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Evaluating Frontline Systemic Therapy for Metastatic RCC

Panelists: Daniel George, MD, Duke Cancer Institute; Neeraj Agarwal, MD, Huntsman Cancer Institute; Robert Alter, MD, Hackensack University Medical Center; Bradley McGregor, MD, Dana-Farber Cancer Institute; Nicholas J. Vogelzang, MD, FASCO, FACP, Comprehensive Cancer Centers of Nevada
Published: Tuesday, Apr 03, 2018



Transcript: 

Daniel George, MD: Let’s talk about that patient you bring up, Bob, who has liver metastases and multiple organs involved; patients who we’ve maybe seen after surgery and they’ve got progression on their next scan. Now we’re thinking more about systemic therapies. But the fields are changing. Nick, where are we today with systemic therapy in the frontline setting?

Nicholas J. Vogelzang, MD, FASCO, FACP: Well, it was a pretty dismal field for a long time.

Daniel George, MD: I’m old enough to know.

Nicholas J. Vogelzang, MD, FASCO, FACP: You’re old enough to remember. We didn’t have much except interferon and an occasional interleukin-2. When we got sorafenib and sunitinib and temsirolimus later, we thought, “Whoa, this is great.” I wrote this editorial, “An Embarrassment of Riches,” because we had 3 drugs. I have to redo the editorial now that we’ve got 10 or 12 drugs. It does give us a historical perspective.

But remember that the 2 go-to drugs, sunitinib and pazopanib, really did change the field. We’ve all written papers about whether it’s better to give sunitinib or pazopanib; they were comparable drugs. Maybe for certain subsegments, pazopanib is better than the sunitinib, and maybe it’s better to give on a certain sunitinib schedule. We can go down the line and try to find out the very best first-line TKI.

But darn, those are good drugs. They’re good drugs. It reminded me of a story. I had a prisoner come in in shackles the other day with belly pain. He said that he had this thing in his abdomen. I looked, and it was a 25-cm mass. He could barely sit up. I went out and I got a sample of one of the TKIs, and I said, “Take this today.” Within 24 hours, his pain was gone. He was back in 3 weeks, and he said, “I don’t know what you gave me, but it was great.” So, you can’t underestimate the power of the active TKI. Now, I’m not going to turn around and give a guy like that immunotherapy until I know what I’m dealing with. But we’ve come a long way, and it’s good to be where we are.

Daniel George, MD: It sure is. I think that’s a great perspective. I share with you some of the early days and frustrations, but now we struggle with toxicity and how to maintain these patients on dose. But that’s a good problem to have. When you have patients responding to therapy and our biggest issue is how to keep them on the drugs, that’s a good problem. We didn’t have those problems before these drugs, so it’s a good perspective. But now we have some newer drugs, and cabozantinib recently had a label expansion based upon some phase II data in the frontline setting. Brad, do you want to tell us about that?

Bradley McGregor, MD: Based on the phase III data with cabozantinib showing survival benefit versus everolimus in the second-line setting, with acceptable safety profile toxicity, Toni Choueiri worked with Alliance researchers to do a randomized phase II trial looking at cabozantinib at the standard 60-mg dose versus sunitinib. That was a 4-weeks-on, 2-weeks-off schedule, and it was designed to show that cabozantinib was superior to sunitinib. They randomized close to 160 patients. Interesting to note, these patients were at intermediate and poor risk by IMDC criteria. Over 10% of them had a PS of 2, and over 30% of them had bone metastases. So, these were sicker patients. At the end of the day, after extensive independent review and investigator review, the data held up, as there was about a 3-month improvement in progressive-free survival with cabozantinib when compared to sunitinib in these patients.

Now, there have been arguments that the progression-free survival of 5 to 6 months in the sunitinib arm is lower than we’ve seen historically in controls, but all of the older studies really had more-favorable-risk patients. And so, looking at some of the data, that number seems to be realistic. Based on this improvement in progression-free-survival with an acceptable safety profile—a comparable toxicity to sunitinib and, if anything, less hematologic toxicities with cabozantinib and more grade 1 fatigue, less grade 3-4 fatigue with cabozantinib in the trial—the FDA actually granted approval to patients with metastatic renal cell carcinoma who received cabozantinib front line. Interestingly enough, this was for all risk categories. So, it was not limited to those with intermediate- and poor-risk disease.

Nicholas J. Vogelzang, MD, FASCO, FACP: Have you been using that?

Bradley McGregor, MD: We have. I had a patient just a couple weeks ago who presented with bone-only metastases. And so, we obviously had data from looking at the METEOR trial that the bone metastases are a poor prognostic factor. Those patients tend to do poorly. The cabozantinib seemed to have a better efficacy in these patients; they still do poorly, but I think it was around 7 versus 2 months in the METEOR trial, with bone metastases, of cabozantinib versus everolimus. So yes, I had a patient, a 56-year-old female, who had bone-only metastases and it was 2 days after the FDA approval for cabozantinib.

Nicholas J. Vogelzang, MD, FASCO, FACP: I’ll put you up against my pazopanib patient with the same thing. She’s doing great. I’m going to be a little skeptical as to which TKI is better. Remember, we did COMPARZ, a big study of sunitinib versus pazopanib, with no difference. I think cabozantinib got a little bit of a pass there. But it’s good because I do like having options, and we’re the ones who should be deciding that anyway. We’re the doctors. If I want to use axitinib frontline, I wish I could in some patients. So, I love the idea of having the option. I’m not sure it’s been as rigorously tested as I would like, but this is the real word. We’ve got a drug, so let’s go with it.

Robert Alter, MD: I remember talking to you about this almost 10 years ago, when XL184 (cabozantinib) came out with the prostate cancer data and we were impressed about its activities in the bone metastases. I think we have extrapolated from that when it comes to now with Cabometyx (cabozantinib) and patients who have significant bone involvement. We would think reactively that Cabometyx in that patient population would probably be better than the other TKIs that we use in first-line therapies. But I agree with you, I think this is still a learning curve that we have. I think all of these therapies do show to us that tolerability is a significant issue. I think that all of our patients are different.

Nicholas J. Vogelzang, MD, FASCO, FACP: I like the mechanism, the MET inhibition. It may well be that the pure VEGF-driven tumors are probably a better prognosis versus the tumors that have already evolved out of VEGF to MET. We talked about this 20 years ago; that MET is the escape mechanism and it may well be that a more advanced tumor already has upregulated MET, and you want to go for it at that point.

So, having the ability to talk to the patient about that is the most important thing. You can think it through and say, “You know, you’ve got 3 first-line choices. Let’s go through what you’d like to do. What are your comorbidities? What are your complication rates? How about your cardiovascular disease? You’ve got GI disease. You’ve had inflammatory bowel disease.” What do you get to choose from here?

Daniel George, MD: I’m presenting at ASCO GU this weekend on the subgroup analysis from cabozantinib. It’s interesting, the point you brought up about MET, because Toni Choueiri looked at, within this study, the MET expression in primary tumors from CABOSUN. About half of patients had high MET expression in their primary tumors, and that group of patients derived a much greater benefit associated with cabozantinib. It really, in my mind, is validating this mechanism; it truly is a multitargeted drug in that setting. Now, I’m not saying MET inhibition is a standard approach. We’re not really set up to go and stain our tumors like that clinically, but I think it’s something that does need further follow-up for sure.

Transcript Edited for Clarity 

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Transcript: 

Daniel George, MD: Let’s talk about that patient you bring up, Bob, who has liver metastases and multiple organs involved; patients who we’ve maybe seen after surgery and they’ve got progression on their next scan. Now we’re thinking more about systemic therapies. But the fields are changing. Nick, where are we today with systemic therapy in the frontline setting?

Nicholas J. Vogelzang, MD, FASCO, FACP: Well, it was a pretty dismal field for a long time.

Daniel George, MD: I’m old enough to know.

Nicholas J. Vogelzang, MD, FASCO, FACP: You’re old enough to remember. We didn’t have much except interferon and an occasional interleukin-2. When we got sorafenib and sunitinib and temsirolimus later, we thought, “Whoa, this is great.” I wrote this editorial, “An Embarrassment of Riches,” because we had 3 drugs. I have to redo the editorial now that we’ve got 10 or 12 drugs. It does give us a historical perspective.

But remember that the 2 go-to drugs, sunitinib and pazopanib, really did change the field. We’ve all written papers about whether it’s better to give sunitinib or pazopanib; they were comparable drugs. Maybe for certain subsegments, pazopanib is better than the sunitinib, and maybe it’s better to give on a certain sunitinib schedule. We can go down the line and try to find out the very best first-line TKI.

But darn, those are good drugs. They’re good drugs. It reminded me of a story. I had a prisoner come in in shackles the other day with belly pain. He said that he had this thing in his abdomen. I looked, and it was a 25-cm mass. He could barely sit up. I went out and I got a sample of one of the TKIs, and I said, “Take this today.” Within 24 hours, his pain was gone. He was back in 3 weeks, and he said, “I don’t know what you gave me, but it was great.” So, you can’t underestimate the power of the active TKI. Now, I’m not going to turn around and give a guy like that immunotherapy until I know what I’m dealing with. But we’ve come a long way, and it’s good to be where we are.

Daniel George, MD: It sure is. I think that’s a great perspective. I share with you some of the early days and frustrations, but now we struggle with toxicity and how to maintain these patients on dose. But that’s a good problem to have. When you have patients responding to therapy and our biggest issue is how to keep them on the drugs, that’s a good problem. We didn’t have those problems before these drugs, so it’s a good perspective. But now we have some newer drugs, and cabozantinib recently had a label expansion based upon some phase II data in the frontline setting. Brad, do you want to tell us about that?

Bradley McGregor, MD: Based on the phase III data with cabozantinib showing survival benefit versus everolimus in the second-line setting, with acceptable safety profile toxicity, Toni Choueiri worked with Alliance researchers to do a randomized phase II trial looking at cabozantinib at the standard 60-mg dose versus sunitinib. That was a 4-weeks-on, 2-weeks-off schedule, and it was designed to show that cabozantinib was superior to sunitinib. They randomized close to 160 patients. Interesting to note, these patients were at intermediate and poor risk by IMDC criteria. Over 10% of them had a PS of 2, and over 30% of them had bone metastases. So, these were sicker patients. At the end of the day, after extensive independent review and investigator review, the data held up, as there was about a 3-month improvement in progressive-free survival with cabozantinib when compared to sunitinib in these patients.

Now, there have been arguments that the progression-free survival of 5 to 6 months in the sunitinib arm is lower than we’ve seen historically in controls, but all of the older studies really had more-favorable-risk patients. And so, looking at some of the data, that number seems to be realistic. Based on this improvement in progression-free-survival with an acceptable safety profile—a comparable toxicity to sunitinib and, if anything, less hematologic toxicities with cabozantinib and more grade 1 fatigue, less grade 3-4 fatigue with cabozantinib in the trial—the FDA actually granted approval to patients with metastatic renal cell carcinoma who received cabozantinib front line. Interestingly enough, this was for all risk categories. So, it was not limited to those with intermediate- and poor-risk disease.

Nicholas J. Vogelzang, MD, FASCO, FACP: Have you been using that?

Bradley McGregor, MD: We have. I had a patient just a couple weeks ago who presented with bone-only metastases. And so, we obviously had data from looking at the METEOR trial that the bone metastases are a poor prognostic factor. Those patients tend to do poorly. The cabozantinib seemed to have a better efficacy in these patients; they still do poorly, but I think it was around 7 versus 2 months in the METEOR trial, with bone metastases, of cabozantinib versus everolimus. So yes, I had a patient, a 56-year-old female, who had bone-only metastases and it was 2 days after the FDA approval for cabozantinib.

Nicholas J. Vogelzang, MD, FASCO, FACP: I’ll put you up against my pazopanib patient with the same thing. She’s doing great. I’m going to be a little skeptical as to which TKI is better. Remember, we did COMPARZ, a big study of sunitinib versus pazopanib, with no difference. I think cabozantinib got a little bit of a pass there. But it’s good because I do like having options, and we’re the ones who should be deciding that anyway. We’re the doctors. If I want to use axitinib frontline, I wish I could in some patients. So, I love the idea of having the option. I’m not sure it’s been as rigorously tested as I would like, but this is the real word. We’ve got a drug, so let’s go with it.

Robert Alter, MD: I remember talking to you about this almost 10 years ago, when XL184 (cabozantinib) came out with the prostate cancer data and we were impressed about its activities in the bone metastases. I think we have extrapolated from that when it comes to now with Cabometyx (cabozantinib) and patients who have significant bone involvement. We would think reactively that Cabometyx in that patient population would probably be better than the other TKIs that we use in first-line therapies. But I agree with you, I think this is still a learning curve that we have. I think all of these therapies do show to us that tolerability is a significant issue. I think that all of our patients are different.

Nicholas J. Vogelzang, MD, FASCO, FACP: I like the mechanism, the MET inhibition. It may well be that the pure VEGF-driven tumors are probably a better prognosis versus the tumors that have already evolved out of VEGF to MET. We talked about this 20 years ago; that MET is the escape mechanism and it may well be that a more advanced tumor already has upregulated MET, and you want to go for it at that point.

So, having the ability to talk to the patient about that is the most important thing. You can think it through and say, “You know, you’ve got 3 first-line choices. Let’s go through what you’d like to do. What are your comorbidities? What are your complication rates? How about your cardiovascular disease? You’ve got GI disease. You’ve had inflammatory bowel disease.” What do you get to choose from here?

Daniel George, MD: I’m presenting at ASCO GU this weekend on the subgroup analysis from cabozantinib. It’s interesting, the point you brought up about MET, because Toni Choueiri looked at, within this study, the MET expression in primary tumors from CABOSUN. About half of patients had high MET expression in their primary tumors, and that group of patients derived a much greater benefit associated with cabozantinib. It really, in my mind, is validating this mechanism; it truly is a multitargeted drug in that setting. Now, I’m not saying MET inhibition is a standard approach. We’re not really set up to go and stain our tumors like that clinically, but I think it’s something that does need further follow-up for sure.

Transcript Edited for Clarity 
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