Editor's Note: In recent years, immunotherapy-based combination regimens have transformed the treatment landscape of renal cell carcinoma (RCC) and have become standard first-line options for advanced clear cell renal cell carcinoma (ccRCC). However, therapeutic progress in non-clear cell renal cell carcinoma (nccRCC) has remained limited. At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, the research team led by Professor Hao Zeng, Professor Xu Hu, and Dr. Junru Chen from West China Hospital, Sichuan University, presented encouraging findings on first-line treatment with cadonilimab plus axitinib in patients with nccRCC, offering a promising new option for this underserved patient population. Oncology Frontier – UroStream invited Dr. Junru Chen to discuss the study and its implications.Oncology Frontier – UroStream
nccRCC is highly heterogeneous, and there is still no universally accepted first-line treatment standard. In addition, response rates to immunotherapy are generally lower than those observed in ccRCC. Compared with traditional PD-1 monotherapy or dual-antibody regimens, what unique mechanistic advantages does the combination of cadonilimab and axitinib offer that may help overcome the intrinsic resistance of nccRCC to immunotherapy?
Dr. Junru Chen:
As we know, nccRCC accounts for approximately 20%–25% of all renal cancers. However, patients with nccRCC have frequently been excluded from large phase III clinical trials, largely because of the disease’s marked heterogeneity and its limited sensitivity to either tyrosine kinase inhibitor (TKI) monotherapy or immune checkpoint inhibitor monotherapy.
The combination regimen presented by our team at ASCO offers two key advantages. First, cadonilimab is a bispecific antibody targeting both PD-1 and CTLA-4. CTLA-4 blockade promotes the early activation and expansion of T cells, while PD-1 inhibition prevents T-cell exhaustion mediated by the PD-1/PD-L1 pathway, thereby maintaining sustained T-cell activation and proliferation and preserving antitumor immune activity.
Second, the regimen incorporates axitinib, an anti-angiogenic TKI. Axitinib helps normalize abnormal tumor vasculature and remodel the tumor microcirculation, creating a more favorable environment for T-cell and immune-cell infiltration into the tumor microenvironment. This ultimately enhances the antitumor immune response and improves tumor-killing efficacy.
Oncology Frontier – UroStream
The study reported highly encouraging results, including an overall objective response rate (ORR) of 51.6%, a disease control rate (DCR) of 96.8%, and a median progression-free survival (PFS) of 17.3 months. Given that this was a single-arm phase Ib/II study, how do you think these findings could reshape the first-line treatment landscape for advanced nccRCC if confirmed in larger studies?
Dr. Junru Chen:
Currently, prospective clinical evidence in advanced nccRCC mainly comes from studies such as KEYNOTE-B61 and SUNNIFORECAST, which have evaluated regimens including pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, and nivolumab plus ipilimumab. Overall, immunotherapy-targeted therapy combinations have demonstrated superior efficacy in nccRCC, whereas dual-immunotherapy approaches have generally produced less favorable progression-free survival outcomes.
Notably, our study achieved particularly encouraging results, with an ORR of 51.6% and a DCR of 96.8%. These outcomes compare favorably with those reported for established regimens such as pembrolizumab plus lenvatinib and nivolumab plus cabozantinib.
More importantly, our study incorporated genomic testing and molecular profiling to precisely define molecular subtypes of non-clear cell RCC, including FH-deficient RCC, TFE3-rearranged RCC, and TFEB-altered RCC. This classification strategy provides valuable clinical evidence supporting a more precise and personalized treatment approach for renal cancer.
Oncology Frontier – UroStream
Cadonilimab is a bispecific antibody independently developed in China, and this multicenter Chinese study was presented on the international stage at ASCO. How do you view the rapid rise of China’s innovative drug development in the field of genitourinary oncology? Looking ahead, what breakthroughs might still be achieved in the treatment of non-clear cell RCC to provide patients with greater hope for long-term survival?
Dr. Junru Chen:
In recent years, China’s innovative biopharmaceutical sector has advanced rapidly, particularly in cutting-edge areas such as antibody-drug conjugates (ADCs), bispecific antibodies, and multispecific antibody platforms. I noted that many of the multi-target and dual-target ADCs presented at the 2024 AACR Annual Meeting originated from China, highlighting the growing international influence and importance of Chinese innovation in drug development.
In the field of nccRCC, the disease’s pronounced heterogeneity remains a major obstacle to further improvements in treatment outcomes. Precision diagnostics—including the accurate identification of specific subtypes such as FH-deficient RCC and TFE3-rearranged RCC—may hold the key to overcoming this challenge.
Both the KEYNOTE-B61 study and our own research have demonstrated that different pathological and molecular subtypes of nccRCC exhibit substantially different responses to immunotherapy-targeted therapy combinations, resulting in varying objective response rates and survival benefits.
Therefore, future research in nccRCC should focus on precision classification and precision medicine. Building on a robust foundation of accurate molecular diagnosis, we can explore more tailored therapeutic combinations and ultimately develop more effective treatment strategies for patients.
About the Experts
Professor Hao Zeng
Dr. Junru Chen
