Front Line Trials in Advanced RCC

Transcript:

Benjamin Garmezy, MD: Dr Barata, what are your thoughts about what you picked for that patient who came through the door? What would have influenced which of those 3 TKI [tyrosine kinase inhibitor] immunotherapy regimens you might have gone with first? Then we can dive in to which patients we might use doublet immunotherapy for.

Pedro Barata, MD, MSc: That’s a great question and a great summary. Let’s comprehensively evaluate all of them. You talked about the CLEAR trial, which supported the combination of lenvatinib-pembrolizumab. I’ll briefly summarize the CheckMate 9ER trial, which investigated a combination of nivolumab with cabozantinib at a dose of 4 mg for cabozantinib. We recently saw updated results with about 44 months of median follow-up. The median overall survival for patients treated with cabozantinib-nivolumab was close to 50 months, compared with 35 for patients treated with sunitinib. In this longer follow-up analysis, the activity of cabozantinib-nivolumab remained confirmed. There was prolongation of all end points. In addition to overall survival, we also saw a benefit of progression-free survival and overall response rate. We saw double digits for response rate with cabozantinib-nivolumab and a very good safety profile. That’s CheckMate 9ER.

We also have data presented at the 42-month follow-up with KEYNOTE-426. That’s for the combination of pembrolizumab with axitinib vs sunitinib. Those results were presented some time ago. In terms of activity with this combination, the data were very similar to what we’ve previously seen with a benefit of progression-free survival and overall survival. This regimen is well tolerated, and we see a benefit of those efficacy end points while we preserve the quality of life of those patients.

I’ll briefly highlight the data with ipilimumab-nivolumab from CheckMate 214. This is the combination that has shown the longer follow-up data. We have data over 5 years. What seems to be attractive about the regimen with longer follow-up is that this conditional survival means that if you achieve a deep response rate, including good PRs [partial responses] and a good CR [complete response], the probability of remaining alive beyond the landmark of 2 and 3 years was pretty high; it’s over 80%. It allows us to understand the concept of durable responders: patients who remain on or off treatment without progressing. That’s critical in this patient population as we want to prevent them from needing a second-line therapy as much as possible.

When I put all these data together, I/O [immuno-oncology]–TKIs have a higher overall response rate by PR. CR seems to be similar, almost 20% more response rate. That’s important if you add those data to the other, which is the low number of progressive disease. You’re talking about single digits for cabozantinib-nivolumab and lenvatinib-pembrolizumab and close to 20% for ipilimumab-nivolumab. If you have a patient who’s symptomatic because of a lot of disease and a high tumor burden, and he’s going down very quickly, I choose I/O–TKI. Whether it’s cabozantinib-nivolumab, lenvatinib-pembrolizumab, or axitinib-pembrolizumab, I’m looking for patients who won’t progress on therapy and those patients for whom I have only 1 chance of success in trying to regain control of their cancer. If I have a patient and predict a good chance that they might be longer term, I save a TKI. This is where I feel very comfortable considering them for ipilimumab-nivolumab. That’s also true for patients who harbor sarcomatoid [RCC] and rhabdoid [tumor cell] features, for example. Any of these I/O–based combos have shown to be remarkably active in tumors that have sarcomatoid and rhabdoid features. Those are some of the factors that I take into consideration.

When I’m thinking about all the options out there, the quality of life for all these agents is either similar or better. The ipilimumab-nivolumab and cabozantinib-nivolumab data show that patients did better than sunitinib on their respective trials. Patients on lenvatinib-pembrolizumab and axitinib-pembrolizumab have been shown to be noninferior for the quality-of-life metrics used. There’s no reason for us to think about a TKI monotherapy. That’s 1 of the take-home points, not to consider TKI monotherapy for most of our patients, such as the patient you just presented.

Benjamin Garmezy, MD: These are excellent points. When I think about doublet immunotherapy combinations—let’s put I/O–TKI to the side for a second—I’m using it in those sarcomatoid and rhabdoid patients. Those patients do better with immunotherapy; that’s critical. I’m also giving it to a few select younger patients, but most patients in the frontline metastatic setting are getting I/O–TKIs. That’s a combination thinking about the higher response rates and the decreased primary progressive disease rates that you alluded to. And they gain experience as time goes. These patients have started on I/O–TKIs, which is new. We’re getting more data and more clinical experience with patients going into CR. With these combinations, they can sometimes come off therapy too. That potential to come off after 2 years may not be 100% unique to ipilimumab-nivolumab, but we have the strongest durability data with the immunotherapy doublets, no question. Those are critical data.

Transcript edited for clarity.