Lancet Oncology Study Highlights Alternating TKI and Monoclonal Antibody Regimen for Untreated Clear Cell RCC

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Summary of  The Lancet Oncology  https://doi.org/10.1016/S1470-2045(26)00394-3
Dr. Prof Saby George et al.

Points

Roswell Park researchers conducted a phase 1/2 clinical trial evaluating alternating pazopanib and bevacizumab in fifty one treatment naive patients with metastatic clear cell renal cell carcinoma.
Quantitative longitudinal follow up over sixty three months demonstrated a median progression free survival of twenty four point eight months and a median overall survival of sixty three months.
Subgroup analysis confirmed superior clinical outcomes among IMDC favorable risk patients achieving a median progression free survival of twenty eight point five months and overall survival of seventy six point nine months.
Safety monitoring identified hypertension in thirty four percent of patients and elevated liver enzymes as the primary grade three or four treatment related adverse events across evaluated cohorts.
Authors concluded that alternating dual VEGF blockade effectively delays drug resistance providing a cost effective clinical alternative to contemporary TKI immunotherapy combinations in advanced kidney cancer.

Summary

This phase 1/2 clinical trial evaluated the safety and efficacy of an alternating dual VEGF-targeted regimen combining pazopanib and bevacizumab in patients with previously untreated metastatic clear cell renal cell carcinoma (mccRCC). Published in The Lancet Oncology by researchers at Roswell Park Comprehensive Cancer Center (NCT01684397), the multicenter investigation addressed the clinical challenge of treatment resistance associated with single-agent TKI therapy. Given that multitargeted TKIs like pazopanib induce compensatory elevations in circulating VEGF ligands, the research sought to determine if alternating administration with bevacizumab—a monoclonal antibody that neutralizes soluble VEGF—could delay resistance and extend survival outcomes.

Phase 1 established the recommended phase 2 dose as oral pazopanib 800 mg daily on days 1–28 paired with intravenous bevacizumab 10 mg/kg on days 36 and 50 within a 10-week cycle. In the phase 2 cohort (n=51 evaluable for activity), 65% (n=33) were classified as IMDC favorable risk. After a median follow-up of 63.7 months (IQR 16.2–73.5), the median progression-free survival (PFS) reached 24.8 months (95% CI, 17.2 to 34.3), and overall survival (OS) reached 63.2 months across the entire cohort. In the favorable-risk subgroup, outcomes were further enhanced, achieving a median PFS of 28.5 months and a median OS of 76.9 months. Grade 3–4 treatment-related adverse events included hypertension in 34% (n=20/59), elevated ALT in 17% (n=10/59), and elevated AST in 12% (n=7/59), with no treatment-related deaths.

The authors conclude that alternating dual VEGF inhibition with pazopanib and bevacizumab provides durable disease control and superior progression-free and overall survival in treatment-naive mccRCC, particularly among IMDC favorable-risk patients. This strategy presents a cost-effective therapeutic alternative to contemporary TKI-immunotherapy combinations, particularly for patients with contraindications to immune checkpoint inhibitors or in resource-limited settings.

Link to the article: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(26)00394-3/fulltext

References

George, S., Vaishampayan, U., Hutson, A., Groman, A., Pili, R., Green, K., Herbst, L., Kallicharan-Smith, R., DiRaddo, A.-M., Farrell, E., Gopalakrishnan, D., Heath, E., Wulff, E., Kilari, D., Appleman, L., & Parikh, R. (2026). Pazopanib alternating with bevacizumab in patients with metastatic clear-cell renal cell carcinoma naive to treatment: A multicentre, single-arm, phase 1/2 trial. The Lancet Oncology, S1470204526003943. https://doi.org/10.1016/S1470-2045(26)00394-3