Selecting the Appropriate IO-TKI in Frontline Setting in Advanced RCC


A comprehensive discussion on how to select the appropriate IO-TKI regimen in the frontline setting in advanced renal cell carcinoma.


Elizabeth Wulff-Burchfield, MD: Let’s get back to my esteemed colleagues. In looking at the approach to frontline treatment of advanced kidney cancer, I’d love if someone would be willing to paint me a picture about, are folks using the same regimen pretty universally, or is there a certain patient profile for whom you would or wouldn’t use one of these particular regimens? And where does axitinib/pembrolizumab fit in? Dr McKay, would you be willing to take that?

Rana McKay, MD: Absolutely. Whenever I have a patient presenting to me in the clinic, there are a couple of variables I like to look at. I like to look at their IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] status. I like to look at their rate of progression, and burden of disease, whether they’re oligometastatic or polymetastatic. Using those criteria, I gauge whether they even warrant therapy to begin with, whether I can get by with a metastasectomy or SBRT [stereotactic body radiation therapy] approach, or whether they warrant systemic therapy. If somebody warrants systemic therapy, [I go to] my decision tree. I literally have this conversation with the patients, I say, “Do we have to play the short game, or do we have the luxury of playing the long game?” And the response rates are very high with the IO [immunotherapy] VEGF-TKIs [tyrosine kinase inhibitors]. There are probably more similarities among those regimens than there are differences. The PFS [progression-free survival] is also quite substantial.

Even though we are now getting long-term follow-up data, I think the question of durability of response is still to be determined. So for those patients who need an immediate response and we have to get their disease in check, I’m leaning toward an IO-VEGF regimen. However, for those patients who have the luxury of playing the long game, I tend to favor nivolumab/ipilimumab. With nivolumab/ipilimumab, the response rates are a bit lower. The primary PD [progressive disease] rate is about 1 in 5, but the long-term durability is also about 1 in 5. There’s no way right now in the clinic that we can a priori, before somebody starts treatment, know which group that patient’s going to be in.

Elizabeth Wulff-Burchfield, MD: May I ask a clarifying question? Does that conversation decision tree look pretty similar if someone needs systemic therapy, whether they have favorable-, intermediate-, or poor-risk disease, with regard to do we need to debulk this patient vs do we have the luxury of time?

Rana McKay, MD: It does actually. Even for my favorable-risk patients, I still talk about nivolumab/ipilimumab as an option. Now that we have even longer and longer follow-up, we’re seeing that the hazard ratios are trending in the right direction for that favorable-risk group. There’s even a plateau there. I think the thing about favorable-risk patients is that those patients are going to do well. Most of the time, they’re asymptomatic from their disease. They’re going to have the opportunity to get multiple subsequent-line therapies, and I think that’s why we’re obscuring the OS [overall survival] signal when we look at it in the context of clinical trials. These patients do well, the event rate is low, they get multiple subsequent lines of treatment. It’s hard to really know what is the true impact on the long-term regimen when looking at OS. So I do think that conversation happens even for the favorable-risk patient. It’s probably even more complex and not as clear-cut for the favorable-risk patients.

Elizabeth Wulff-Burchfield, MD: I do find that the conversations are the hardest for the favorable-risk patients. They’re so much more nuanced. It’s hard when you’re meeting someone new because you don’t understand their values in order to capitalize on that and provide them additional insight.

Dr Barata, building on that, would you say that you have particular patient profiles that you would recommend among these regimens, whether it’s one of the TKI-IO regimens, nivolumab/ipilimumab, or otherwise?

Pedro Barata, MD: Here are a few thoughts, and I agree with Dr McKay completely. I guess I use different words, but the message there is the same. One thing is recommendation, the other thing is what we do—style, practice, familiarity with the regimens. The recommendation is that most patients we see should be getting an IO-based combination. That’s the recommendation, that’s based on level 1 data. The question about, do I favor one combination vs the other, to use Dr McKay’s words from earlier, they [have] more in common than they are different. That seems to be the case.

We can all debate about TKI or VEGF-TKI being dose dependent, and what does that mean in terms of safety? What does that mean in terms of efficacy? We certainly see different profiles from the quality-of-life perspective. But we’re not sure if there’s really an IO-based combination better than another. Now, we do tend to be more comfortable with some than others, and for a number of reasons, the data that the different trials provide to us help us make those decisions. So everything I’m going to share next has to do with my interpretation of the data, not so much a recommendation. I cannot tell you that cabozantinib/nivolumab, which I would probably have done for this patient, is better or worse than others. But I certainly use some data out there based on the phase 3 trials to make those [choices].

I think what is critical when you’re playing this short game, the question is, can you minimize the chances of the patient not benefiting from a certain treatment? That’s progressive disease rate. So I use the data with single digits where you get cabozantinib/nivolumab or get lenvatinib/pembrolizumab, you’re looking at around 5%, 6% rate of PD as the best response. That means that [almost] everybody on these IO-based combinations will get some benefit out of it because they won’t progress on treatment. I think that’s crucial. So things like symptomatic disease, very high tumor burden, a lot of disease in places that make me concerned, for example the liver, are definitely factors I use to make a decision about what to do.

I agree with the thought process around nivolumab/ipilimumab. We don’t quite know who the patients are who are going to benefit from it. Although we do know that if you end up having sarcomatoid or rhabdoid features, you’re more likely to benefit. It’s not a guarantee of success, but you’re closer to seeing advantage of it.…If we go back and think about who were the patients using IL-2 [interleukin-2] back in the days, a lot of them were good risk. Low tumor burden, no symptoms, low volume of disease, patients were doing great. And the reason for that we think is in the genomics, in the molecular profiling of those tumors. If you look at the good risk, you’re definitely going to find an immunogenic signature.

What does that mean? What exactly those genes are remains to be answered clearly, but there’s definitely a role that perhaps we have not identified precisely for immunotherapy in the good-risk [patients]. That’s my argument to do an IO-based combination in the good-risk [patients] and not so much a TKI monotherapy because I do believe you never know what you’re getting. Are you getting angiogenic tumor, are you getting immunogenic? Sometimes it’s a mix. By throwing 2 different mechanisms of action, I think perhaps you’re covering both bases.

Then I completely agree [with my colleagues], unfortunately, we’re not able to provide durable remissions for the vast majority of our patients. The longer follow-up right now with nivolumab/ipilimumab is over 5 years. We just saw data with cabozantinib/nivolumab [over] 44 months, which I think you’re going to show us as well. We’re getting there, [we have] over 3 years of follow-up.

The question we have is, what happens to these patients 3, 4, 5, 6, 7 years later? Right now for nivolumab/ipilimumab it seems that about 1 out of 5 will remain like that. We have seen data with cabozantinib/nivolumab and lenvatinib/pembrolizumab for patients who have completed 2 years of immunotherapy, then stop immunotherapy and continue on the TKI alone. Those patients seem to do remarkably well for an additional 2 years. But the reality of it is, for most of our patients, maybe 4 out of 5, if not more, end up progressing.

Also, factors like the quality-of-life data from the PROs [patient-reported outcomes], and…you’ve done wonderful work on that as well, can help us decide how comfortable you are with a certain regimen vs the others. We don’t compare across trials, but we do have the same comparator, and that’s sunitinib. Even though we use different instruments, and I’ll let you talk more about that, I do believe the quality-of-life input is relevant when we have the patient in front of us, and we have this discussion about what to do given all the options available.

Elizabeth Wulff-Burchfield, MD: Thank you so much, what a great summary. The quality-of-life are is very meaningful to me. I do think there are patients who are very happy to trade the life they have before treatment for the very different life they might have on an aggressive treatment regimen. Some people really don’t have the option to prioritize their quality of life in decision-making if we know they’re very unlikely to get to second-line [therapy], at least if that’s at risk.

Transcript edited for clarity.

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