4 Questions With an Expert: Cabometyx and the Future of Kidney Cancer Care

Cabometyx (cabozantinib) significantly reduced the risk of death by 34 percent compared with Afinitor (everolimus) among patients with previously treated advanced renal cell carcinoma (RCC), according to results from the METEOR trial. These phase 3 findings were presented at the 2016 Annual Meeting of the American Society of Clinical Oncology, a gathering of 30,000 oncology professionals in Chicago.

Can you give an overview of the study?

CURE spoke with Jorge Garcia, a medical oncologist at the Cleveland Clinic and one of the researchers on the study about the benefit of Cabometyx and what’s next for the treatment of RCC. This trial has led to the approval of Cabometyx in advanced renal cell carcinoma in the second line of space. It was first published last year in The New England Journal of Medicine.

This morning, Dr. Choueiri presented the final survival analysis for the METEOR data, something we didn’t have before we published. METEOR is a randomized phase 3 trial that elevated the impact and the efficacy of Cabometyx against Afinitor in patients without primary therapy with TKI. Over 600 patients were randomized to receive Cabometyx at the standard dose of 60 mg per day orally or Afinitor at 10 mg a day orally.

The primary endpoint was progression through survival tied with a secondary endpoint of survival. The trial initially demonstrated that there was a significant progression-free survival improvement, increasing from 3.5 to 7.6 months. Additionally, overall survival was 16.5 months with Afinitor and 21.4 months for Cabometyx.

What impact has the FDA approval had on treatment for RCC?

The responses to this therapy are what one would expect to see in a second line of space. In total, 17 percent of patients responded to therapy with Cabometyx by RECIST criteria compared with less than five percent of patients responding to Afinitor. Dr. Choueiri also presented the subset analysis across many subgroups, including patients who have bone metastases as well as patients who were classified as good, intermediate or poor risk. No matter what subgroup you have, it appears that treating with Cabometyx improves outcomes not only in progression-free survival but also survival.Since 2005, we have many new treatments for managing patients with RCC. However, none of the agents we have approved in the past have demonstrated survival benefit, at least statistically. We know these agents can show improvement, but statistically we weren’t able to prove it. Cabometyx is the second agent in the last year or so that has been FDA approved with survival improvement. Before that, Opdivo (nivolumab), which also helps with survival improvement, was approved in November. Now patients are moving from primary TKI therapy with Sutent (sunitinib)/Votrient (pazopanib) and will have an extra choice in the second line of space.

With more agents being improved, are you finding there are going to be more challenges in sequencing?

Are there any questions regarding Cabometyx you're hoping to answer within the next few years?

The biggest question is going to be whether we use Opdivo or Cabometyx for second-line therapy. That question remains heavily debated at this point. Many of us will pick an agent based on tolerability. Opdivo certainly has some side effects that are related to checkpoint inhibition, but it’s an easier agent for most patients. Cabometyx, to some extent, may have more complications in the sense that an oncologist has to be more thoughtful with symptom management. There were significant issues with dose reduction. Around 60 percent of patients in the trial had their doses reduced, which means patients went from 60 to 40 to 20 mg, which is the lowest dose. If you look at the entire patient population in the trial, 20 percent of patients received the lowest dose.The biggest question, in my opinion, is if you start someone on a TKI do you use Opdivo or Cabometyx as your second agent of choice? You’ll hear different opinions. At this point, I would argue based on registration, most people are going from TKI to Opdivo. I don’t think we truly know who is the right patient for Opdivo or Cabometyx. It’s going to be a practice style at this point. For patients, it’s a huge opportunity because now we have almost nine agents approved. I think sequence will continue to be the same, but whether we use Opdivo or Cabometyx remains to be seen.There was a phase 2 trial looking at Cabometyx against Sutent in untreated metastatic RCC patients that demonstrated a very significant progression-free survival difference in favor of Cabometyx. The question is: Would you do Cabometyx now or would you expand Cabometyx use in the frontline space? There are also questions about the use of immunotherapy agents and assessing their use in the frontline space. If approved, will sequencing change dramatically? There is also interest to look at Cabometyx in combination with an immunotherapy.