The study results, according to one expert, show that Cabometyx should be considered the new standard for systemic therapy in patients with metastatic papillary renal cell carcinoma.
Data from a randomized phase 2 clinical trial have demonstrated that Cabometyx (cabozantinib) significantly prolonged progression-free survival compared to Sutent (sunitinib) in patients with metastatic papillary renal cell carcinoma (RCC).
Moreover, results of the SWOG 1500 study — which were presented during the virtual 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium — showed that Cabometyx reduced the risk of disease progression or death by 40% versus Sutent.
The drug was also associated with a higher response rate (23%) than Sutent (4%) in the patient population enrolled onto the study. Complete responses to therapy, however, were only observed in those who received Cabometyx. And although the trial also compared Sutent to Xalkori (crizotinib) and AZD6094 (savolitinib), both of those treatment arms were discontinued early as neither appeared better than Sutent.
“Although discordances were observed in subtype classification, (Cabometyx) had a homogeneous effect across treatment groups,” lead study author Dr. Sumanta K. Pal said in an oral presentation of the data. “With this in mind, (Cabometyx) 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. The standard of care in these patients have included VEGF-targeted therapies, including Sutent. However, Pal highlighted that the estimates of efficacy of these options are varied. In fact, response rates for those therapies range from 0% to 24%, and progression-free survival (the time from treatment to disease progression or worsening) has ranged from 1.6 months to 8 months.
“To date, there have been no randomized data specifically in [patients with] papillary RCC showing an advantage of one systemic therapy over another,” Pal noted.
Multiple studies have suggested that the MET proto-oncogene may be a potential driver of papillary RCC. Although it is more common in type 1 compared with type 2 disease, the MET mutation and copy number alteration occur in a proportion of both subtypes. In the SWOG 1500 trial, the study authors sought to determine whether different MET inhibitors could improve clinical outcomes relative to Sutent in patients with metastatic papillary RCC.
Notably, SWOG 1500 is the first randomized trial to exclusively enroll patients with metastatic papillary RCC and complete patient 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 up to one prior lines of therapy, provided they had not received previous treatment with Sutent.
Patients were randomized to receive either Sutent, Cabometyx, Xalkori or AZD6094. They were also separated into different groups depending on disease subtype (type 1 vs. 2 vs. not otherwise specified) and number of therapies they had already received (0 vs. 1).
Measuring progression-free survival was the main goal of the study. Other goals included assessing overall survival, responses to therapy and side effects.
Of note, the study was designed to permit dose reductions for each of the four agents if needed.
From April 2016 to December 2019, 152 patients (median age, 66 years; range, 29 to 89 years; 75% men; 77% White) were enrolled onto the SWOG 1500 trial at 65 cancer centers across the United States and Canada. As a result of an analysis during the study, the AZD6094 and Xalkori arms were closed in December 2018.
Few patients had received prior systemic therapy (7%), and as anticipated by the study authors, a minority of patients had type 1 histology, ranging from 17% to 20% across study arms. Additionally, 61% of patients had intermediate risk disease. Moreover, 70% of patients had prior nephrectomy (surgical removal of one or both kidneys). Few patients had central nervous system metastases (less than 1%).
The median progression-free survival with Cabometyx was 9 months versus 5.6 months with Sutent. The authors plan to continue following overall survival results, 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 overall survival in the Cabometyx arm relative to the Sutent arm, at 20 months versus 16.4 months, respectively.
More serious or severe side effects were reported in 68% of patients in the Sutent arm, 74% of patients in the Cabometyx arm, 37% of patients in the Xalkori arm, and 39% of patients in the AZD6094 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 treatment-related side effects was highest with Sutent (24%), followed by Cabometyx (23%), Xalkori (16%), and AZD6094 (10%).
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