Renal Cell Carcinoma Research and Shared Decision Making With Bradley McGregor, MD

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're here at the ASCO Annual Meeting, and I'm joined by Dr. Bradley McGregor. Thanks so much for joining us today.

Bradley McGregor, MD: Thanks so much for having me.

Oncology Data Advisor: You're presenting here the results of the phase 2 study of cabozantinib with nivolumab and ipilimumab for advanced RCC with variant histologies. What were the results of the study and how are they significant for patients with RCC?

Dr. McGregor: When we think about renal cell carcinoma, there have been so many advances in how we treat renal cell carcinoma, but a lot of that has been relegated to clear cell. About 20% of renal cell carcinoma is these variant histologies, where we really are still working to find the best treatment for these patients overall. It had some really exciting data recently on different combinations, immunotherapy–tyrosine kinase inhibitor (IO-TKI), and we had the trial of nivo, ipi, and cabozantinib (cabo) for clear cell, COSMIC, showing an improvement in progression-free survival with the triplet. So, as that trial was going on, we designed this trial to really explore the triplet in those patients with variant renal cell histologies. All patients could have one prior line of therapy, not including immunotherapy or cabo. Patients were enrolled on trial who had a variant histology, and they received a cabo dose of 40 mg daily, with the standard nivo and ipi for four cycles, followed by maintenance cabo and nivolumab, and patients were treated until unacceptable toxicity or progression.

We enrolled 40 patients into the first cohort. As expected, the majority of them were male. A majority of these patients were papillary, although we did have 11 patients with chromophobe, some translocation, and unclassified as well. We had relatively short follow-up at this time; the mean follow-up was just over 10 months. The response rate was unfortunately only 18%. So, when we look at that, it's relatively disconcerting, although I think we need more time. So, if we look at patient, there are several patients on therapy who have shrinkage, maybe not quite at that 30% mark, but who are still on therapy and their disease is shrinking, which I think is noteworthy. So, I think further follow-up would be really important. We do have patients though who responded incredibly well to this overall. I have a patient with fumarate hydratase (FH) deficient RCC who presented with ptosis, and he's in essentially a complete response (CR) doing amazingly well. But obviously there's some activity.

What about the toxicity? There was certainly notable toxicity. Over close to half the patients required high-dose steroids. As we've seen with COSMIC-313, there are a lot of live function test (LFT) abnormalities. So, this is early data, 40 patients. We saw a signal of activity in 14, the patients still remain on therapy, so how can we do better? We've already started a second cohort of 20 patients, starting with a lower dose of cabozantinib upfront, hoping to minimize some of the LFT toxicities and some of the other issues upfront, to allow patients to get the full induction and go on to maintenance therapy.

Oncology Data Advisor: Great. Since these are still early data and the trial's still progressing, it might be too soon to say, but how do you foresee these results to be translated into the treatment landscape?

Dr. McGregor: So, I would argue with these results that this triplet should not be a standard of care for patients with renal cell carcinoma, variant histology. At this point in time, I think we need to do better, and we need to look for novel approaches. This was one approach. I think we're continuing to tweak it, and longer follow-up will be critical to determine how this really factors into treatment.

Oncology Data Advisor: Okay, great. In light of this in other directions, are there any other studies in RCC that you're looking forward to?

Dr. McGregor: Yes. I mean, this was the first trial looking at triplet therapy in RCC variant histology, but there's going to be data presented at this meeting with updates on the combination of cabozantinib/nivolumab in RCC variant histology, and lenvatinib with pembrolizumab in RCC variant histology, with really impressive response rates over 50%. So I think that's really exciting, and it's really representing an advancement in the field overall. That's something we haven't seen, at all, when you look at the historical standard sunitinib response rates around 20%. And now we're having these incredible response rates. So, I think that's super, super exciting in variant histology.

And then, in terms of clear cell renal carcinoma, we're going to see some long-term updates from CLEAR with the final survival analysis. Pembrolizumab/axitinib (axi) is going to have an updated survival analysis, which is really going to look at the durability of these IO-TKI combinations in that. And then how do we think about it in second-line? Novel agents, the role of belzutifan We had the CONTACT-3, which shows that addition of tislelizumab to cabozantinib improve progression-free survival versus cabozantinib alone. So, I think there's a lot of learning more about what's already been done in the frontline setting, novel approaches in the second-line setting, and continued advances in the variant histology.

Oncology Data Advisor: Definitely, it'll be exciting to hear the results of all these trials. One of the last questions I have for you is, since this year's theme for ASCO is "Partnering with Patients," do you have any examples of how you partner with patients to incorporate shared decision making when you're treating?

Dr. McGregor: I mean, ultimately, every single treatment decision that we make is a shared decision. When we talk about this in the clinic—and we're fortunate to be at an institute that has clinical trials, right?—the clinical trials are truly a shared decision making. As we go through the different options, we talk about the options that are available at this point in time, and there are treatments A, B, and C. These are the relative benefits of A versus B versus C, and then, what's important to you? What matters to the patient? If you look at renal cell carcinoma, if you look at the National Comprehensive Cancer Network (NCCN) guidelines, there are so many options that you can use in frontline and second-line; there's not one that's preferred. And that reason is because we have great data for all of them. So it really does come down to what matters to the patient.

So, are they in a situation where they really want to avoid a pill and they want to do a double IO therapy? Are they in a situation where they travel farther away? So, potentially coming in every six weeks versus every four weeks makes a difference. Are they in a situation where they really care about what happens in that first scan and they're not looking to that long-term, or do they care about potentially coming off treatment long-term? There are so many factors that come into play, so I sort of take it as an honor to help guide that decision, but not to make that decision. Ultimately, the patient makes the decision and I'm there to provide some guidance and some knowledge to help make that the best decision possible for them at that given point in time, with the understanding that every decision we make, we may have to tweak.

I tell my patients all the time, "There are no highways, it's all local roads." So, we're going to go, and we're not going to be getting on and going 90 miles per hour on the expressway. We're going to be stopping at every point and saying, "Should we turn or keep going?" And we just have to constantly reevaluate.

Oncology Data Advisor: Definitely. That's a great example, and a really valuable perspective. So thank you so much for talking to us about this today.

Dr. McGregor: Thank you so much.

About Dr. McGregor

Bradley McGregor, MD, is a Senior Physician and Director of Clinical Research, Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute. He is also a Professor of Medicine at Harvard Medical School. Dr. McGregor is an active participant in clinical trials researching combination immunotherapies for various genitourinary cancers. As well, he takes interest and helps research antibody-drug conjugates in heavily treated kidney and bladder cancers.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.