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Cabozantinib (Cabometyx) came out on top as upfront therapy in metastatic papillary renal cell carcinoma (RCC) in a randomized phase II study.

Treatment with the multikinase inhibitor yielded a median progression-free survival (PFS) of 9.0 months, as compared to 5.6 months with sunitinib (Sutent), which has been the default standard of care in this setting (HR 0.60, 95% CI 0.37-0.97, one-sided P=0.019), reported Sumanta Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, California.

Overall response rate was significantly improved with cabozantinib compared with sunitinib (23% vs 4%, P=0.01), and 5% versus none, respectively, had complete responses, according to findings presented at the virtual Genitourinary Cancers Symposium (GUCS) and published simultaneously in the .

Pal called the findings "absolutely" practice-changing.

"What's great about this is now that data are out there, cabozantinib sort of becomes immediate frontline standard," he told 番茄社区app. "This is one of those findings where you can hear it at [GUCS] and take it to the clinic on Monday and implement this."

Median overall survival (OS), a secondary endpoint, numerically favored the cabozantinib arm (20 vs 16.4 months, HR 0.84, 95% CI 0.47-1.51), though the trial was not powered to assess differences in OS.

Papillary is the most common non-clear cell RCC, accounting for roughly 15%-20% of all kidney cancers, and these patients are typically excluded from most clinical trials. No optimal therapy exists for the disease, and while sunitinib has been considered a standard option, studies have shown with the agent. MET alterations are a key driver of papillary RCC, which led to the current study.

From 2016 to 2019, the SWOG 1500 trial randomized 147 eligible patients at 65 centers in the U.S. and Canada to one of four study arms: sunitinib (control; n=46) versus the MET kinase inhibitors cabozantinib (n=44), crizotinib (Xalkori; n=28), or savolitinib (n=29). Enrollment in the latter two treatment groups was halted after a prespecified futility analysis showed no PFS benefit with either crizotinib (2.8 months) or savolitinib (3 months) over sunitinib, a multitargeted kinase inhibitor. Median OS was 19.9 months with crizotinib and 11.7 months with savolitinib.

"Savolitinib and crizotinib are really specific inhibitors of MET, they kinda inhibit MET and perhaps not much else," said Pal. "Cabozantinib inhibits a broad spectrum of targets that are relevant to kidney cancer."

In an in the Lancet, Delphine Borchiellini, MD, of Université Côte d'Azur in Nice, and Philippe Barthélémy, MD, of Institut de Cancérologie Strasbourg Europe, both in France, noted some limitations of the trial, including the fact that a lower proportion of patients with type 2 papillary RCC, which is associated with worse outcomes, were ultimately included in the cabozantinib arm.

"Most importantly, the choice of a common histological approach, not related to MET status, can be challenging for the evaluation of both savolitinib and crizotinib," they wrote. "This challenge might partly explain the disappointing results of selective MET inhibitors in this study, even if additional identification of MET alterations (not available yet but ongoing) will clarify this point."

Still, Borchiellini and Barthélémy concluded that SWOG 1500 "provides the best level of evidence currently available for patients with advanced [papillary RCC], and cabozantinib could be contemplated as a new option in this situation."

Pal said researchers will expand on these findings with a phase II trial testing cabozantinib with or without immunotherapy in this setting.

Study Details

Patients in SWOG 1500 had a median age of 66, 76% were men, and 78% were white. Eligible criteria allowed for one prior treatment, excluding VEGFR or MET inhibitors (7% had received a previous therapy). All agents were administered orally, at doses of 50 mg for sunitinib (4 weeks on/2 weeks off), 60 mg for cabozantinib (daily), 250 mg for crizotinib (twice daily), and 600 mg for savolitinib (daily), with dose reductions to prespecified levels allowed for each.

Most patients had type 2 papillary RCC (54%), followed by not otherwise specified in 28% and type 1 in 18%. According to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, 26% had favorable-risk disease, 61% had intermediate-risk, and 14% had high-risk disease.

Grade 3/4 adverse events (AEs) occurred in 37% of patients assigned to cabozantinib, 69% of those assigned sunitinib, 74% of those on crizotinib, and 39% of those receiving savolitinib. One fatal thromboembolic event occurred in the cabozantinib group. Treatment discontinuation for AEs occurred in 23% of patients on cabozantinib, in 24% with sunitinib, in 14% of those receiving crizotinib, and in 10% with savolitinib.