SWOG 1500: PFS longer with cabozantinib than sunitinib in mPRCC

Cabozantinib reduces the risk of disease progression or death by 40 percent compared with the current standard sunitinib in patients with metastatic papillary renal cell carcinoma (mPRCC) – a primary malignant tumour of the renal tubular epithelium – in the phase 2 SWOG 1500 study.

Progression-free survival (PFS) was significantly prolonged with cabozantinib vs sunitinib (9 months vs 5.6 months, hazard ratio [HR], 0.6; 95 percent confidence interval [CI], 0.37-0.97). [ASCO GU 2021, abstract 270]

“Cabozantinib resulted in a dramatic improvement in PFS,” said Dr Sumanta (Monty) Pal,  clinical professor of medical oncology at City of Hope in Duarte, California, US, and SWOG Cancer Research Network investigator. “For the first time, we have an agent that benefits outcomes in this rare patient population, where previously there was no real true standard of care.”

Local pathologic review showed that 18 percent of patients had type I histology, 54 percent had type II histology, and 28 percent had mixed/other histology, with corresponding frequencies per central review of 30 percent, 45 percent, and 25 percent, respectively.

Cabozantinib benefits persisted in those with type I (local assessment, HR, 0.26; 95 percent CI, 0.07-1.01; central assessment, HR, 0.56; 95 percent CI, 0.22-1.45), and type II (local assessment, HR, 0.57; 95 percent CI, 0.3-1.06; central assessment, HR, 0.62; 95 percent CI, 0.31-1.24) histology.

The new reference standard for systemic therapy in mRCC?

“Despite discordances observed in the subtype classifications, cabozantinib appeared to have a homogenous effect across treatment groups,” Pal said at ASCO GU 2021. “Our data support cabozantinib as a new reference standard for systemic therapy in eligible patients with metastatic RCC.”

The confirmed overall response rate (ORR) of 23 percent (complete response, 5 percent) with cabozantinib was significantly higher vs the 4 percent ORR (complete response, 0 percent) with sunitinib (p=0.01).

Small-molecule c-MET kinase inhibitors crizotinib and savolitinib were also evaluated in the SWOG 1500 study, but both failed to demonstrate benefits vs sunitinib (PFS 2.8 and 3 months, respectively vs 5.6 months).

Cabozantinib wins vs c-MET kinase inhibitors

Pal and team compared all three putative kinase inhibitors with sunitinib on the contention that MET signalling is a key molecular driver in PRCC. “We’d like to find out if any of the three drugs could delay tumour growth, and ironically, a drug that I was involved in, in the phase 1 development – cabozantinib – made the mark and improved patient outcomes,” Pal excitedly reported.

The data were from 147 patients (median age 66 years, 76 percent men) who had mPRCC and a Zubrod performance status of 0–1. They may have received up to one prior systemic therapy, excluding VEGF- or MET-directed therapy. Ninety-two percent of the patients had no prior therapy.

Patients received sunitinib 50 mg daily on a 4 weeks-on, 2 weeks-off schedule (n=46), cabozantinib 60 mg daily (n=44), crizotinib 250 mg twice daily (n=28), or savolitinib 600 mg daily (n=29). The primary endpoint was PFS for each MET kinase inhibitor vs sunitinib; secondary endpoints were overall survival (OS), response rate, and adverse events.

Accrual for the crizotinib (median PFS, 2.8 months) and savolitinib (median PFS, 3 months) groups was halted early for futility. Interestingly, there was a slight trend toward improvement with cabozantinib vs sunitinib (20 months vs 16.4 months) in the preliminary OS results. Yet there were no significant differences seen overall.

Median OS was 19.9 months with crizotinib vs 11.7 months with savolitinib.

Grade 3–4 adverse events occurred among 68 percent of patients on sunitinib, 74 percent on cabozantinib, 37 percent on crizotinib, and 39 percent on savolitinib. There was one grade 5 adverse event with cabozantinib.

Understanding the biology in rare cancers ‘critical’

“Understanding the biology in rare cancers, whether it’s a rare type of kidney cancer, or breast cancer, or ovarian cancer, is critical,” Pal emphasized. “Developing trials around that biology is challenging, but as we’ve demonstrated in SWOG 1500, it is doable and necessary if we’re going to move the needle for these patients.”

Despite these advances, mutant inhibitor-resistant kinases evolve quickly. Appropriate multitargeted inhibitors or combinations for mPRCC should be studied rigorously.