Dual Antiangiogenic Therapy Shows Improved Outcomes in Advanced Kidney Cancer
Phase III trial demonstrates belzutifan plus lenvatinib significantly improved progression-free survival versus cabozantinib in previously treated renal cell carcinoma patients, while neoadjuvant studies show promise for locally advanced disease.
Dual antiangiogenic therapy for previously treated kidney cancer significantly improved progression-free survival versus a single drug in the LITESPARK-011 trial. Median PFS improved from 10.7 months with single-agent cabozantinib to 14.8 months with the hypoxia-inducible factor inhibitor belzutifan and lenvatinib. However, overall survival, a second primary endpoint, did not differ significantly (34.9 vs 27.6 months) at the interim analysis.
The LITESPARK-011 study is the first phase III trial of a HIF inhibitor plus a VEGF inhibitor and the first phase III trial in renal cell carcinoma previously treated with immunotherapy to show an improved outcome versus contemporary VEGF inhibition. The international study enrolled patients with unresectable locally advanced/metastatic clear cell renal cell carcinoma that had progressed after first- or second-line anti-PD(L)1 treatment.
After a median follow-up of 29 months, the belzutifan-lenvatinib combination resulted in a 30% reduction in the hazard for disease progression or death (95% CI 0.59-0.84, P=0.0007). Landmark PFS analyses favored the combination at 12 months (55% vs 41.0%) and 24 months (35.6% vs 19.1%).
The combination was associated with an objective response rate of 52.6% versus 40.2% with cabozantinib, though the difference did not reach statistical significance at the final analysis. A significant difference was evident at a first interim analysis after a median follow-up of 19 months (52.6% vs 39.6%, P=0.0002). Median duration of response was almost twice as long with the combination versus single-agent cabozantinib (23.0 vs 12.3 months).
Use of the combination came with some trade-offs in toxicity. Belzutifan plus lenvatinib caused more anemia and proteinuria but less diarrhea, hand-foot syndrome, stomatitis, and dysgeusia. Two adverse events of special interest, hypoxia and cardiac dysfunction, occurred in patients treated with the combination but almost no patients randomized to cabozantinib.
Belzutifan inhibits angiogenesis by blocking transcription of pro-angiogenic genes, including VEGF. A strong rationale exists for combining the drug with a VEGF inhibitor in RCC to increase antiangiogenic activity. In a phase II study of patients with previously treated RCC (more than half with ICIs), the combination of belzutifan and cabozantinib led to an ORR of 31%. By comparison, a phase III study of cabozantinib showed an ORR of 17% in patients previously treated with tyrosine kinase inhibitors.
In the neoadjuvant setting for locally advanced disease, a cohort of 17 non-metastatic RCC patients, most with high-risk features and venous tumor thrombus, received checkpoint inhibitor plus tyrosine kinase inhibitor combinations, predominantly lenvatinib plus pembrolizumab. After a median of seven months of treatment, median radiographic tumor reduction was 27%, comparable to or exceeding reductions reported in prospective neoadjuvant CPI+TKI trials and clearly superior to CPI monotherapy, which has shown minimal primary tumor shrinkage.
More than half of patients experienced pathological T-stage downstaging, and 17.6% achieved a complete pathological response (ypT0), despite no correlation between imaging response and residual viable tumor. Venous tumor thrombus response was clinically relevant: 50% of patients with vena cava involvement experienced a reduction in Mayo thrombus level, with no progression observed. Nephrectomy and thrombectomy were feasible in all patients, with acceptable perioperative morbidity. Major complications were limited and occurred primarily in complex thrombus cases.