ASCO GU 2021: Sunitinib Versus Cabozantinib, Crizotinib or Savolitinib in Metastatic Papillary Renal Cell Carcinoma (pRCC): Results from the Randomized Phase II SWOG 1500 Study

(UroToday.com) While there has been a rapid proliferation of treatment options for patients with advanced renal cell carcinoma, these studies have focused on patients with clear cell histology. In contrast, there is a relative dearth of data for the treatment of advanced non-clear cell RCC. Therefore, patients with these tumors may receive agents on the basis of their activity in ccRCC. However, VEGF-receptor inhibitors have been shown to have relatively low activity in patients with papillary RCC (pRCC). However, MET signaling is a key molecular driver in pRCC. Given that there is no optimal therapy for metastatic pRCC, in a plenary abstract presentation in the Oral Abstract Session: Renal Cell Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Sumanta Pal and colleagues provide results of the SWOG 1500 study examining an existing standard (sunitinib) to putative MET kinase inhibitors in patients with pRCC. Notably, this study was concurrently published in The Lancet.1


The authors recruited patients with pathologically verified pRCC with measurable metastatic disease and Zubrod performance status 0-1. Patients were eligible for inclusion if they had received up to 1 prior systemic therapy excluding VEGF-directed agents.

Patients were then randomized in a 1:1:1:1 fashion to receive either sunitinib 50 mg oral daily (6-week cycles: 4 weeks on/2 weeks off), cabozantinib 60 mg oral daily, crizotinib 250 mg oral twice daily, or savolitinib 600 mg oral daily. Randomization was stratified based on receipt of prior therapy and pRCC subtype (I vs II vs not otherwise specified [NOS]) based on local review.

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The authors sought to assess the primary endpoint of progression-free survival (PFS) for each experimental arm versus sunitinib. In terms of a power calculation, the authors determined that they would have 85% power to detect a 75% improvement in median PFS with a 1-sided alpha of 0.10 using intent-to-treat analysis with 41 eligible patients per arm. A pre-planned futility analysis was performed after half of the anticipated PFS events occurred. Secondary endpoints included toxicity, response rate, and overall survival.

Over three and a half years between April 2016 and December 2019, 152 patients were enrolled of whom 5 were ineligible. The included patients had a median age of 66 (range:29-89) and the majority (76%) were male. The vast majority (92%) had not received prior systemic therapy. According to local pathologic review, 18%, 54%, and 28% of patients had type I, type II, and NOS papillary subtype histology, respectively. However, at the time of central review, this histological distribution was 30%, 45%, and 25% for type I, type II, and NOS, respectively.

Due to a futility analysis that demonstrated a hazard ratio for progression-free survival of more than 1.0, accrual to the savolitinib and crizotinib arms was halted early while accrual continued to completion in the sunitinib and cabozantinib arms. Median PFS was significantly higher with cabozantinib relative to sunitinib (hazard ratio 0.60, 95% confidence interval 0.37-0.97).

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Objective response rates were also higher with cabozantinib than with sunitinib, crizotinib, and savolitinib, with 2 complete responses and 8 partial responses noted among the 44 patients randomized to cabozantinib.

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Median overall survival was 20 months for those receiving cabozantinib and 16.4 months for those receiving sunitinib.

Grade 3 or 4 adverse events occurred in 68%, 74%, 37%, and 39% of patients receiving sunitinib, cabozantinib, crizotinib, and savolitinib, respectively; one grade 5 adverse event was seen with cabozantinib.

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Dr. Pal then concluded that this multi-arm randomized trial demonstrated that cabozantinib, but not savolitinib or crizotinib, demonstrated meaningful prolongation of PFS in pRCC patients compared to sunitinib.

Presented by: Sumanta K. Pal, MD, Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021

References:

  1. Pal S, Tangen C, Thompson Jr E "et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial." The Lancet. 2021. S0140-6736(21)00152-5.
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