Courtney Marabella 

Results of the phase 2 SWOG 1500 study presented during the 2021 Genitourinary Cancers Symposium showed that cabozantinib (Cabometyx) significantly improved progression-free survival (PFS) versus sunitinib (Sutent) in patients with metastatic papillary renal cell carcinoma (pRCC).

The median PFS with cabozantinib was 9.0 months versus 5.6 months with sunitinib, translating to 40% reduction in the risk of disease progression or death (HR, 0.60; 

The agent also led to a significantly higher response rate relative to sunitinib, at 23% versus 4.0%, respectively, in this population (

 = .010). Complete responses were only observed among those who were given cabozantinib. Moreover, although sunitinib was also compared with crizotinib (Xalkori) and savolitinib (AZD6094), those arms of the study were terminated prematurely in a futility analysis, as neither showed benefit in PFS relative to sunitinib.

“Although discordances were observed in subtype classification, cabozantinib had a homogeneous effect across treatment groups,” presenting author Sumanta K. Pal, MD, FASCO, who is also a medical oncologist and assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, said in an oral presentation of the data. “With this in mind, cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC.”

Papillary RCC is a rare malignancy, accounting for 15% of all RCC cases. VEGF-targeted therapies, such as sunitinib, have previously comprised the standard of care in these patients; however, the estimates of efficacy of these options vary, noted Pal. Response rates for these therapies across retrospective and prospective series, range from 0% to 24%, and PFS has ranged from 1.6 months to 8.0 months.

“To date, there have been no randomized data specifically in [patients with] papillary RCC showing an advantage of 1 systemic therapy over another,” Pal noted.

Multiple studies have suggested that the 

 proto-oncogene may be a potential driver of papillary RCC. Although it is more common in type I compared with type II disease, the 

 mutation and copy number alteration occur in a proportion of both subtypes. In the SWOG 1500 trial, investigators sought to determine whether different MET inhibitors could improve clinical outcome relative to sunitinib in patients with metastatic papillary RCC.

Notably, SWOG 1500 (NCT02761057) is the first randomized trial to exclusively enroll patients with metastatic papillary RCC and complete accrual. To be eligible for enrollment, patients had to have a histologically confirmed diagnosis of papillary RCC and measurable disease. Patients were permitted for inclusion if they had received 0 to 1 prior lines of therapy, provided they had not received previous treatment with sunitinib. Additionally, patients had to have a Zubrod performance status ranging from 0 to 1.

Patients were randomized 1:1:1:1 to the sunitinib, cabozantinib, crizotinib, or savolitinib arms. Participants were stratified based on disease subtype (type I vs II vs not otherwise specified [NOS] per local review) and number of prior therapies (0 vs 1). The primary end point of the study was PFS, while key secondary end points included overall survival (OS), response rate, adverse effects (AEs). Exploratory evaluations of 

A central component of the overall study design was the use of a coordinated central pathologic review, Pal noted. Images of tissues reviewed locally were secondarily reviewed by 3 central pathologists, and classified as either type I pRCC, type II pRCC, or pRCC NOS. Mixed features in specimens were deemed pRCC NOS, and any disagreements in specimen type were classified by majority opinion. If no agreement was reached, specimens were either re-reviewed or classified as pRCC NOS, explained Pal.

Notably, the study design permitted dose reduction for each agent used. In the trial, oral sunitinib was delivered on the conventional 4-weeks-on, 2-weeks-off schedule, at a daily dose of 50 mg, with dose reductions to 37.5 mg and 25 mg permitted. Oral cabozantinib was delivered at a daily dose of 60 mg, with dose reductions to 40 mg and 20 mg allowed. Moreover, oral crizotinib was given at a twice-daily dose of 250 mg, with reductions to twice-daily 200 mg and once-daily 250 mg permitted. Lastly, oral savolitinib was administered at a daily dose of 600 mg, with dose reductions to 400 mg and 200 mg allowed.

Investigators’ key assumptions were that PFS for sunitinib would be approximately 6 months, with comparator arms achieving a PFS of 10.5 months. As is standard for a randomized phase 2 study, investigators explored a 1-sided a of 0.1 with a b of 85%. With these considerations in mind, 41 patient per study arm would be required, for a total of 164 patients overall. In accounting for 10% ineligible patients, investigators assumed they would need to accrue an additional 4 patients per study arm, for a total of 180 patients.

Additionally, a prespecified futility analysis was implemented after 15 PFS events were reported in each of the experimental arms and 20 PFS events occurred in the sunitinib arm. If the PFS HR was greater than 1 for a MET inhibitor versus sunitinib, the arm was recommended for closure.

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. As a result of the futility analysis, the savolitinib and crizotinib arms were closed in December 2018.

Patients had a median age of 66 years (range, 29-89), and the majority were male (75%) and white (77%). Few patients had received prior systemic therapy (7%), and as anticipated by investigators, a minority of patients had type I histology, ranging from 17% to 20% across study arms. Additionally, the majority of patients had intermediate risk by International Metastatic RCC Database Consortium Risk Group criteria (61%). Moreover, 61% had a performance status of 0, while 39% had a status of 1. Mixed histologies were observed in 15% to 24% of patients and over 70% of patients had prior nephrectomy. Few patients had central nervous system metastases (less than 1%).

A preliminary assessment of discordances based on pathologic subtype was also presented. Thirteen patients were categorized by local assessment with type I disease and they were noted to have type 2 disease on central assessment, Pal said. In contrast, 3 patients with type II disease per local assessment were characterized to have type I by central assessment.

“Ultimately these didn’t appear to have a key bearing on the key finding from our study,” said Pal. “Irrespective of central and local assessment, patients with type I and type II disease appeared to have benefit with cabozantinib.”

OS will continue to be followed among studies arms, but in a preliminary assessment, no significant differences were seen between the arms examined, said Pal. Notably, however, there is a slight trend toward improved OS in the cabozantinib arm relative to the sunitinib arm, at 20.0 months versus 16.4 months, respectively.

Grade 3/4 AEs 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 seen with the agents in SWOG 1500 were similar to those reported in larger studies, noted Pal. Moreover, the rate of treatment discontinuation due to AEs linked with study medication was highest with sunitinib (24%), followed by cabozantinib (23%), crizotinib (16%), and savolitinib (10%). Sixteen patients remained on protocol at the time of last follow-up.

Grade 3/4 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, concluded Pal.

1. Sumanta K. Pal, Catherine Tangen, et al. Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma (pRCC): Results from the randomized phase II SWOG 1500 study. 

. 2021;339(suppl 6):270. doi:10.1200/JCO.2021.39.6_suppl.270

Articles

Papillary renal cell carcinoma (RCC) is a rare malignancy, accounting for 15% of all RCC cases. 

Cabozantinib significantly delays progression in papillary RCC

Epidemiologic evidence presented during the 2021 Genitourinary Cancers Symposium provides teeth to the argument suggested in other recent analyses that the reduction in prostate-specific antigen (PSA) screening over that past decade is likely directly responsible for the rise in cases of metastatic prostate cancer in the United States.

“To reduce the incidence of metastatic prostate cancer in the United States, we support policies that promote shared decision making to optimize PSA screening, such as the updated USPSTF guidelines,” presenting study author Vidit Sharma, MD, a chief resident in the Department of Urology at Mayo Clinic, said during a poster presentation of the data.

PSA screening was found to reduce metastases and mortality in patients with prostate cancer, according to results from the randomized ERSPC trial. However, screening has also been known to result in significant harms from overdiagnosis and overtreatment of low-risk prostate cancer, Sharma noted. As a result, the USPSTF found insufficient evidence to recommend PSA screening in 2008 and went on to recommend against it in 2012.

“Several subsequent studies have found that there has been a rise in prostate cancer diagnosis since that change,” Sharma said. “Although the implication of these studies is that decreases in PSA screening were responsible for the rise in metastases, this has not been directly demonstrated.”

The objective of this study was to test the hypothesis that reductions in PSA screening were responsible for increased incidence of metastatic prostate cancer at diagnosis. To do this, investigators examined statewide variation in PSA screening, as well as statewide variation in the incidence of metastatic disease at diagnosis from 2002 to 2016.

Investigators extracted age-adjusted incidence of metastatic prostate cancer diagnosis per 100,000 men from the North American Association of Central Cancer Registries for each state. Additionally, survey-weighted PSA screening estimates for men 40 years of age or older were extracted from the Behavioral Risk Factor Surveillance System, which collected data on PSA screening every 2 years from 2002 onward.

These data were then analyzed in a multi-panel time series by state, using a random effects linear regression model, which looked at random effect at the state level, as well as related changes in PSA screening to incidence of prostate cancer metastases within and between states.

Results showed a significant variation in the incidence of PSA screening between states in men aged 40 years or older (range, 40.1%-70.3%). However, after 2010, a significant decrease in the median percentage of PSA screening across all states (range, 61.8%-50.5%) was observed. Additionally, investigators also noted a significant variation in the incidence of age-adjusted metastatic prostate cancer at diagnosis by state (range, 3.3 to 14.3 per 100,000 men) until 2010, when median incidence increased across all states. 

Investigators found that states with larger decreases in PSA screening, there was a larger increase in the incidence of metastatic prostate cancer at diagnosis. Data from the random effects linear regression model confirmed that reductions in PSA screening were related to rises in metastatic disease at diagnosis (-14.9; 95% CI, 12.3-17.5 per 100,000; 

“Overall, variation in PSA screening explained 27% of variation in metastatic disease at diagnosis,” Sharma concluded.

1. Vidit Sharma, Abhishek Venkataramana, et al. Association of reductions in PSA screening across states with increased metastatic prostate cancer in the United States

. 2021;39(suppl 6):228. doi:10.1200/JCO.2021.39.6_suppl.228

“To reduce the incidence of metastatic prostate cancer in the United States, we support policies that promote shared decision making to optimize PSA screening," said Vidit Sharma, MD.

Courtney Marabella

Articles

Cabozantinib significantly delays progression in papillary RCC

Evidence mounts that rise in metastatic prostate cancer is linked to PSA screening reduction