Expert Discusses Evolving Roles of Cabozantinib, Nivolumab in RCC

Jorge A. Garcia, MD

Over the past decade, there have been several new agents approved for the treatment of patients with advanced renal cell carcinoma (RCC). However, it was the approvals of nivolumab (Opdivo) in November 2015 followed by cabozantinib (Cabometyx) in April 2016, that have made the biggest difference, explains Jorge A. Garcia, MD, of the Department of Hematology and Oncology at Cleveland Clinic.

“Since 2005, we have had many new treatments for the management of patients with advanced RCC; however, the biggest challenge was that none of the agents that we had approved prior to nivolumab and cabozantinib demonstrated a survival benefit—at least statistically,” he says. “Obviously, with the nivolumab approval last year, cabozantinib is now the second agent in the history of RCC able to demonstrate a survival improvement. The impact of that is that now patients will have an extra choice in second-line treatment.”

OncLive: What did we learn from the METEOR trial?

He also provides considerations to make when selecting between the 2 agents in the second-line setting and the possibility of immunotherapy and cabozantinib combinations in the first-line setting for the future.Garcia: This is the trial that led to the approval of cabozantinib in advanced RCC in the second-line space. This was actually published last year in The New England Journal of Medicine.¹ At the 2016 ASCO Annual Meeting, the final survival analysis for the METEOR data was presented.²

METEOR is a randomized phase III trial that evaluated the impact and efficacy of cabozantinib against everolimus (Afinitor) in patients who failed primary therapy with tyrosine kinase inhibitors. Six hundred plus patients were randomized to receive either cabozantinib at the standard dose of 60 mg/day orally or everolimus at the standard dose of 10 mg/day.

The primary endpoint was progression-free survival (PFS) tied with a secondary endpoint of survival. The trial initially demonstrated that PFS was significantly improved with cabozantinib—nearly double compared with everolimus—from 3.9 months to 7.4 mouths, with a hazard ratio of 0.51. This means that there was a 49% risk reduction in progressing when patients receive cabozantinib.

The final survival analysis presented at ASCO not only continued to demonstrate the PFS improvement, but also showed a survival improvement in the secondary endpoint, from 16.5 months with everolimus, to approximately 21.4 months with cabozantinib. Here, the hazard ratio was 0.66—demonstrating a 34% risk reduction in mortality for those who receive cabozantinib over everolimus.

What factors should be considered when choosing between nivolumab and cabozantinib in this setting?

The responses to this therapy are what we would expect to see in the second-line space; there were 17% of patients responding to therapy by RECIST criteria, compared with less than 3% with everolimus. A subset analysis was presented across many subgroups, including patients with bone metastases and patients who have good-risk, poor-risk, and intermediate-risk disease. The bottom-line was that no matter what subgroup you have, it appears that treatment with cabozantinib improves outcomes with not only PFS, but also overall survival.The biggest question is now going to be whether we use nivolumab or cabozantinib in the context of second-line therapy. That question remains highly debated at this point.

Most of us will probably select an agent mainly based on tolerability. Nivolumab certainly has some side effects that are related to checkpoint inhibition, but it’s an easier agent for most patients.

To some extent, cabozantinib may have a few more complications in the sense that you have to be more in touch with how you manage patients. There are significant issues with dose reduction; 60% of the patients in the METEOR trial were dose reduced. If you look at the entire population of the trial, 20% of patients actually received the lowest dose of 20 mg. This is an agent that inhibits KDR, which is a VEGF receptor-2. It is similar to other agents; however, the difference with cabozantinib is that it is also a MET and AXL inhibitor, so it has a different mechanism of action.

What other remaining questions with cabozantinib should be answered in the next couple of years?

I don’t think we truly know who is the right patient for nivolumab versus who is the right patient for cabozantinib. It is going to be up to practice style, at least at this point.There was a phase II trial of cabozantinib against sunitinib (Sutent) in metastatic RCC that demonstrated a significant advantage for cabozantinib. The question is, “Could you expand cabozantinib into the frontline space?” Clearly, the biggest question is not around moving this agent as a single-agent into the frontline space, but in combination. Right now, these oral checkpoint inhibitors are being assessed in the frontline space and, if they get approved in the frontline space, sequencing is really going to be a question.

There is an interest in a combination of cabozantinib and PD-1 inhibitor, as well. In animal models, one can see that when you inhibit VEGFR, you can actually increase overexpression of PD-L1. With a dual VEGFR/MEK/AXL inhibitor, one could argue that a logical combination with PD-L1 agents would be the next step.

References

1. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. N Engl J Med. 2015;373(19):1814-1823.
2. Choueiri TK, Powles T, Escudier BJ, et al. Overall survival (OS) in METEOR, a randomized phase 3 trial of cabozantinib (Cabo) versus everolimus (Eve) in patients (pts) with advanced renal cell carcinoma (RCC). J Clin Oncol. 34, 2016 (suppl; abstr 4506).

In an interview with OncLive, Garcia discusses the final survival data from the phase III METEOR trial, which was the basis for cabozantinib’s FDA approval, as well as the role the agent will now play along with nivolumab in advanced RCC.