In the phase II SWOG 1500 study reported in The Lancet, Pal et al found that among three comparator MET kinase inhibitors, cabozantinib prolonged progression-free survival vs sunitinib in metastatic papillary renal cell carcinoma.

Study Details

In the open-label trial, 147 eligible patients from sites in the United States and Canada were randomly assigned between April 2016 and December 2019 to receive sunitinib at 50 mg 4 weeks on/2 weeks off (n = 46), cabozantinib at 60 mg daily (n = 44), crizotinib at 250 mg twice daily (n = 28), or savolitinib at 600 mg daily (n = 29), with prespecified dose reductions permitted for each treatment. Treatment continued until radiographic progression, clinical deterioration, or unacceptable toxicity. Patients had received up to one previous systemic therapy, excluding vascular endothelial growth factor–directed and MET-directed agents.

The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. A futility analysis was performed after 15 progression-free survival events were observed in each of the cabozantinib, crizotinib, and savolitinib groups; if the hazard ratio for an experimental group vs sunitinib was > 1, the group was recommended for closure.

Progression-Free Survival

Assignment to the savolitinib and crizotinib groups was terminated after the prespecified futility analysis. Planned accrual was completed for the sunitinib and cabozantinib groups.

At final analysis, median progression-free survival was 5.6 months (95% confidence interval [CI] = 2.9–6.7 months) in the sunitinib group, 9.0 months (95% CI = 5.6–12.4 months) in the  cabozantinib group, 2.8 months (95% CI = 2.6–3.6 months) in the crizotinib group, and 3.0 months (95% CI = 2.8–7.2 months) in the savolitinib group. For the cabozantinib vs sunitinib comparison, the hazard ratio favoring cabozantinib was 0.60 (95% CI = 0.37–0.97, P = .019).  Savolitinib and crizotinib did not improve progression-free survival vs sunitinib.

Confirmed objective response rates were 23% in the cabozantinib group vs 4% in the sunitinib group (P = .010). Response rates were 0% and 3% with crizotinib and savolitinib. Complete response was observed in two cabozantinib patients (5%); all other responses in study groups were partial responses.

Median overall survival was 16.4 months (95% CI = 12.8–21.6 months) with sunitinib, 20.0 months (95% CI = 11.3 months to not reached) with cabozantinib, 19.9 months (11.2 months to not reached) with crizotinib, and 11.7 months (95% CI = 6.7–28.9 months) with savolitinib. The hazard ratio for cabozantinib vs sunitinib was 0.84 (95% CI = 0.47–1.51). No significant differences in overall survival were observed between treatment groups.

Adverse Events

Grade 3 or 4 adverse events occurred in 69% of patients in the sunitinib group, 74% of the cabozantinib group, 37% of the crizotinib group, and 39% of the savolitinib group. The most common of these in the cabozantinib group were hypertension (33% vs 18% in sunitinib group), hand-foot syndrome (21% vs 0%), fatigue (14% vs 7%), and thromboembolic events (12% vs 0%). The most common in the sunitinib group were hypertension, anemia (13% vs 0% in cabozantinib group), decreased white blood cell count (11% vs 0%), nausea (9% vs 0%), and decreased neutrophils (9% vs 0%). One patient in the cabozantinib died from a thromboembolic event.

The investigators concluded: “Cabozantinib treatment resulted in significantly longer [progression-free survival] compared with sunitinib in patients with metastatic [papillary renal cell carcinoma].”

Sumanta K. Pal, MD, City of Hope Comprehensive Cancer Center, is the corresponding author for The Lancet article.

Disclosure: The study was funded by the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.