Editor's Note: During the 2026 European Society for Medical Oncology (ESMO) Congress, updated results from the FRONTIER study exploring first-line fruquintinib plus serplulimab in non-clear cell renal cell carcinoma were presented. Non-clear cell renal cell carcinoma encompasses multiple pathological subtypes with substantial differences in biological behavior and molecular characteristics, and the available treatment evidence remains limited. Oncology Frontier – UroStream invited Professor Jiwei Huang from Renji Hospital, Shanghai Jiao Tong University School of Medicine, to discuss the rationale behind the study design, updated efficacy data, and biomarker investigations, providing insights into research directions for personalized treatment of non-clear cell renal cell carcinoma.Clinical Rationale: Exploring the Value of Targeted Therapy Plus Immunotherapy in a Heterogeneous Population
Oncology Frontier – UroStream: The FRONTIER study selected fruquintinib plus serplulimab as first-line treatment for non-clear cell renal cell carcinoma. What were the main clinical needs and scientific rationale behind this choice? How can treatment strategies account for differences among pathological subtypes?
Professor Jiwei Huang: Non-clear cell renal cell carcinoma is a patient population that deserves greater attention. Most previous Phase III clinical trials have focused on clear cell renal cell carcinoma, which accounts for approximately 80%–85% of metastatic renal cell carcinoma. In clear cell renal cell carcinoma, targeted therapy combined with immunotherapy has become one of the standard first-line treatment options. These regimens achieve ORRs of approximately 50%–60% and median progression-free survival (PFS) of approximately 17–20 months.
Non-clear cell renal cell carcinoma is considerably more complex, with substantial differences among subtypes in terms of biological behavior, genetic alterations, and molecular characteristics. In designing the FRONTIER study, we sought to draw on the experience with targeted therapy combined with immunotherapy in clear cell renal cell carcinoma and further evaluate the efficacy of this strategy in non-clear cell disease.
The current results demonstrate encouraging antitumor activity, with an investigator-assessed ORR of 59% and a median PFS of approximately 19.4 months. These findings provide a positive signal for further research.
However, when the different pathological subtypes are examined separately, treatment responses may vary across populations. Based on current observations, renal cell carcinoma associated with transcription factor E3 (TFE3) rearrangements may respond relatively poorly to targeted therapy plus immunotherapy, whereas fumarate hydratase (FH)-deficient renal cell carcinoma may demonstrate better efficacy. These differences warrant further validation. Subsequent studies will need to distinguish the various subtypes more precisely and establish more targeted treatment cohorts accordingly, with the aim of further improving outcomes.
Building the Evidence Base: Further Studies to Validate Early Efficacy Signals
Oncology Frontier – UroStream: How should we interpret the updated efficacy data from the FRONTIER study? Given that the current findings come from a single-arm Phase II study, how should we understand their clinical significance and the need for further validation?
Professor Jiwei Huang: The updated efficacy results are encouraging overall, with an ORR of 59% and a median PFS of approximately 19.4 months. The overall efficacy exceeded our initial expectations for this treatment regimen.
To establish a higher level of clinical evidence based on the current Phase II study, further Phase III clinical trials will be necessary. The challenge is that non-clear cell renal cell carcinoma is a relatively rare malignancy, making Phase III trials difficult to conduct.
We hope that more pharmaceutical companies and other relevant stakeholders will help advance subsequent research, expanding the current small-scale Phase II investigation involving approximately 40 patients. This would provide a more substantial evidence base to guide treatment decisions for this patient population.
Patient Selection: Advancing Precision Stratification Through Molecular Characteristics and Dynamic Monitoring
Oncology Frontier – UroStream: In pursuing personalized treatment for non-clear cell renal cell carcinoma, how should researchers identify patients who are most likely to benefit? What evidence can molecular subtyping, biomarkers, and dynamic monitoring provide for future studies?
Professor Jiwei Huang: Precisely identifying patients who are most likely to benefit from treatment is a central scientific question that our research team has been investigating over the long term.
Within the overall study design, we have incorporated corresponding exploratory analysis modules, and some molecular biomarker analyses that have not yet been publicly disclosed are still ongoing.
Through an analysis of the tumor immune microenvironment, the study aims to identify patient subgroups that may benefit from targeted therapy combined with immunotherapy, as well as populations that may have primary resistance. Once benefiting populations have been identified, treatment selection can be more precisely tailored. For patients with resistance, the feasibility of treatment intensification strategies will require further investigation.
Our team believes that these directions will also be important trends in the future development of this field.
In addition, dynamic monitoring of biomarkers such as kidney injury molecule-1 (KIM-1) and circulating tumor DNA (ctDNA) may help identify patients who are responding to treatment at an early stage. How to translate the findings of these exploratory analyses into more reliable criteria for patient selection will require further in-depth investigation in subsequent studies.
Summary
The FRONTIER study provides encouraging early efficacy signals for targeted therapy combined with immunotherapy in non-clear cell renal cell carcinoma. Professor Jiwei Huang emphasized that this disease is characterized by substantial pathological and molecular heterogeneity, and that the current single-arm Phase II findings still require validation through further research.
More detailed stratification across different subtypes, combined with investigations of the tumor immune microenvironment and dynamic biomarkers, may help identify populations likely to benefit from treatment as well as those at risk of resistance, providing a basis for more targeted therapeutic research.
Professor Jiwei Huang
