Is pazopanib therapy prior to cytoreductive nephrectomy safe and efficacious in patients with previously untreated metastatic renal cancer?
In this phase 2 study of 104 patients, most gained clinical benefit with pazopanib therapy. A majority were able to undergo nephrectomy, and biomarker analysis revealed substantial changes to key proteins (vascular endothelial growth factor receptor 2 and programmed cell death ligand 1).
Nephrectomy after upfront pazopanib therapy is feasible and associated with good outcomes in selected patients.
The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.
To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.
Design, Setting, and Participants
Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.
Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.
Main Outcomes and Measures
The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.
Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel–Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response.
Conclusions and Relevance
Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.
Powles T, Sarwar N, Stockdale A, Sarker S, Boleti E, Protheroe A, Jones R, Chowdhury S, Peters J, Oades G, O’Brien T, Sullivan M, Aitchison M, Beltran L, Worth D, Smith K, Michel C, Trevisan G, Harvey-Jones E, Wimalasingham A, Sahdev A, Ackerman C, Crabb S. Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer. JAMA Oncol. 2016;2(10):1303-1309. doi:10.1001/jamaoncol.2016.1197