ASCO 2019: Randomized, Double-Blind Phase III Study of Pazopanib versus Placebo in Patients with mRCC who have no Evidence of Disease Following Metastasectomy: A Trial of the ECOG-ACRIN Cancer Research Group

Chicago, IL (UroToday.com) Metastasectomy has been performed for metastatic renal cell carcinoma (mRCC) for over 80 years, either in a synchronous or metachronous fashion. However, patients with no evidence of disease after metastasectomy for mRCC are at high risk of recurrence, but no systemic therapy has been shown to benefit this population – as such, this is an unmet need. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival (PFS) in patients with measurable RCC metastatic disease.1   Leonard Appleman, MD, PhD, and colleagues presented results of their phase III trial testing pazopanib versus placebo in patients with mRCC who have no evidence of disease following metastasectomy. The hypothesis of E2810 was that pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered no evidence of disease after metastasectomy.

For E2810, patients with no evidence of disease following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily versus placebo for 52 weeks. Patients were stratified by 1 vs > 1 site of resected disease, and by disease-free interval ≤ vs > 1 year. Key eligibility criteria included (i) synchronous or metachronous primary/metastases allowed, (ii) any number of resected metastases or past surgeries allowed, (iii) a clear cell histological component, (iv) no evidence of disease on baseline staging scans, (v) ECOG PS 0-1, (vi) enrolled within 12 weeks of surgery, and (vii) no prior systemic therapy. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years.  As follows is the study schema:
ASCO 2019 E2810 study schema

From August 2012 to July 2017, there were 129 patients enrolled: 66 patients in the pazopanib arm and 63 in the placebo arm. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint as the hazard ratio for DFS was 0.85 (95% CI 0.55-1.31; p=0.47) in favor of pazopanib.
ASCO 2019 E2810 study Pazopanib

At the time of unblinding, 17% of subjects had died and the HR for OS was 2.65 (95% CI 1.02-6.9; p=0.05) in favor of placebo.
ASCO 2019 E2810 study overall survival

Dr. Appleman concluded his presentation of E2810 with the following points:
  • Pazopanib did not improve DFS in patients with mRCC rendered surgically no evidence of disease by metastasectomy
  • These results are consistent with PROTECT2 study of pazopanib after nephrectomy
  • There was a trend toward decreased OS with pazopanib with early follow-up (16% event rate overall with median follow-up of 30 months)
  • There remains an unmet need to investigate systemic therapy after metastasectomy for RCC – randomized studies are feasible, but sample size has limited statistical power
Clinical trial information:  NCT01575548

Presented by: Leonard J. Appleman, MD, PhD, UPMC Hillman Cancer Center, Pittsburgh, PA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA 

References:
  1. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369(8):722-731.
  2. Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(35):3916-3923.
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