Upfront Therapy for mRCC - Episode 3

mRCC: Risk Status and Other Factors for Therapy

July 27, 2018

Martin H. Voss, MD:IMDC risk status, as we have now said, becomes a very relevant piece of information, especially in the first-line setting for our patients now. And it’s interesting to note that for the 2 most recent approvals in that space, cabozantinib but also ipilimumab/nivolumab studies were analyzed specifically in that setting. Now, it is relevant to understand that the FDA approvals don’t integrate IMDC risk status for both of these. So, rightfully for ipilimumab/nivolumab, the FDA has limited its approval to patients with IMDC intermediate- or poor-risk disease, and they do so because the benefit over sunitinib was not seen in favorable-risk patients, indeed the opposite was the case as we have discussed.

Cabozantinib is FDA approved now for untreated and pretreated metastatic kidney cancer, and there is no limitation set or no specification given for risk status. Meaning, the CABOSUN trial in the first-line setting was conducted only in intermediate- and poor-risk disease. However, the FDA approval is not limited to that group but specifies that patients only have to have metastatic RCC. Similarly, both of these regimens were tested in the trials that we have discussed in patients with clear-cell histology. They have not looked at patients with less common variants that we often summarize as non—clear cell renal cell cancer. The FDA approvals for both of these drugs, just like for all other agents we have, are not limited to clear-cell kidney cancer, meaning insurance approval can be requested for patients with non–clear cell histology. So, also with the limitation that we do not have dedicated data from prospective clinical trials yet, all of that is ongoing presently.

We, of course, have all the data to guide choice of tyrosine kinase inhibitors in the first-line setting. For many years, we have discussed sunitinib and pazopanib as the 2 standards that have been used most widely really across the globe. They, too, of course have been compared in a large randomized trial. The COMPARZ study published in theNew England Journal of Medicinein 2012, at its time, was the largest trial ever conducted in kidney cancer. About 1200 patients were randomized in that trial, which was a noninferiority study, to prove that pazopanib was not inferior to sunitinib in terms of progression-free survival in treatment-naïve patients. It was a positive study in that there was no inferiority for pazopanib in that setting.

There were a lot of secondary analyses built in to that trial, many of which aim toward the tolerability of drugs, toxicity profiles for the 2 agents in comparison, and the quality of life scores. And on this trial, most of these favor pazopanib, as was concluded to be the more tolerable agent between the 2. Proponents of sunitinib since then have argued that the treatment schedule for sunitinib can be adjusted easily in order to make this a more tolerable, more manageable agent. So, sunitinib, when it was originally approved based on its pivotal trial back in 2006, has always been given on a 50 mg 4-week on, 2-week off schedule. And ever since it hit the market, there are many efforts, initially retrospectively and then also some prospective efforts, that have looked into alternative schedules to make this agent more tolerable. The most commonly used one is 150 mg on a 2-week on, 1-week off schedule, which, in the span of 6 weeks, delivers the same amount of medication but gives more frequent and shorter breaks for toxicity not to build up for so long and for the treatment intermission not to be as long.

There’s a small randomized phase II study from Korea that has actually looked at this with a primary efficacy endpoint of progression-free survival in treatment-naïve patients. And that study met its primary endpoint, suggesting that the 2-week on, 1-week off schedule was in fact more efficacious than 4-week on, 2-week off. And such as all the prior retrospective efforts, it had also demonstrated better tolerability for the novel schedule. So, certainly, many investigators now have more and more been using the 2-week on, 1-week off schedule for sunitinib-treated patients.

The Canadian investigators have been very invested in sunitinib, and there have been data to suggest individualizing the treatment schedule—not only in terms of adjustment for toxicity but also dose escalation in patient who do not show any signs of toxicity—can be helpful, both in terms of tolerance and efficacy. So, sunitinib is not often used entirely, and if it is being used, there is certainly more and more evidence to suggest that individualizing schedules are helpful.

Transcript edited for clarity.