Two Treatment Options

In November, the FDA approved the immune checkpoint inhibitor nivolumab for patients with advanced RCC who had received 1 or 2 prior regimens of antiangiogenic therapy. Nivolumab was approved based on results from CheckMate 025, a phase 3 trial that contrasted the effects of the PD-1 inhibitor with those of everolimus.2

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Patients in this trial assigned to nivolumab had significant improvements in overall survival (25.0 versus 19.6 months; P = .002) and objective response rate (25% versus 5%; P < .001). There was no significant difference in median progression-free survival between the 2 groups.

“Both drugs are a different class of agents and both were tested against everolimus, not each other, so it is hard to compare them,” Dr Choueiri said. “Both had an overall survival benefit and a response benefit, but nivolumab, like many single-agent PD-1 inhibitors, does not have a progression-free survival benefit over the standard of care, while cabozantinib does. Is that enough to choose 1 over the other? It is hard to say.”

Dr Haas agreed, but added that “patients are very excited about nivolumab because it is an immunotherapy, and they perceive it to be less toxic.”

Adverse Effects

In the METEOR trial, 39% of patients assigned cabozantinib experienced grade 3 or worse adverse events, the most common of which were hypertension, diarrhea, fatigue, palmar-plantar erythrodysesthesia syndrome, anemia, hyperglycemia, and hypomagnesemia.

“The safety profile and toxicities with cabozantinib are similar to other TKIs, so clinicians need to be familiar with how to manage these side effects and how to dose properly to maintain response,” Dr Choueiri said.

In CheckMate 025, 19% of patients assigned nivolumab experienced grade 3 or worse adverse events, the most common of which was fatigue.

“It is going to be difficult to get people to go right to treatment with cabozantinib rather than nivolumab, because patients are very excited about nivolumab,” Dr Haas said. “Only about 30% of the population, however, demonstrate responses [to nivolumab]; it is not going to be a drug that is going to serve everybody well.”

There are groups of patients, such as those with rheumatoid arthritis or those who have undergone transplant, who cannot receive immune checkpoint inhibitors because these drugs modulate the immune system and could cause existing comorbidities to manifest.

According to Dr Haas, there is a lot that physicians still do not know about who will respond to immunotherapy, though there is a better understanding about who will respond to VEGF receptor TKIs.

“We know that about 80% of patients benefit in some way from a VEGF receptor TKI,” she said. “The patients I would think of for cabozantinib are those who have performed well on previous TKIs, who haven’t had a lot of side effects, and who really do not want to be coming back and forth to clinic every 2 weeks for an infusion.”

Continuing Research

“At this point we have almost an embarrassment of riches and it will be hard to pick a second-line therapy,” Dr Choueiri said. “This question may not be relevant in the next year or 2, because these 2 drugs are already being combined with each other or other drugs in clinical trials.”

RELATED: Targeted Therapy Has Led to Better Survival Among African Americans, Caucasians

Cabozantinib may eventually be a first-line treatment option for patients with RCC. In May, cabozantinib’s manufacturer, Exelixis, announced  that a phase 2 trial demonstrated the drug’s significant improvement of progression-free survival, in contrast with sunitinib, for patients with previously untreated RCC.3

“This just demonstrates what a dynamic environment we are currently in for the research of treatments for RCC,” Dr Choueiri concluded.


  1. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomized, open-label, phase 3 trial. Lancet Oncol. June 5, doi: 10.1016/S1470-2045(16)30107-3 [Epub ahead of print]
  2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813.
  3. Ipsen’s partner Exelixis announced results from randomized phase 2 trial CABOSUN that demonstrate that cabozantinib significantly improved progression-free survival versus sunitinib in previously untreated advanced renal cell carcinoma. Published May 23, 2016. Accessed June 22, 2016.