An alternating regimen of pazopanib and bevacizumab has shown promising activity in previously untreated metastatic clear-cell renal cell carcinoma (RCC), achieving a median progression-free survival (PFS) of 24.8 months in a multicentre phase 1/2 trial.

The findings, published in The Lancet Oncology by George et al. (2026), suggest that sequential targeting of vascular endothelial growth factor (VEGF) signalling warrants further investigation, particularly for patients with favourable-risk disease. However, the researchers emphasised that randomised phase 3 evidence is needed to establish its comparative effectiveness.

VEGF receptor tyrosine kinase inhibitors (TKIs) have long been central to metastatic RCC treatment, although immune checkpoint inhibitor combinations now dominate first-line care. The investigators hypothesised that administering bevacizumab during planned breaks from pazopanib could counter increases in circulating VEGF associated with TKI treatment, potentially delaying resistance while limiting overlapping toxicities.

The study was conducted at five US academic cancer centres. Phase 1 enrolled 25 patients to determine the recommended dose, while phase 2 enrolled 53 treatment-naive patients. The efficacy analysis included 51 patients, comprising 45 from phase 2 and six eligible participants from phase 1. Most had favourable-risk disease according to International Metastatic Renal Cell Carcinoma Database Consortium criteria (65%).

Patients received oral pazopanib 800 mg daily for 28 days, followed by a seven-day break, then intravenous bevacizumab 10 mg/kg on days 36 and 50 of each 10-week cycle.

After a median follow-up of 63.7 months, median PFS was 24.8 months (95% CI 17.2–34.3), meeting the phase 2 primary endpoint. The 12-month PFS rate was 73%, while median overall survival was 63.2 months. The objective response rate was 55%, including two complete responses and 26 partial responses.

In an exploratory analysis, median PFS was 28.5 months for patients with favourable-risk disease and 19.8 months for those with intermediate-risk disease.

Treatment-related toxicity remained substantial. Among 59 patients assessed for safety, the most common grade 3–4 events were hypertension (34%), increased alanine aminotransferase (17%) and increased aspartate aminotransferase (12%). Adverse events prompted treatment delays in 81% and dose reductions in 59%. Five patients (8%) discontinued treatment because of drug-related serious adverse events. No treatment-related deaths occurred.

The researchers suggested that this approach could offer an alternative for selected patients unable to receive immunotherapy, including those with autoimmune conditions, or in resource-limited settings.

Nevertheless, the single-arm design, relatively small sample size and predominantly favourable-risk population limit interpretation. The findings are encouraging but require confirmation in a randomised phase 3 trial before the regimen can be considered an established alternative to contemporary immunotherapy-based treatments.

Source: The Lancet Oncology