Editor's Note: Clear cell sarcoma is an extremely rare subtype of soft tissue sarcoma. Owing to its low incidence and limited clinical understanding, there has long been no established standard treatment, and therapeutic options remain limited. The c-MET pathway plays a critical role in the development and progression of clear cell sarcoma. However, previous studies of MET inhibitors have yielded disappointing results, highlighting the urgent need for better treatment strategies and more precise methods of identifying patients likely to benefit.At the recent 29th Chinese Society of Clinical Oncology (CSCO) Academic Annual Meeting, Professor Binghao Li of the Second Affiliated Hospital of Zhejiang University School of Medicine presented interim findings from VEBrant, a phase II study investigating vebreltinib in combination with immunotherapy for clear cell sarcoma [1]. He shared detailed insights into the exploration of this combination in advanced clear cell sarcoma. Oncology Frontier invited Professor Li for an exclusive interview to discuss the clinical implications of the study findings.
Oncology Frontier:
Clear cell sarcoma is a relatively rare type of soft tissue sarcoma, and treatment options specifically targeting this disease remain limited. Vebreltinib is a MET inhibitor that has been investigated in several clinical settings in recent years. Could you introduce the background and key design considerations behind this phase II study? What were the main endpoint results presented at this year’s CSCO meeting?
Professor Binghao Li: Clear cell sarcoma is indeed an extremely rare soft tissue sarcoma for which no standard treatment has yet been established. The c-MET pathway plays an important role in its development and progression. However, a previous study of crizotinib, a type Ia MET inhibitor, in clear cell sarcoma reported an objective response rate (ORR) of only 3.8%, indicating limited clinical benefit [2].
Vebreltinib is a highly selective type Ib MET inhibitor that has previously demonstrated antitumor activity in solid tumors harboring various MET alterations, including MET exon 14 skipping, MET amplification, and MET fusions. Against this background, we initiated VEBrant, an investigator-initiated, multicenter, prospective phase II clinical study.
The study enrolled patients with advanced clear cell sarcoma harboring the EWSR1-ATF1 fusion and excluded those who had previously received any MET inhibitor. Before enrollment, all patients had received immune checkpoint inhibitor treatment for at least four months without experiencing tumor shrinkage. After enrollment, patients received vebreltinib at 200 mg twice daily in combination with the same PD-1/PD-L1 agent they had previously been receiving.
The study used Simon’s two-stage design, with a planned total enrollment of 30 patients. The primary endpoint was ORR assessed according to RECIST version 1.1. Secondary endpoints included disease control rate (DCR), other clinical outcomes, and safety.
At the CSCO meeting, we reported the primary endpoint data available as of September 2026. Among 23 evaluable patients, the ORR was 35%, the DCR was 70%, and median progression-free survival (PFS) was 4.2 months. Median overall survival (OS) had not yet been reached [1].
Oncology Frontier:
The presentation also included biomarker findings. What considerations informed the exploration of biomarkers during the study design? What preliminary insights do the current results offer regarding the identification of patients who may benefit from MET-TKIs such as vebreltinib?
Professor Binghao Li: During the study design, we recognized that although the c-MET pathway plays a critical role in clear cell sarcoma, previous clinical studies of MET inhibitors had not produced satisfactory results. This may be attributable to differences in drug selectivity and heterogeneity within the patient population.
We therefore wanted to investigate the relationship between c-MET expression and treatment efficacy by measuring tumor c-MET expression using immunohistochemistry with the SP44 antibody. Our goal was to identify patients who might be more likely to benefit from MET inhibitor treatment.
To date, we have collected c-MET expression data from 23 patients, with a median H-score of 110. Further stratified analysis of 17 patients who had completed efficacy assessments revealed that patients with an H-score of 120 or higher had a DCR of 100%, including four cases of partial response (PR) and two cases of stable disease (SD). Median PFS in this group exceeded 12 months.
By comparison, patients with an H-score below 120 had a DCR of 64%, including three cases of PR, four cases of SD, and four cases of progressive disease (PD). Median PFS in this group was only four months.
These preliminary findings suggest that c-MET expression levels may be an independent factor influencing the efficacy of MET inhibitors. Patients with an H-score of 120 or higher may be more likely to derive clinical benefit from vebreltinib. Of course, this conclusion is based on interim data from a small patient population. Longer follow-up and studies involving larger cohorts are needed to validate these findings.
Oncology Frontier:
In clinical practice, physicians pay close attention to both efficacy and safety. Based on the current study data, how has vebreltinib performed in terms of safety in patients with clear cell sarcoma? How do you assess its potential clinical value in treating this disease?
Professor Binghao Li: The current data demonstrate clear antitumor activity with vebreltinib in patients with advanced clear cell sarcoma. An ORR of 35%, a DCR of 70%, and a median PFS of 4.2 months all suggest that this treatment warrants further investigation in this rare sarcoma subtype, for which therapeutic options are limited.
Regarding safety, 80% of the 25 patients experienced treatment-related adverse events. Grade 3 or higher treatment-related adverse events occurred in 20% of patients, corresponding to five cases: four cases of rash and one case of fever. These events may have been associated with the PD-1/PD-L1 therapy. Overall, the safety profile was manageable, and symptoms could be effectively alleviated through appropriate clinical interventions. No severe toxicities beyond those expected with known MET-TKIs were observed.
To manage adverse events, we initiated prophylactic doxycycline or minocycline when treatment began. No additional cases of grade 3 or higher rash occurred thereafter.
In terms of potential clinical application, I believe vebreltinib could offer a new treatment option for patients with advanced clear cell sarcoma. In particular, combining it with an immune checkpoint inhibitor may help overcome the immunotherapy resistance commonly encountered in clinical practice. c-MET expression could also be considered as a biomarker to help identify appropriate patients for treatment.
However, median OS data remain immature, and longer follow-up is needed to further characterize the treatment’s long-term efficacy and safety.
Oncology Frontier:
Because clear cell sarcoma is so rare, prospective clinical studies can face challenges with patient enrollment and sample size. What strategies did your team adopt to address these challenges during the design and implementation of this phase II study? What lessons might these experiences offer for future clinical research in rare tumor subtypes?
Professor Binghao Li: The extremely low incidence of clear cell sarcoma makes prospective clinical research challenging, particularly in terms of patient recruitment and sample size. We adopted several strategies during the study design and implementation to address these difficulties.
First, we used a multicenter collaborative model. By involving multiple centers, we aimed to accelerate patient enrollment and overcome the difficulties that individual centers face when recruiting patients with rare tumors.
Second, we adopted Simon’s two-stage design, with a planned total enrollment of 30 patients. This approach allows us to maintain scientific rigor while keeping the sample size manageable. It also enables the study process to be adjusted in a timely manner based on interim results while helping safeguard patients’ interests.
Regarding treatment strategy, we combined vebreltinib with the immune checkpoint inhibitor that each patient had already been receiving. This design reflects real-world clinical practice and responds to the strong demand among patients for combination treatment, with the potential to deliver greater clinical benefit.
For eligibility criteria, we carefully selected patients with EWSR1-ATF1 fusion-positive clear cell sarcoma and excluded those who had previously received MET inhibitors. This was intended to maximize the homogeneity of the study population and minimize the influence of confounding factors on the results.
In addition, because rigorous randomized controlled trials are difficult to conduct in rare tumors, we established an external real-world control group. This group had no fixed sample size, enrolled patients during the same period as the treatment group, and was used only for exploratory analyses rather than formal statistical comparisons. Although baseline differences between the groups may exist, the external control still provides an important additional reference for interpreting the study findings.
Overall, I believe these experiences offer useful guidance for future research involving rare tumor subtypes. Multicenter collaboration, appropriate statistical designs, biomarker-guided enrichment of the study population, treatment strategies informed by clinical practice and patient needs, and external real-world control data are all important considerations when designing high-quality studies in rare cancers.
Professor Binghao Li
