met inhibitors with unique scaffold architectures that may improve efficacy and mitigate resistance. Innovations such as TPX-0022’s compact multicyclic scaffold have been developed to provide improved oral bioavailability and metabolic stability compared to traditional linear inhibitors. Additionally, novel therapeutic constructs such as antibody–drug conjugates, bispecific antibodies targeting c-Met alongside EGFR or PD-1/PD-L1, and engineered CAR-T cells are being investigated to broaden the therapeutic options against c-Met–driven cancers.

Biomarker innovation is also on the rise. New methods for real-time monitoring of c-Met expression—such as the use of PET probes that target intracellular domains of c-Met—are currently under clinical evaluation. These advances aim not only to predict and monitor treatment response but also to help adjust therapeutic strategies dynamically as the tumor evolves. In parallel, adaptive clinical trial designs that integrate genomic and proteomic profiling are likely to become more mainstream, thereby enhancing the precision with which therapies are matched to individual patients’ tumor biology.

Ongoing trials are thus providing a roadmap for the future. The combination of improved drug design with sophisticated patient stratification and dynamic monitoring will, in the near future, make it possible to better overcome the challenges of drug resistance, reduce off-target effects, and ultimately improve survival outcomes for patients with c-Met–driven cancers.

Conclusion
In summary, the latest update on ongoing clinical trials related to c-Met reveals a dynamic and rapidly evolving field that is moving toward more personalized and effective treatment strategies. Early-phase studies—such as the TPX-0022 phase I/II trial—have shown encouraging safety profiles and preliminary efficacy in advanced NSCLC and gastric cancer, highlighting the potential of novel agents designed with improved pharmacological properties. The SPARTA study for vebreltinib (APL-101) is similarly advancing, with multiple cohorts enrolled and objective responses being observed in patients with specific MET genetic alterations.

The clinical trial methodologies now emphasize adaptive, biomarker-driven designs that rely on robust genomic and proteomic profiling to ensure precise patient selection and real-time monitoring of therapeutic efficacy. The integration of advanced imaging modalities and liquid biopsy techniques into ongoing trials further enhances the ability to monitor and adjust treatment strategies dynamically.

As these trials progress, interim results and emerging data suggest that combination strategies—whereby c-Met inhibitors are paired with other targeted agents or immunotherapies—could be key in overcoming resistance and improving patient outcomes. Nevertheless, significant challenges remain, including the heterogeneity of c-Met alterations, the development of acquired resistance, and potential safety concerns. Future research will need to focus on next-generation inhibitors, refined patient selection, and adaptive clinical trial designs to fully realize the therapeutic potential of targeting c-Met.

In conclusion, the current clinical development of c-Met inhibitors is marked by promising advances in drug design, patient stratification, and adaptive trial methodologies. Ongoing studies are expected to shape the future of targeted cancer therapy, potentially offering improved outcomes for patients battling c-Met–driven cancers. The integration of novel biomarkers and combinatory approaches stands to significantly impact treatment paradigms in the coming years, ultimately bringing us closer to more effective and personalized cancer care.