Cabozantinib (Cabometyx) improved progression-free survival and response rates in patients with untreated metastatic renal cell carcinoma compared with the standard of care, sunitinib (Sutent), according to the results of a phase II multicenter randomized trial called CABOSUN reported at the 2016 ESMO (European Society for Medical Oncology) Congress.1 This study confined enrollment to poor- and intermediate-risk patients, whereas other large trials in renal cell carcinoma have included favorable-risk patients.
Cabozantinib improved progression-free survival and overall response rate compared to sunitinib, with a similar safety profile. These data show that cabozantinib has the potential to become a first-line standard treatment.— Toni Choueiri, MD
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“Treatment-naive poor- and intermediate-risk renal cell carcinoma represents an unmet clinical need. This study showed positive progression-free survival and positive overall response rates with a short median follow-up. All results were in the right direction. This may change practice,” said lead author Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Boston. (For more on this study, also called the ALLIANCE A031203 trial, see The ASCO Post Newsreels on ASCOPost.com for a discussion by Dr. Choueiri.)
Both cabozantinib and sunitinib are tyrosine kinase inhibitors, but cabozantinib inhibits a broader range of enzymes, including vascular endothelial growth factor receptor (VEGFR), MET, and AXL, whereas sunitinib is a VEGFR inhibitor. “Both MET and AXL seem to be associated with tumor progression but more important, animal models showed that the development of resistance to VEGFR inhibitors like sunitinib can be mediated through AXL and MET,” Dr. Choueiri explained.
Cabozantinib has been approved by the U.S. Food and Drug Administration as second-line therapy for advanced renal cell carcinoma after failure on prior VEGFR-targeted therapy.
Study Details and Results
The study randomized 157 patients with untreated poor- or intermediate-risk metastatic renal cell carcinoma to receive either oral cabozantinib (60 mg/d) or sunitinib (50 mg/d) for 4 weeks on and 2 weeks off treatment until disease progression. In addition to being poor- or intermediate-risk, patients enrolled in the trial had unfavorable risk factors beyond traditional criteria. A total of 36% had bone metastasis, and 13% had an ECOG (Eastern Cooperative Oncology Group) performance status of 2, both of which are associated with a poor response to therapy, noted Dr. Choueiri. Crossover to the other therapy was not allowed in this trial.
Median progression-free survival was 8.2 months with cabozantinib vs 5.6 months with sunitinib, representing a 31% reduction in the median rate of disease progression or death (P = .012). Overall response rate was 46% with cabozantinib vs 18% with sunitinib, according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria.
Although preliminary with a short median follow-up, overall survival was 30.3 months with cabozantinib vs 21.8 months with sunitinib. Overall survival will be updated over the next several months, Dr. Choueiri revealed.
The median number of cycles given to patients was five for cabozantinib vs two for sunitinib. The rate of grade 3 or higher adverse events was similar for each treatment: 70.5% in the cabozantinib arm vs 72.2% in the sunitinib arm. The most frequently reported side effects with cabozantinib were hypertension, diarrhea, hand-foot syndrome, and fatigue.
Dose reductions were needed in 58% and 49% of patients, respectively. About 20% of patients in each arm discontinued treatment.
Regarding the implications of the study, Dr. Choueiri said: “Sunitinib is the standard of care and the most widely used drug in metastatic renal cell carcinoma. Median progression-free survival is 8 to 11 months in a general population that includes all risk groups. Patients at poor and intermediate risk have a worse prognosis, with a median progression-free survival reported as low as 5.6 months on the first targeted therapy. Cabozantinib improved progression-free survival and overall response rates compared to sunitinib, with a similar safety profile. Cabozantinib represents a first-line treatment option for patients with poor- and intermediate-risk renal cell carcinoma.”
Even though favorable-risk patients were not included in this study, Dr. Choueiri said there was no biologic or clinical reason to suggest that cabozantinib would not be effective in those patients.
Further “These data show that cabozantinib has the potential to become a first-line standard treatment,” he said. ■
Disclosure: Dr. Choueiri received institutional funds from Exelixis and Pfizer and advisory board compensation from Pfizer.
A phase III trial is warranted. I would want positive phase III data before I give cabozantinib to poor- and intermediate-risk patients.— Bernard Escudier, MD
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Formal discussant of this trial, Bernard Escudier, MD, Chairman of the Renal Cancer Unit...!-->!-->