Cabozantinib achieved a statistically significant and clinically meaningful extension in progression-free survival compared with sunitinib in patients with metastatic papillary renal cell carcinoma, a relatively uncommon type of renal cell carcinoma, according to the randomized phase II SWOG 1500 study presented during the virtual edition of the 2021 Genitourinary Cancers Symposium.¹ Cabozantinib also led to much higher rates of objective response compared with sunitinib.

“SWOG 1500 is the first randomized controlled trial conducted exclusively in papillary renal cell carcinoma to complete accrual. Cabozantinib prolonged progression-free survival, meeting the study endpoint, and significantly increased overall response rate compared with sunitinib. Cabozantinib should be considered a new reference standard of care for systemic therapy of metastatic papillary renal cell carcinoma,” stated lead author Sumanta K. Pal, MD, a medical oncologist and Assistant Clinical Professor at City of Hope, Duarte, California.

Sumanta K. Pal, MD

Cabozantinib reduced the risk of disease progression or death by 40% vs sunitinib, meeting the primary endpoint of the trial (P = .019). Median progression-free survival with cabozantinib was 9.0 months vs 5.6 months with sunitinib. The objective response rate was 23% for cabozantinib vs 4% for sunitinib (P = .010). Complete responses were observed exclusively among those treated with cabozantinib.

“Papillary renal cell carcinoma is a rare malignancy, accounting for 15% of all renal cell carcinoma cases. VEGF-targeted therapies such as sunitinib have previously been the standard of care in these patients; however, the estimates of efficacy of these options vary,” Dr. Pal said. Across historical series, response rates for these therapies ranged from 0% to 24%, and progression-free survival ranged from 1.6 months to 8.0 months.

“To date, there have been no randomized data specifically in [patients with] papillary renal cell carcinoma showing an advantage of one systemic therapy over another,” Dr. Pal told listeners.

Evidence suggests that the MET proto-oncogene may be a potential driver of papillary renal cell carcinoma. Although it is more common in type 1 than in type 2 disease, the MET mutation and copy number alteration occur in a proportion of both subtypes. The goal of SWOG 1500 was to determine whether MET inhibitors could improve outcomes compared with sunitinib in metastatic papillary renal cell carcinoma.

Study Details

Eligibility for SWOG 1500 included a histologically confirmed diagnosis of papillary renal cell carcinoma and measurable disease. Patients could have received up to one prior line of therapy, except sunitinib. Additionally, patients had to have a Zubrod performance status of 0 to 1.

From April 2016 to December 2019, a total of 152 patients were enrolled to the SWOG 1500 trial at 65 cancer centers across the United States and Canada. Patients were randomly assigned 1:1:1:1 to four different treatment arms: cabozantinib, crizotinib, savolitinib, or sunitinib. The crizotinib and savolitinib arms were terminated prematurely due to futility analysis. Stratification factors included disease subtype (type 1 vs 2 vs not otherwise specified per local review) and number of prior therapies (0 vs 1). The primary endpoint of the study was progression-free survival. Key secondary endpoints included overall survival, response rate, and adverse effects. Dr. Pal said that exploratory evaluations of MET mutational status and MET expression are ongoing.

The study design called for a coordinated central pathologic review. Images reviewed locally were then reviewed centrally by three pathologists for disease subtype.

All four study drugs were given as oral formulations, and dose reductions were allowed. Sunitinib was given as per the conventional 4-weeks-on, 2-weeks-off schedule, at a daily dose of 50 mg. Cabozantinib was given at a daily dose of 60 mg. Crizotinib was given at a twice-daily dose of 250 mg. Savolitinib was given at a daily dose of 600 mg.

A prespecified futility analysis occurred after 15 progression-free survival events were reported in each of the experimental arms and 20 events occurred in the sunitinib arm. If the progression-free survival hazard ratio was greater than 1 for a MET inhibitor vs sunitinib, the arm was closed for futility.

Baseline characteristics were well balanced across treatment arms. The median age of patients was 66 years (range, 29–89 years), and the majority were male (75%) and White (77%). Few patients received prior systemic therapy (7%), and a minority of patients had type 1 histology, ranging from 17% to 20% across study arms. The majority of patients had intermediate-risk disease, as per the International Metastatic Renal Cell Carcinoma Database Consortium Risk Group criteria (61%). More than 70% of patients had prior nephrectomy. Few patients had central nervous system metastases (less than 1%).

Key Findings

There were some discordances in pathologic subtypes between local and central reviews. A total of 13 patients categorized as having type 1 disease were found to have type 2 disease on central assessment; 3 patients with type 2 disease per local assessment were characterized to have type 1 by central assessment.

“Ultimately, these discordances didn’t appear to have a bearing on the key finding from our study,” Dr. Pal explained. “Irrespective of central and local assessments, patients with type 1 and type 2 disease appeared to benefit from cabozantinib.”

The data for overall survival are not yet mature. No significant differences were seen to date, but a numerical trend toward improved survival was observed with cabozantinib vs sunitinib: 20.0 months vs 16.4 months, respectively.

Grade 3 or 4 adverse events were reported in 68% of patients in the sunitinib arm, 74% of patients in the cabozantinib arm, 37% of patients in the crizotinib arm, and 39% of patients in the savolitinib arm. Toxicities in SWOG 1500 were similar to those reported in larger studies of these agents.

The rate of treatment discontinuation due to treatment-related adverse events was highest with sunitinib (24%), followed by cabozantinib (23%), crizotinib (16%), and savolitinib (10%). A total of 16 patients remained on protocol at the time of last follow-up.

Grade 3 or 4 laboratory toxicities with sunitinib, cabozantinib, crizotinib, and savolitinib occurred in 68%, 74%, 37%, and 39%, of patients, respectively. One grade 5 effect was observed in the cabozantinib arm, secondary to a thromboembolic event. 

Publisher's Note: This article was originally published in the March 25, 2021 issue of The ASCO Post.

DISCLOSURE: Dr. Pal has served as a consultant or advisor to Astellas Pharma, Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer.

REFERENCE

1. Pal SK, Tangen C, Thompson IM, et al: Sunitinib versus cabozantinib, crizotinib, or savolitinib in metastatic papillary renal cell carcinoma: Results from the randomized phase II SWOG 1500 study. 2021 Genitourinary Cancers Symposium. Abstract 270. Presented February 13, 2021.