Cabozantinib Maintains Efficacy in Advanced RCC Irrespective of Prior Treatment

Mototsugu Oya, MD, PhD

Patients with advanced renal cell carcinoma (RCC) who were treated with the multikinase inhibitor cabozantinib (Cabometyx) following both immunotherapy (IO) and non-IO regimens demonstrated promising responses, suggesting the agent’s efficacy regardless of prior therapy, according to data from a pooled analysis of patients treated on the phase 3 METEOR (NCT01865747) and the phase 2 Japanese C2001 (NCT03339219) that were presented at the 2020 ASCO Virtual Scientific Program.

Both groups had similar rates of progression-free survival (PFS) at 6 months, with 65.5% of patients in the IO group and 58.3% of those in the non-IO group remaining free of disease progression or death. The median PFS in months for both groups were not reached versus 7.4, respectively.

More than 90% of patients were alive at 6 months in both the IO (90.8%) and the non-IO (90.6%) groups. Median overall survival (OS) was 19.5 months (95% CI, 12.4-not reached) in patients with prior IO and 21.9 months (95% CI, 18.7-23.7) in those without IO.

Tumor response by independent review committee was similar between patients who were treated with prior immunotherapy and those without. In the prior IO group (n = 33), the objective response rate (ORR) was 21.2% (95% CI, 9.0%-38.9%). Similar rates were observed in patients who had never received IO (n = 332), at 17.2% (95% CI, 13.3%-21.7%). In both groups, the ORR was made up exclusively of partial responses.

Rates of stable disease were similar in the 2 groups, at 54.5% of patients in the prior IO group and 66.6% in the non-IO group. Corresponding clinical benefit rates, or the rate of responses plus stable disease, were 75.8% (95% CI, 57.7%-88.9%) and 83.7% (95% CI, 79.3%-87.5%).

“Results of this pooled analysis suggest that cabozantinib is effective regardless of previous treatments in patients with [advanced] RCC,” the study authors ,who were led by Mototsugu Oya, MD, PhD, of the Department of Urology of Keio University School of Medicine in Tokyo, Japan, wrote in their poster.

All patients experienced treatment-emergent adverse effects (TEAEs) and the rate of grade 3 or greater events were comparable between the 2 groups. Treatment discontinuation due to TEAEs occurred in 12.1% who had prior IO and 14.4% of those who never received IO. Corresponding rates of serious TEAEs were 51.5% and 46.2%. The investigators reported that most TEAEs were manageable with dose modifications.

A greater proportion of those treated in the non-IO group experienced diarrhea (75.7% vs 54.5% with prior IO) and nausea (36.4% vs 50.8%). Patients in the IO group experienced a greater proportion of palmar-plantar erythrodysesthesia syndrome (57.6% vs 44.4% with no prior IO) and proteinuria (30.3% vs 16.5%). Notably, there were no differences in TEAEs typically associated with IO treatment, such as pneumonitis, endocrinopathy, or infusion-related reactions.

Baseline patient characteristics were well balanced between the 2 arms, with a slightly higher proportion of patients considered to have poor-risk disease (by International Metastatic Renal Cell Carcinoma Database Criteria) being in the prior IO group (24.2% vs 16.0% with no prior IO). The median patient age in both groups was 62 years and most patients were men. Karnofsky performance status was 80% to 100% in 93.9% and 91.6% of patients in the IO and non-IO groups, respectively. At least half of patients in each group had 3 or more involved organs per independent review committee.

The median number of prior systemic therapy regimens was higher in the IO group at 3 versus 1 in the non-IO group. Patients in the IO group were more likely to have received greater than 1 prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. Patients receiving 2 prior VEGFR inhibitors accounted for 51.5% of those in the IO group and 22.6% of those in the non-IO group; 9.1% and 3.3% of patients, respectively, had 3 or more prior VEGFR inhibitors. The most common prior VEGFR inhibitors received were sunitinib (Sutent), pazopanib (Votrient), and axitinib (Inlyta). In the IO group, the most common prior IO therapy received was nivolumab (Opdivo) in 84.8% of patients.

The pooled analysis included patients from both clinical trials who received oral cabozantinib 60 mg daily. Inclusion criteria for both studies included advanced or metastatic clear-cell RCC, the receipt of prior VEGFR inhibitor therapy with disease progression within 6 months, and a Karnofsky performance status of 70% or greater. There were no limits on the number of prior therapies received and patients with a history of exposure to PD-1/L1/L2 inhibitors were eligible.

Out of 331 cabozantinib-treated patients on the METEOR trial, 18 were included in the prior IO group and 313 were in the non-IO cohort. Out of 35 patients treated in the C2001 study, prior IO was used in 15 versus 20 who never received IO. This resulted in an efficacy analysis population of 365 patients.

Oya M, Tamada S, Tatsugami K, et al. A pooled analysis of the efficacy and safety of cabozantinib post immunotherapy in patients with advanced renal cell carcinoma. J Clin Oncol. 2020;38(suppl 15):5089. doi:10.1200/JCO.2020.38.15_suppl.5089

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