At the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Professor Xieqiao Yan from Peking University Cancer Hospital delivered a comprehensive presentation on the latest advances in kidney cancer therapy. His report focused on emerging clinical evidence surrounding the HIF-2α inhibitor belzutifan, particularly its evolving role in advanced clear cell renal cell carcinoma (ccRCC) after PD-1–based therapy, as well as in the postoperative adjuvant setting. The findings offer important new insights for clinical decision-making in the post-PD-1 era.Mechanism-Driven Therapy and the Clinical Significance of HIF-2α Inhibition
The development of clear cell renal cell carcinoma is closely associated with mutations in the VHL gene. Loss of VHL function leads to abnormal accumulation of hypoxia-inducible factor 2-alpha (HIF-2α), which subsequently promotes tumor angiogenesis and cancer progression. Belzutifan, the world’s first oral HIF-2α inhibitor, has therefore emerged as a highly promising targeted therapy.
Long-term follow-up data from the LITESPARK-004 study demonstrated sustained efficacy in patients with VHL-associated renal cancer. After a median follow-up of 61.8 months, the objective response rate (ORR) increased over time and ultimately reached 70.0%.
In East Asian populations, the phase II LITESPARK-015 study further strengthened the evidence base. Among Chinese and Japanese patients with VHL-associated renal cancer, belzutifan achieved an ORR of 88.2%, while the 24-month progression-free survival (PFS) rate reached 88.1%. Notably, all patients were able to avoid surgical intervention during treatment. These encouraging data contributed to the inclusion of belzutifan as a key therapeutic recommendation in the Chinese Expert Consensus on the Diagnosis and Management of VHL Syndrome (2025 Edition).
LITESPARK-011: A New Standard for Immunotherapy-Pretreated Advanced ccRCC
For patients with advanced ccRCC whose disease progressed after PD-(L)1 inhibitors and VEGFR tyrosine kinase inhibitors, treatment options have remained limited. The phase III LITESPARK-011 study addressed this challenge by comparing belzutifan plus lenvatinib with cabozantinib.
The combination regimen demonstrated a clear progression-free survival advantage. Median PFS reached 14.8 months in the combination arm, compared with 10.7 months in the cabozantinib group, corresponding to a 30% reduction in the risk of progression.
Tumor response outcomes were similarly encouraging. The ORR was 52.6% with belzutifan plus lenvatinib, significantly higher than the 40.2% observed with cabozantinib. Complete response rates were also improved, reaching 5.4% versus 1.1%, respectively.
Although overall survival data have not yet reached statistical significance, the trend favored the combination strategy, with median overall survival extending to 34.9 months compared with 27.6 months in the control arm.
Taken together, these findings position belzutifan plus lenvatinib as a highly promising new standard option for patients with immunotherapy-pretreated advanced renal cancer.
Expanding Therapeutic Strategies: Combination Therapy and Next-Generation HIF-2α Inhibitors
Efforts to overcome resistance to single-agent therapy have led to increasing interest in combination approaches. In the LITESPARK-024 study, investigators explored the combination of belzutifan with the CDK4/6 inhibitor palbociclib in heavily pretreated ccRCC patients.
The study demonstrated a median PFS of 9.1 months at the recommended phase II dose, while the ORR reached 21.1%. These results support the biological rationale for combining HIF-2α inhibition with CDK4/6 blockade and suggest potential synthetic lethality between the two pathways.
Meanwhile, next-generation HIF-2α inhibitors are also beginning to show clinical promise. In the ARC-20 study, the novel agent casdatifan demonstrated meaningful antitumor activity in heavily pretreated patients who had received a median of three prior treatment lines. The 100 mg once-daily cohort achieved an ORR of 35% and a median PFS of 12.2 months, with a low discontinuation rate due to treatment-related adverse events, highlighting both efficacy and favorable tolerability.
Real-World Validation of Belzutifan
Beyond clinical trials, real-world evidence has provided additional support for the clinical utility of belzutifan. A Mayo Clinic study evaluating heavily pretreated patients reported a median PFS of 5.7 months, closely mirroring the 5.6 months observed in the pivotal LITESPARK-005 trial.
The safety profile in routine practice was also consistent with prior studies. Hypoxia and anemia remained the most important adverse events requiring clinical attention, emphasizing the need for careful monitoring of oxygen saturation and hemoglobin levels during treatment.
LITESPARK-022 and the Future of Adjuvant Therapy
The role of HIF-2α inhibition is now expanding into the postoperative setting. The phase III LITESPARK-022 trial evaluated pembrolizumab plus belzutifan versus pembrolizumab alone in patients with high-risk ccRCC following surgery.
The combination significantly improved disease-free survival. At 24 months, the DFS rate reached 80.7% in the combination arm compared with 73.7% in the pembrolizumab monotherapy arm, translating into a 28% reduction in the risk of recurrence or death.
The benefit appeared particularly notable in younger patients, male patients, and those with intermediate-to-high recurrence risk. Although grade 3 or higher adverse events were more frequent with the combination regimen, no new safety concerns emerged.
These results suggest that pembrolizumab plus belzutifan may become a new standard for adjuvant therapy in high-risk renal cancer.
Outlook
Professor Xieqiao Yan concluded that the rapid development of HIF-2α inhibitors is reshaping the therapeutic landscape of kidney cancer. From precision treatment for VHL-associated disease, to breakthroughs in advanced ccRCC after immunotherapy failure, and now to promising advances in postoperative adjuvant therapy, HIF-2α–targeted strategies are opening a new chapter in renal cancer management.
As ongoing LITESPARK studies continue to mature and additional combination regimens emerge, kidney cancer treatment is expected to evolve toward approaches that are increasingly precise, effective, and better tolerated.
Expert Profile
Professor Xieqiao Yan Peking University Cancer Hospital
