Commenting on both the CheckMate 025 and METEOR studies, Sumanta K. Pal, MD, Co-Director of the Kidney Cancer Program at City of Hope Comprehensive Cancer Center, Duarte, California, said, “Cabozantinib (Cometriq) will probably be approved for advanced renal cell carcinoma. There is debate about whether to use cabozantinib or nivolumab (Opdivo) second-line, and there is a lot of discussion focused on second-line and third-line treatment,” he noted.
Major Challenges
“From my perspective, the big challenge between cabozantinib or nivolumab as second-line therapy is twofold. Nivolumab does not improve progression-free survival in this setting. It only achieves a tumor delay of 4 months and is associated with a relatively high rate of progressive disease, with 40% of patients having progressive disease as their best response…. On the other hand, a vast majority of patients derive benefit from cabozantinib. Only 15% have their best response as progressive disease, and 85% have responses or disease stabilization.”
He continued, “Another challenge is that although the assumption is that every patient on second-line therapy will go on to third-line therapy, there is attrition with each subsequent line of therapy. Only about 50% of patients on second-line therapy will go on to third-line therapy,” he said. Tolerance is another issue with VEGFR tyrosine kinase inhibitors, typically used as first-line agents, he pointed out.
Turning to a broader discussion of second- and third-line therapy, Dr. Pal said that agents such as axitinib (Inlyta) have not been compared with everolimus, and everolimus may still be used. “We are even talking about fourth- and fifth-line therapy with axitinib and everolimus,” he noted.
“Also tivozantinib is still around. A study is evaluating tivozantinib vs sorafenib (Nexavar) as third-line and fourth-line therapy, and if that study is positive, it may reinvigorate interest in using tivozantinib in the front line as well,” Dr. Pal said.
Second-Line ‘Trifecta’
“The take-home message for me is that cabozantinib achieves the trifecta for second-line therapy: improved progression-free survival—in fact, the best of any drug in this setting—improved response rates, and a strong trend toward improved overall survival. I would be very surprised if overall survival was not superior in the mature data,” he said.
Negative observations for nivolumab include primary progressive disease in 38% of second-line recipients compared to about 15% for cabozantinib. Anecdotally, investigators have said that nivolumab is less toxic than cabozantinib, but if you compare the tables of all-cause adverse events from trials side-by-side, the differences in toxicity become attenuated. In CheckMate 025, the rates of grade 3 and 4 adverse events were 37% with everolimus vs 19% with nivolumab. In METEOR, the rates of grade 3 and 4 adverse events were 58% with everolimus vs 68% with cabozantinib.
“This is an unfair comparison, because adverse events were all-cause in METEOR and only treatment-related in CheckMate 025. If you just looked at 19% vs 68%, it would not be an accurate picture. If you look at the package insert for nivolumab, the rate of all-cause adverse events is 56%, which begins to approach the 68% reported with cabozantinib. The difference has shrunk,” he said.
“If you look at the data the right way and consider the ‘trifecta’ that I mentioned before, as well as acceptable toxicity, that swings me in favor of cabozantinib as second-line therapy,” he concluded. ■
Disclosure: Dr. Pal has received consulting fees from Pfizer, Novartis, Genentech, Exelixis, and Bristol-Myers Squibb.
