Copenhagen, Denmark—The current standard for the first-line targeted treatment of metastatic renal-cell carcinoma (RCC) came out on the short end of a randomized comparison with the new multikinase inhibitor cabozantinib (Cabometyx), according to results reported at the 2016 European Society for Medical Oncology Congress.
The phase 2 CABOSUN clinical trial, limited to patients with intermediate- or high-risk metastatic RCC, ended with a median progression-free survival (PFS) of 5.6 months for sunitinib (Sutent) compared with 8.2 months for cabozantinib (P = .012).
The PFS in the cabozantinib arm is consistent with results typically seen with sunitinib in patients with standard-risk metastatic RCC, said Toni Choueiri, MD, Dana-Farber Cancer Institute, Boston.
“Sunitinib is a standard-of-care therapy in first-line metastatic renal-cell carcinoma. Trials of first-line treatment with VEGF [vascular endothelial growth factor] receptor tyrosine kinase inhibitors have demonstrated a median progression-free survival of 8 to 11 months. Patients with intermediate- and poor-risk disease have a worse prognosis, associated with a median PFS of 5.6 months for intermediate and poor-risk patients,” said Dr Choueiri. “Cabozantinib represents a potential first-line treatment option in patients with advanced renal-cell carcinoma.”
An inhibitor of MET, AXL, and VEGF receptors, cabozantinib received FDA approval in April 2016 for the treatment of patients with previously treated advanced RCC. Because patients with intermediate- or high-risk metastatic RCC have worse outcomes with first-generation tyrosine kinase inhibitors, investigators sought to determine whether cabozantinib may improve outcomes for this subgroup of patients.
Dr Choueiri reported findings from the phase 2 CABOSUN clinical trial, which was limited to patients with previously untreated, poor-prognosis metastatic RCC, as defined by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Investigators randomized 157 patients, 81% of whom met the IMDC criteria for intermediate-risk disease and 19% for poor-risk disease. In addition, 13% of patients had an Eastern Cooperative Oncology Group performance status of 2, and 36.3% had bone metastases.
For comparison, Dr Choueiri noted that 25% to 30% of patients enrolled in the RECORD-3 (Motzer RJ. J Clin Oncol. 2014;32:2765-2772) and COMPARZ (Motzer RJ. N Engl J Med. 2013;369:722-731) clinical trials of first-line targeted therapy for metastatic RCC met the criteria for favorable-risk disease. In addition, fewer patients in both clinical trials had poor performance status or bone metastases compared with patients in the CABOSUN study.
In CABOSUN, patients were randomized to receive standard doses of sunitinib or cabozantinib, and followed until disease progression, death, or unacceptable toxicity. PFS was the primary end point, and the objective response rate was the secondary end point.
The results showed a significant advantage in favor of treatment with cabozantinib, which resulted in a 31% reduction in the hazard for disease progression or death (P = .0012). Patients who received cabozantinib also had a substantial improvement over sunitinib in the objective response rate (46% vs 18%, respectively).
The PFS advantage has yet to translate into an overall survival (OS) benefit, although a trend in favor of cabozantinib had emerged, Dr Choueiri reported. Approximately 50% of patients in the study died at the last data analysis, showing a median OS of 30.3 months with cabozantinib versus 21.8 months with sunitinib. The 20% reduction in the hazard for survival was associated with overlapping confidence intervals.
The rates of grade ≥3 adverse events were similar in the cabozantinib (70.5%) and sunitinib (72.2%) groups. The rates were similar for specific types of adverse events, with the exception of hematologic adverse events, which were more common with sunitinib than with cabozantinib (22.2% vs 2.6%, respectively). Overall, 16 patients in each treatment arm discontinued therapy because of adverse events.
During a press briefing, Dr Choueiri said that, on the basis of the CABOSUN study results, he would consider using cabozantinib as first-line therapy for patients with metastatic RCC, at least in the subgroup of patients with intermediate- or high-risk disease. However, a specialist not involved in the study said that additional studies with longer follow-up will be required to determine whether cabozantinib should supplant the current first-line standard therapy with sunitinib.
“Obviously, this study will raise a lot of questions, such as whether these results are expandable to all patients with metastatic renal-cell carcinoma, including the good prognosis group; whether cabozantinib should become a new standard of care in the first-line setting; and how we should interpret all the ongoing phase 3 first-line studies, which selected sunitinib as the control arm,” said Bernard Escudier, MD, Chair of the Urology Committee, Gustave Roussy Institute, Villejuif, France.
However, the study raised “a lot of new expectations for the treatment of metastatic renal-cell carcinoma,” Dr Escudier acknowledged.
