The Pazopanib Trial in Renal Cell Carcinoma
The pazopanib trial refers to a pivotal phase III, open-label, international, multicenter study that demonstrated pazopanib 800 mg orally daily significantly improved progression-free survival (PFS) compared to placebo in patients with advanced clear cell RCC, establishing it as a standard first-line treatment option. 1
Key Trial Design and Population
The landmark trial evaluated pazopanib versus placebo in 435 patients with advanced clear cell RCC who had received 0-1 prior treatments 1. The study included both treatment-naïve patients and those previously treated with cytokines 1.
Primary Efficacy Results
Treatment-Naïve Patients
- Objective response rate: 32% 2
- Median PFS: 11.1 months 2
- PFS was significantly longer with pazopanib versus placebo in this subpopulation 1
Cytokine-Pretreated Patients
- Objective response rate: 29% 2
- Median PFS: 7.4 months versus 4.2 months with placebo 1
- This established pazopanib as a category 1 recommendation after cytokine therapy 1
Overall Survival
- No significant difference in overall survival was observed between pazopanib and placebo groups 1
- This represents an important limitation of the trial findings, as the survival benefit did not materialize despite PFS improvements 1
Mechanism of Action
Pazopanib is an oral multitargeted tyrosine kinase inhibitor that works primarily through antiangiogenic properties by inhibiting 1, 2:
- Vascular endothelial growth factor receptors (VEGFR-1, -2, and -3)
- Platelet-derived growth factor receptor-α and -β (PDGFR-α and -β)
- Stem cell factor receptor (c-KIT)
Safety Profile and Critical Toxicities
Most Common Adverse Events (≥20%)
The trial identified the following frequent adverse reactions 3:
- Diarrhea (52%)
- Hypertension (40%)
- Hair color changes (38%)
- Nausea (26%)
- Anorexia (22%)
- Vomiting (21%)
- Fatigue (19%)
Critical Grade 3/4 Toxicities Requiring Monitoring
Hepatotoxicity is the most notable severe toxicity, with elevated alanine transaminase (ALT) in 30% and aspartate transaminase (AST) in 21% of patients 1, 4. This mandates:
- Liver function monitoring before treatment initiation
- Regular monitoring during treatment
- Dose interruption, reduction, or discontinuation based on severity 1, 4
Other serious adverse events include cardiac rhythm irregularities, requiring appropriate monitoring 4.
Comparative Efficacy: COMPARZ Trial
The COMPARZ noninferiority study directly compared pazopanib with sunitinib and demonstrated 1:
- Similar safety and efficacy between the two agents
- Pazopanib was noninferior to sunitinib for PFS 5
- Pazopanib showed superior health-related quality of life compared to sunitinib, with lower incidences of fatigue, hand-foot syndrome, and stomatitis 5
- Significantly more patients preferred pazopanib over sunitinib, primarily due to better overall quality of life and less fatigue 5
Current Treatment Recommendations
Based on the trial data, NCCN guidelines list pazopanib as 1:
- Category 2A, other recommended regimen for patients with clear cell RCC across all risk groups (favorable, intermediate, and poor risk)
- Category 1 recommendation after cytokine therapy 1
- Category 3 recommendation after tyrosine kinase inhibitor failure (no data available in this setting) 1
The Adjuvant PROTECT Trial
A separate phase III trial (PROTECT, NCT01235962) evaluated adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced RCC at high risk of relapse 6, 7. This trial was negative:
- No significant difference in disease-free survival (HR 0.86; 95% CI 0.70-1.06; P=0.165) for pazopanib 600 mg versus placebo 7
- No significant difference in overall survival (HR 1.0; 95% CI 0.80-1.26) 6
- High rates of treatment discontinuation due to hepatotoxicity (ALT elevation: 16% at 600 mg, 18% at 800 mg) 7
- Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC 6
Clinical Practice Implications
Pazopanib 800 mg orally once daily remains a valid first-line treatment option for advanced clear cell RCC across all risk groups, particularly when quality of life considerations favor its use over sunitinib 1, 5. However, the lack of overall survival benefit and significant hepatotoxicity risk require careful patient selection and vigilant monitoring 1, 6.
The drug must be administered on an empty stomach (at least 1 hour before or 2 hours after a meal), with dose reductions to 200 mg daily for patients with moderate hepatic impairment 3.