Case Analyses in Renal Cell Carcinoma - Episode 12

Case 2: TIVO-3 Study in mRCC

Dr Eric Jonasch and the panel discuss TIVO-3 trial data and use of tivozanib and HIF3α inhibitors in mRCC.

Robert Motzer, MD: We’ve reviewed the third-line treatment options for this patient, and with pembrolizumab-axitinib in the first line. Cabozantinib is the second-line drug of choice, and lenvatinib-everolimus is given in the third line. One of the newly approved drugs for RCC [renal cell carcinoma] is tivozanib, which was approved based on the TIVO-3 trial. Eric, we’d like if you could review the TIVO-3 results and give us a little insight into your take on the outcome data.

Eric Jonasch, MD: Absolutely. Here is the trial schema. This was the trial testing tivozanib vs sorafenib in individuals with advanced clear-cell renal cell carcinoma that progressed on 2 or 3 prior systemic regimens, including at least 1 VEGFR-TKI [vascular endothelial growth factor receptor - tyrosine kinase inhibitor]. They had to have a performance status of 0 or 1. Stratification was by prior regimen and also by IMDC [International Metastatic RCC Database Consortium] prognostic score. It was a 1:1 randomization. Primary end point was PFS [progression-free survival] by independent review, and secondary end points were the expected ones.

Here are the major outcome data for this trial. We see the Kaplan-Meier curve for PFS on the left. The hazard ratio is 0.73 with a 95% confidence interval not overlapping 1. The medium PFS for tivozanib was 5.6 months vs 3.9 months for sorafenib. We can see the objective response rate was 23% vs 11%. The disease control rate was 82% vs 69%. For the overall survival and the hazard ratio, there was a trend. The hazard ratio was 0.91, which was fully overlapping 1, and the P value was .47.

Here’s the tornado plot showing the safety. There was clearly more hypertension in tivozanib, and there were similar degrees of asthenia and fatigue. In the sorafenib side it looked like the tornado was imbalanced from the diarrhea, hand-foot syndrome, and rash. In the table on the right, we see that the percentage of patients that required dose interruption was 50% vs 64% for tivozanib vs sorafenib. Dose reduction was 25% vs 39%. Dose discontinuation was 21% vs 30%, and then grade 3/4 treatment-related adverse event was 46% vs 55%.

Robert Motzer, MD: Thanks very much. Tivozanib is the new kid on the block in terms of TKIs. Have any of you had experience with tivozanib in any of the trials since it’s been approved?

Tom Hutson, DO, PharmD: Yes.

Robert Motzer, MD: Can you tell us your hands-on experience with tivozanib?

Tom Hutson, DO, PharmD: Tivozanib has been utilized in clinical trials for several years. I was involved in some of the earlier studies and then recently in the TIVO-3 trial as well as prescribing it. I’ve actually prescribed it to a few patients. It’s based upon having data in the setting in the modern era of patients who’ve had prior exposure to I/O [immuno-oncology] and the newer generation—TKIs, cabozantinib, or lenvatinib-everolimus —and it’s become my preferred agent in the third- and fourth-line settings. The difference between whether I give it third or fourth line is dependent upon the exposure to patients and whatever TKI they received in the frontline setting.

But it’s moved to that point. You could make an argument: “What makes you say that tivozanib is any better than axitinib or any other potential salvage regimen?” It’s because tivozanib with the TIVO-3 data included that trial population, and we have prospective data that support its use. It’s become the de facto unless other data come along to show something superior.

Robert Motzer, MD: Thanks very much. That’s a great discussion on tivozanib. Let’s wind up this case with a brief discussion of some of the newer drugs that are coming. One of the additional questions that we should discuss is the new HIF2A [Hypoxia-Inducible Factor-2] Alpha inhibitors.

Eric, I know you’ve been pivotal in terms of working with these compounds in VHL [Von Hippel-Lindau] disease, and Bradley as well in metastatic disease. Eric, what’s your level of excitement? Is this a promising treatment strategy for us moving forward?

Eric Jonasch, MD: There are 3 studies in the public domain. One that we published in Nature Medicine a couple of months ago looked at 55 patients who had had a median of 3 prior therapies who were treated with belzutifan, the HIF2A inhibitor. It demonstrated an objective response rate of 25% and, more important, a progression-free survival of 14.5 months and great tolerability.

At least in that single-arm phase 1B [trial, those are] promising data. Look, we have some great data presented at ESMO [European Society for Medical Oncology Congress] that we just heard about that showed that together with cabozantinib there were once again good data. In the VHL-patient population, we’re incredibly proud to have the first approved drug in VHL disease. These aren’t patients with metastatic disease, but they have multifocal bilateral renal cell carcinomas, hemangioblastomas, pancreatic neuroendocrine tumors—all the lesions. Yes, I’m pretty bullish about this agent. It’s actually got a role in renal cell carcinoma and definitely in VHL disease.

Robert Motzer, MD: That’s great. Bradley, in wrapping up this case, do you want to speak to this agent or any of the newer strategies that you’re particularly excited about for metastatic RCC?

Bradley McGregor, MD: I’m excited about belzutifan. This drug seems to have a very favorable toxicity profile. We’ll look forward to the phase 3 trial against everolimus. But I’m really excited for looking at the use of that in combination therapy earlier in the disease course, when they knew the disease is more VHL driven. To that extent, [we’re using] combination therapies in the frontline trying to see if we can get more durable responses up front. Combinations like nivolumab-ipilimumab with cabozantinib, like in the COSMIC trial, will be important. Ongoing trial looking to add on lenvatinib vs lenvatinib and pembrolizumab are going to be very interesting. I’ve seen some negative data…and I applaud looking for novel targets because we had a lot of advance in renal cell, but there’s been a lot of the same drugs in combination and doing this and there. Continuing advances and look for new targets, hoping to find some different biomarkers that can respond to 1 therapy vs the other, are going to be important as we look toward the next steps.

Robert Motzer, MD: On that optimistic and well-thought-out note, we’ll conclude this case discussion for case No. 2, for this favorable-risk patient who we’ve followed through with in second- and third-line therapy. Thanks very much to our panel.

Eric Jonasch, MD: Clearly the HIF2A inhibitor data are pretty strong. For example, in the phase 2 study that we published in Nature Medicine a couple of months ago, a 55-patient phase 1B2 study were individuals who had received a median of 3 prior lines of therapy and had an objective response rate of 25%. More important, they had a progression-free survival of 14.5 months and really good tolerability. We saw that the combination of cabozantinib plus belzutifan was also pretty interesting in terms of progression-free survival data and objective response rate. It’s definitely an interesting regimen, and it shows that the phase 2 data that we published was not a fluke.

We’re very excited about the data with the HIF2A inhibitor and VHL disease, whereas of August 13, 2021, we have FDA approval for this disease, which had never had a prior systemic therapy. We saw responses in the multifocal bilateral renal cell carcinomas, and we saw responses in the hemangioblastomas, which we’d never seen to this degree, and also in pancreatic neuroendocrine tumors. Thus, I’m pretty bullish about this regimen.

Transcript edited for clarity.