A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt University Medical Center, focused on the spectrum of therapy for frontline renal cell carcinoma (RCC), including a comparison of monotherapy and doublet and triplet treatment options. Dr. Rini was joined by a panel that included Monty Pal, MD; Moshe Ornstein, MD; and Shuchi Gulati, MD, MSc.
In the final segment of the roundtable series, the panel shares interesting clinical trial data in development, including CONTACT-03, TiNivo-2, and more.
Dr. Rini: Let’s close with new data you’re looking forward to in the next year. Or drugs, we didn’t touch on belzutifan, a HIF inhibitor. What’s exciting? What do you think is going to come out and impact practice? We talked about CheckMate 8Y8, so we’ll take that off the table. What other data is coming, and what might be most impactful?
Dr. Pal: I don’t know how soon it’s coming, but this phase 3 trial of everolimus versus belzutifan in heavily refractory patients probably is going to be the first I would imagine of these phase 3 studies to hit. I can’t imagine that belzutifan wouldn’t win out against everolimus with the response rate of 2% and a progression-free survival (PFS) of 1.6 months in its own phase 3 trial. If belzutifan doesn’t hit the bar, we have a problem. Once that agent comes into practice, I think the big dilemma is going to be do we go tyrosine kinase inhibitor (TKI)/immuno-oncology (IO) to TKI and then to an agent like tivozanib? Or will we go down the path of belzutifan? It’s going to be a really interesting dilemma. I’m not quite sure what I’ll do at this point.
[Editor’s note: This discussion was filmed prior to the release of results from the CONTACT-03 trial. Read more updated information on the trial’s findings.]
Dr. Rini: I’m not either. Shuchi, what are you looking forward to?
Dr. Gulati: Definitely the belzutifan and also the CONTACT-03 data to guide us on the sequencing question.
Dr. Rini: CONTACT-03 is cabozantinib/atezolizumab versus cabozantinib in an IO-refractory population. TiNivo-2, which is still accruing, is tivozanib/nivolumab versus tivozanib in pretty much that same population, including post-adjuvant, so adjuvant pembrolizumab failures were allowed in CONTACT-03 as well. We’re not going to cover that, but that’s a whole segment of patients we have no idea what to do with. It’s kind of asking, do patients get a second shot at immune therapy? Do you think for those studies there has to be an overall survival (OS) benefit for the them to get used? I think they’re probably PFS/OS co-primaries.
Dr. Pal: It’s going to be so hard to demonstrate an OS advantage, and that hasn’t really been our bar in the refractory setting to date.
Dr. Rini: Maybe it should be.
Dr. Pal: Maybe it should be.
Dr. Ornstein: Up until now, the bar for frontline has been OS, and the bar in the refractory setting has really been the PFS benefit.
Dr. Rini: But I guess I would counter, and I’m not sure I have a strong opinion on this, that’s because we haven’t had curative drugs in the refractory setting. We would hope that immune therapy can be curative in the refractory setting. If there’s a statistically significant PFS, they’ll get approved and used. We say, you can’t show OS when we haven’t shown it. Then a potent drug comes along and suddenly you show it. That has happened in other diseases. Do you think there will be an OS advantage?
Dr. Ornstein: I don’t think so. I’m not convinced there’s going to be a PFS advantage. We don’t see a ton of PFS benefits from IOs in general, and I think something happens to a patient’s RCC biology when there’s disease progression on an IO agent, and I’m really not convinced about the activity. We had TiNivo-2 and CONTACT-03 open and we accrued. I think it’s an important question to answer, but I’m really curious to see the results.
Dr. Pal: I’ve just seen so many patients referred into my practice who have been on 3 or 4 sequential IO-based therapies. I’m just thinking to myself, what an amazing societal economic cost. This is coming out with zero data.
Dr. Rini: There’s an immunotherapy halo effect, right? Where you might not do that with a MEK inhibitor or something else. There’s this halo effect because you’re always holding out for that durable disease control. We’ve all had patients who were rescued. We all have those dramatic patients who were rescued. It’s a bit in desperation. I’m not justifying it, but I think I understand the philosophy.
Dr. Pal: I was doing this talk last night with Dave McDermott, MD, and Chuck Drake, MD, was actually in the audience, which was amazing. It was a great opportunity. I don’t know why he came to my talk. I asked him, “What do you think about this principle of IO followed by IO?” He said, “To many folks out there treating breast cancer and other diseases, the paradigm exists.” With HER2-directed therapies, for instance, you use that through the continuum of treatments for breast cancer. ER/PR-positive is the same. There is that paradigm in oncology, but we probably do need to try to deflate it if it’s not helping patients.
Dr. Rini: There’s the paradigm, but diseases are different. Like you said, myeloma is different. We certainly need level 1 evidence.