Cabozanitinib Shows Anti-Tumor Activity Beyond Clear-Cell Renal Cell Carcinoma

The tyrosine kinase inhibitor (TKI) cabozantinib may have anti-tumor activity across non–clear-cell renal cell carcinomas (RCCs), according to a new study published in The Lancet Oncology.

“While still sparse, emerging data suggest that checkpoint inhibitors may be active against some non–clear-cell RCC. Given the potential for sustained benefit from this class of drugs, they may be considered early on in the management of non–clear-cell RCC,” James Brugarolas, MD, PhD, director of the Kidney Cancer Program at UT Southwestern Medical Center in Dallas, told Cancer Network.

Oral cabozantinib is approved for patients with metastatic RCC based on the results of studies among patients with clear-cell RCC histology. Until now, only two small retrospective studies involving fewer than 50 patients with non–clear-cell RCC have been reported and shown activity with TKI therapy, according to the study authors.

“A major reason we undertook this study was to confirm the efficacy that anecdotally many of us were observing in our clinics,” said study corresponding author Lauren C. Harshman, MD, an oncologist at the Lank Center for Genitourinary Cancers, Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School in Boston.

Harshman and colleagues conducted a multicenter, international, retrospective cohort study of 112 patients with metastatic non–clear-cell RCC who were treated with cabozantinib during any treatment line. Between 2015 and 2018, the patients were enrolled at 21 centers in the United States and at 1 in Belgium. Patients who had mixed tumors with a clear-cell histology component were excluded. Among the 112 patients, 59% had papillary histology, 15% had Xp11.2 translocation histology, 13% had unclassified histology, 9% had chromophobe histology, and 4% had collecting duct histology.

The researchers found that 27% of patients treated with cabozantinib achieved an objective response across all histologies. The median time to treatment failure was 6.7 months, and the median progression-free survival (PFS) was 7 months with a median follow-up of 11 months. The median overall survival (OS) rate was 12 months. “Our findings of a 27% objective response rate, with 74% of patients achieving some degree of clinical benefit, response, or stable disease, in a generally heavily pretreated group of patients, support the use of cabozantinib in non–clear-cell histologies while we await the ongoing prospective studies,” Harshman told Cancer Network.

The most common adverse events (AEs) of any grade were fatigue (52%) and diarrhea (34%). The most common grade 3 AEs were skin toxicity and hypertension. “In the absence of available prospective data, our study provides additional evidence for the safety and potential activity of cabozantinib in patients across the metastatic non–clear-cell renal cell carcinoma spectrum,” concluded the authors.

Harshman said non–clear-cell histologies are a rare and heterogeneous group of diseases, making prospective study difficult. Subsequently, these patients have few proven standard treatment options. Cabozantinib is an inhibitor of multiple tyrosine kinase receptors implicated in tumor progression, including VEGFR, MET, RET, KIT, and AXL.

“We can’t ignore that cabozantinib, while one of the most potent agents for advanced RCC, also comes with more toxicities, in part because it hits a greater number of targets,” said Harshman.

Due to the scarcity of information regarding optimal treatments for non-clear cell RCC, the study is significant, noted Brugarolas. This retrospective analysis showed that most patients receiving cabozantinib had been previously treated with another TKI, such as sunitinib, and more than 40% had received immunotherapy, he noted.

“An important question is what to do after progression on checkpoint inhibitors and TKIs, and a regimen that may be worth evaluating is the combination of lenvatinib and everolimus,” Brugarolas told Cancer Network.