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Goals in Previously Treated Advanced Renal Cell Carcinoma

Panelists: Sumanta Kumar Pal, MD, City of Hope; Neeraj Agarwal, MD, MS, Huntsman Cancer Institute; Bradley McGregor, MD, Dana-Farber Cancer Institute; Tian Zhang, MD, Duke Cancer Institute
Published: Wednesday, Apr 24, 2019



Transcript: 

Sumanta Kumar Pal, MD: Neeraj, you started out 1 of our conversations earlier discussing the transition from first-line to second-line to third-line therapy, and I agree with you. Only about 20% of patients were making it to third-line therapy, by and large.

Neeraj Agarwal, MD: In academic cancer centers.

Sumanta Kumar Pal, MD: At academic cancer centers.

Neeraj Agarwal, MD: This is about those doctors who are actually focusing on taking care of kidney cancer patients. These data are from them, so I can’t even imagine what may be happening. Maybe it’s superior, but it’s likely inferior in those community settings [that] do not have the resources to take care of these patients.

Tian Zhang, MD: You mean even fewer patients going on to receive second-line, third-line, and fourth-line treatments?

Neeraj Agarwal, MD: Yes.

Sumanta Kumar Pal, MD: So with these principles that you have in [the] second-line setting—response rate, PFS [progression-free survival], etc—that were different from frontline, does that hold in the third-line setting? Is your strategy different?

Neeraj Agarwal, MD: Absolutely. In fact, I like the way you presented the data at all the ASCO [American Society of Clinical Oncology Annual] Meetings. You called it a trifecta of response: objective responses, progression-free survival, and overall survival [OS]. I think for a given patient of mine, all of those 3 goals are important. It doesn’t matter what we like as physicians. Some people talk about complete responses, but we need to never forget that complete responses are happening in a very small number of patients. About 90% patients are not experiencing complete responses with ipilimumab-nivolumab. So in my view, all these criteria are important: overall survival, complete response, objective response, and progression-free survival. And in second line, third line, or even later lines, those remain very important.

Tian Zhang, MD: I think these criteria are great when we’re thinking about populations, clinical trials, and these statistics. But I tell my patients, these are really just statistics of a population, and it’s great that we’re getting the majority of patients to live longer with this therapy versus that therapy. But every patient is a little bit different, and you never know if your patient is going to have a great response to axitinib in the second line. Maybe that’s a great drug and they can be on it for a good amount of time. Based on disease characteristics, we talk about personalized treatments. Unfortunately, I wish we had better molecular characteristics for our patients and better prediction of who will respond to what agents. But we currently can’t because those data are still really new and early. And as we’re thinking through molecular characteristics, why not try them on any therapy that’s available as standard of care?

Sumanta Kumar Pal, MD: Makes sense to me.

Neeraj Agarwal, MD: But until we have biomarkers, I think I like to stick to clinically available data. And the best drug is the 1 that offers all 3 benefits: overall survival, progression-free survival, and response rates.

Sumanta Kumar Pal, MD: Absolutely. And we do actually have some third-line data—on this topic of third-line treatment—from ASCO GU Genitourinary Cancers Symposium this year with tivozanib. Brad, do you want to give us a quick take on the TIVO-3 [tivozanib-3] trial?

Bradley McGregor, MD: Obviously we had looked at tivozanib a while ago.

Neeraj Agarwal, MD: In the first-line setting.

Bradley McGregor, MD: Right, in the first-line setting. Response rates were very intriguing, and there were longer follow-ups. So this was in later-line therapies, such as tivozanib versus sorafenib. Granted, sorafenib is probably not something that’s used much at all in renal cell carcinoma. But it did show that tivozanib was an effective agent, more so than sorafenib in these later line settings.

Sumanta Kumar Pal, MD: What do you think is going to be the fate for tivozanib now?

Bradley McGregor, MD: I think time will tell as we get longer follow-up.

Neeraj Agarwal, MD: But still, progression-free survival was very modestly improved with tivozanib in less than 2 months if I’m not mistaken. And we are talking about this being compared with an inactive drug, sorafenib. So in my personal view, it’s not very exciting. I think we need to be offering our patients those novel clinical trials that are using standard VEGF TKIs [tyrosine kinase inhibitors] and drugs targeting novel targets in their cancer cells.

Sumanta Kumar Pal, MD: Makes sense, so a new mechanism of action.

Neeraj Agarwal, MD: Yes.

Sumanta Kumar Pal, MD: But sticking to what we have right now, you had mentioned this trifecta with cabozantinib: OS, PFS, and response rate. One of the data sets that emerged at ASCO GU this year had to do with cabozantinib and tumor shrinkage. Can you tell us a little bit about that? This comes from the METEOR trial.

Neeraj Agarwal, MD: Yes, a retrospective analysis of the METEOR trial. In patients who had responses defined as 30% or more, which is partial response, ultimately the overall survival was much better compared with patients who did not have any shrinkage. So patients who had any shrinkage or who had a partial response did much better compared with patients who did not have shrinkage of disease. Having said that, I think the most important thing I gleaned from these data, or from the presentation, was that if my patient is showing response to cabozantinib, I can safely assume that patient is going to live much longer than if the patient was not experiencing any shrinkage in their disease.

Sumanta Kumar Pal, MD: That makes sense. So tumor shrinkage, clinical benefit.

Tian Zhang, MD: I think early on, too, 1 of the criteria they had in this analysis was an early shrinkage, within the first 3 months, on that first set of scans. And so if I get that early signal, it’s a much better prognosis for my patient, and I’m able to say, “Hey, look, we’ve been on cabozantinib for 3 months, you have this 40% shrinkage of some target lesions, and this is a really good prediction for how you’ll do overall.”

Neeraj Agarwal, MD: And also the clinical [implication] for me is the patient is traveling long distances and is reluctant to do as many scans. We do scans every 2 or 3 months in salvage therapy setting. And really, if I see 30% or more shrinkage, a partial response in these patients for the first scan, I would be more accepting of not doing so many scans, maybe delay the next scan if they really want to do that. However, if I don’t see that early shrinkage or any shrinkage at all, I think I will be less likely to or very hesitant to delay the next scans.

Tian Zhang, MD: Yes, absolutely.

Sumanta Kumar Pal, MD: I think it’s a great, very practical application of the data. That makes a ton of sense.

Transcript Edited for Clarity

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Transcript: 

Sumanta Kumar Pal, MD: Neeraj, you started out 1 of our conversations earlier discussing the transition from first-line to second-line to third-line therapy, and I agree with you. Only about 20% of patients were making it to third-line therapy, by and large.

Neeraj Agarwal, MD: In academic cancer centers.

Sumanta Kumar Pal, MD: At academic cancer centers.

Neeraj Agarwal, MD: This is about those doctors who are actually focusing on taking care of kidney cancer patients. These data are from them, so I can’t even imagine what may be happening. Maybe it’s superior, but it’s likely inferior in those community settings [that] do not have the resources to take care of these patients.

Tian Zhang, MD: You mean even fewer patients going on to receive second-line, third-line, and fourth-line treatments?

Neeraj Agarwal, MD: Yes.

Sumanta Kumar Pal, MD: So with these principles that you have in [the] second-line setting—response rate, PFS [progression-free survival], etc—that were different from frontline, does that hold in the third-line setting? Is your strategy different?

Neeraj Agarwal, MD: Absolutely. In fact, I like the way you presented the data at all the ASCO [American Society of Clinical Oncology Annual] Meetings. You called it a trifecta of response: objective responses, progression-free survival, and overall survival [OS]. I think for a given patient of mine, all of those 3 goals are important. It doesn’t matter what we like as physicians. Some people talk about complete responses, but we need to never forget that complete responses are happening in a very small number of patients. About 90% patients are not experiencing complete responses with ipilimumab-nivolumab. So in my view, all these criteria are important: overall survival, complete response, objective response, and progression-free survival. And in second line, third line, or even later lines, those remain very important.

Tian Zhang, MD: I think these criteria are great when we’re thinking about populations, clinical trials, and these statistics. But I tell my patients, these are really just statistics of a population, and it’s great that we’re getting the majority of patients to live longer with this therapy versus that therapy. But every patient is a little bit different, and you never know if your patient is going to have a great response to axitinib in the second line. Maybe that’s a great drug and they can be on it for a good amount of time. Based on disease characteristics, we talk about personalized treatments. Unfortunately, I wish we had better molecular characteristics for our patients and better prediction of who will respond to what agents. But we currently can’t because those data are still really new and early. And as we’re thinking through molecular characteristics, why not try them on any therapy that’s available as standard of care?

Sumanta Kumar Pal, MD: Makes sense to me.

Neeraj Agarwal, MD: But until we have biomarkers, I think I like to stick to clinically available data. And the best drug is the 1 that offers all 3 benefits: overall survival, progression-free survival, and response rates.

Sumanta Kumar Pal, MD: Absolutely. And we do actually have some third-line data—on this topic of third-line treatment—from ASCO GU Genitourinary Cancers Symposium this year with tivozanib. Brad, do you want to give us a quick take on the TIVO-3 [tivozanib-3] trial?

Bradley McGregor, MD: Obviously we had looked at tivozanib a while ago.

Neeraj Agarwal, MD: In the first-line setting.

Bradley McGregor, MD: Right, in the first-line setting. Response rates were very intriguing, and there were longer follow-ups. So this was in later-line therapies, such as tivozanib versus sorafenib. Granted, sorafenib is probably not something that’s used much at all in renal cell carcinoma. But it did show that tivozanib was an effective agent, more so than sorafenib in these later line settings.

Sumanta Kumar Pal, MD: What do you think is going to be the fate for tivozanib now?

Bradley McGregor, MD: I think time will tell as we get longer follow-up.

Neeraj Agarwal, MD: But still, progression-free survival was very modestly improved with tivozanib in less than 2 months if I’m not mistaken. And we are talking about this being compared with an inactive drug, sorafenib. So in my personal view, it’s not very exciting. I think we need to be offering our patients those novel clinical trials that are using standard VEGF TKIs [tyrosine kinase inhibitors] and drugs targeting novel targets in their cancer cells.

Sumanta Kumar Pal, MD: Makes sense, so a new mechanism of action.

Neeraj Agarwal, MD: Yes.

Sumanta Kumar Pal, MD: But sticking to what we have right now, you had mentioned this trifecta with cabozantinib: OS, PFS, and response rate. One of the data sets that emerged at ASCO GU this year had to do with cabozantinib and tumor shrinkage. Can you tell us a little bit about that? This comes from the METEOR trial.

Neeraj Agarwal, MD: Yes, a retrospective analysis of the METEOR trial. In patients who had responses defined as 30% or more, which is partial response, ultimately the overall survival was much better compared with patients who did not have any shrinkage. So patients who had any shrinkage or who had a partial response did much better compared with patients who did not have shrinkage of disease. Having said that, I think the most important thing I gleaned from these data, or from the presentation, was that if my patient is showing response to cabozantinib, I can safely assume that patient is going to live much longer than if the patient was not experiencing any shrinkage in their disease.

Sumanta Kumar Pal, MD: That makes sense. So tumor shrinkage, clinical benefit.

Tian Zhang, MD: I think early on, too, 1 of the criteria they had in this analysis was an early shrinkage, within the first 3 months, on that first set of scans. And so if I get that early signal, it’s a much better prognosis for my patient, and I’m able to say, “Hey, look, we’ve been on cabozantinib for 3 months, you have this 40% shrinkage of some target lesions, and this is a really good prediction for how you’ll do overall.”

Neeraj Agarwal, MD: And also the clinical [implication] for me is the patient is traveling long distances and is reluctant to do as many scans. We do scans every 2 or 3 months in salvage therapy setting. And really, if I see 30% or more shrinkage, a partial response in these patients for the first scan, I would be more accepting of not doing so many scans, maybe delay the next scan if they really want to do that. However, if I don’t see that early shrinkage or any shrinkage at all, I think I will be less likely to or very hesitant to delay the next scans.

Tian Zhang, MD: Yes, absolutely.

Sumanta Kumar Pal, MD: I think it’s a great, very practical application of the data. That makes a ton of sense.

Transcript Edited for Clarity
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