Immune checkpoint inhibitor (ICI)-based combinations have transformed first-line treatment for metastatic clear-cell renal cell carcinoma (ccRCC). However, identifying appropriate treatment strategies remains particularly important for patients with favourable-risk disease and those who may not be suitable candidates for immunotherapy.
VEGF-targeted therapies have long been used in metastatic RCC, although the development of acquired resistance can limit their effectiveness. One proposed mechanism involves increased VEGF ligand concentrations during treatment with tyrosine kinase inhibitors (TKIs). Pazopanib, a VEGFR-targeting TKI, and bevacizumab, a monoclonal antibody targeting VEGF, inhibit the same signalling pathway through different mechanisms.
Based on this rationale, investigators evaluated whether administering bevacizumab during scheduled breaks from pazopanib could improve tolerability and prolong progression-free survival compared with historical expectations.
On October 27, 2026, The Lancet Oncology published the study titled “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 study was authored by Saby George, Ulka Vaishampayan, Alan Hutson, Adrienne Groman, Roberto Pili, Kelly Green, Laurie Herbst, Rushka Kallicharan-Smith, Ann-Marie DiRaddo, Elongia Farrell, Dharmesh Gopalakrishnan, Elisabeth Heath, Elizabeth Wulff, Deepak Kilari, Leonard Appleman, and Rahul Parikh.
Conducted across five academic cancer centres in the United States, the trial (NCT01684397) investigated the safety and antitumour activity of an alternating schedule of pazopanib and bevacizumab in patients with metastatic ccRCC.
Study Design and Treatment Approach
This multicentre, single-arm phase 1/2 trial enrolled adults with histologically confirmed metastatic ccRCC, measurable disease according to RECIST 1.1, an ECOG performance status of 0–1, and adequate organ function. The phase 1 portion evaluated four dose levels to establish the recommended phase 2 dose (RP2D). In phase 1, patients could have received up to one previous treatment with high-dose IL-2 or an anti-PD-1 agent, either alone or in combination with a CTLA-4 inhibitor. Only treatment-naive patients were enrolled in phase 2.
The RP2D was established as pazopanib 800 mg orally once daily on days 1–28, followed by a 7-day break, and bevacizumab 10 mg/kg intravenously on days 36 and 50, administered within a 10-week treatment cycle. The primary endpoint of phase 1 was determination of the RP2D, while the primary endpoint of phase 2 was median progression-free survival (PFS). In phase 2, secondary endpoints included the 12-month PFS rate and overall survival (OS), while safety was assessed in all treated patients. Objective response rate (ORR) was assessed in a post-hoc analysis of phase 2.
Between November 2012 and June 2018, 25 patients were enrolled in phase 1, of whom 18 were evaluable for dose-limiting toxicity. The maximum tolerated dose was not reached, and the highest planned dose was selected for phase 2. Between January 2019 and October 2023, 53 patients were enrolled in phase 2. The final per-protocol efficacy population included 51 patients who completed at least one treatment cycle: 45 from phase 2 and six treatment-naive patients from phase 1 who met the eligibility criteria.
The median age was 66 years, and most patients had favourable-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classification. Overall, 33 patients (65%) had favourable-risk disease, while 18 (35%) had intermediate-risk disease.
Efficacy Results
After a median follow-up of 63.7 months (IQR 16.2–73.5), median PFS, the primary endpoint of phase 2, was 24.8 months (95% CI 17.2–34.3). The 12-month PFS rate was 73% (37/51 patients; 95% CI 58–84), compared with the historical benchmark of approximately 45% used in the study design. Median OS reached 63.2 months (95% CI 47.6–96.6), with 24 deaths reported during follow-up.
The post-hoc ORR was 55% (28/51 patients; 95% CI 40–69), including two complete responses (4%) and 26 partial responses (51%). An additional 22 patients (43%) achieved stable disease, while one patient (2%) had progressive disease as the best response.
Outcomes According to IMDC Risk
Exploratory subgroup analyses showed numerically longer survival outcomes among patients with favourable-risk disease. In the favourable-risk group, median PFS was 28.5 months (95% CI 16.8–42.0), compared with 19.8 months (95% CI 7.4–25.2) among patients with intermediate-risk disease.
A similar pattern was observed for OS. Median OS was 76.9 months (95% CI 42.0–76.9) in the favourable-risk group and 63.1 months (95% CI 28.2–64.2) in the intermediate-risk group. The investigators also reported durable disease control in several patients who achieved partial responses or stable disease, with some maintaining disease control for more than two years.
Although these findings are encouraging, the subgroup analyses were exploratory, and the relatively small number of patients limits definitive conclusions regarding differences between risk groups.
Safety and Tolerability
The safety analysis included 59 patients who received at least one dose of study treatment. The most frequently reported treatment-related adverse events were diarrhoea and fatigue (66% each), nausea (55%), and hypertension (53%). Among grade 3–4 treatment-related adverse events, hypertension was the most common, occurring in 34% (20/59) of patients. Elevated alanine aminotransferase (ALT) was reported in 17% (10/59), elevated aspartate aminotransferase (AST) in 12% (7/59), and proteinuria in 10% (6/59).
Treatment modifications were frequent. Adverse events led to treatment delays in 48 patients (81%), while 35 patients (59%) required dose reductions. Five patients (8%) discontinued the study because of drug-related serious adverse events. One patient died following multiorgan failure, which investigators considered unrelated to study treatment. No treatment-related deaths were reported.
Overall, the investigators identified no new safety signals with the alternating regimen, although treatment-related toxicity frequently required dose adjustments or interruptions.
Clinical Implications
The findings suggest that alternating pazopanib and bevacizumab has promising antitumour activity in treatment-naive metastatic ccRCC, particularly in a population predominantly comprising patients with favourable-risk disease.
These results support further evaluation of the alternating antiangiogenic approach. By targeting the VEGF pathway through different mechanisms without administering both agents simultaneously, the regimen was designed to potentially delay resistance while limiting overlapping toxicity. However, the study did not directly establish whether this approach improves tolerability or delays resistance compared with other available treatments.
An important limitation is that the trial was initiated before ICI-based combinations became established as standard first-line treatment for metastatic ccRCC. During the prolonged recruitment period, treatment options changed considerably, potentially influencing patient selection and the distribution of IMDC risk categories.
Furthermore, the single-arm design and limited sample size prevent direct conclusions about comparative efficacy or safety against contemporary ICI-based combinations. Cross-trial comparisons should therefore be interpreted cautiously.
The investigators suggested that the regimen may warrant further evaluation in patients who cannot receive immune checkpoint inhibitors, including those with contraindications to immunotherapy, or in settings with limited access to newer treatments. However, its role in these populations remains investigational.
Conclusion
The phase 1/2 trial demonstrated promising antitumour activity with alternating pazopanib and bevacizumab in treatment-naive metastatic ccRCC, with a median PFS of 24.8 months, median OS of 63.2 months, and ORR of 55%. The findings are particularly encouraging in a study population predominantly composed of patients with favourable-risk disease.
However, the single-arm design, relatively small sample size, and absence of a contemporary comparator limit conclusions about the regimen’s efficacy and safety relative to current first-line treatments. Further evaluation in randomised phase 3 trials is needed to establish whether this alternating antiangiogenic strategy offers a clinically meaningful treatment option for patients with metastatic ccRCC.
The full article is available in The Lancet Oncology.
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