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The Rationale for Cabozantinib in Advanced RCC

Panelists:Robert A. Figlin, MD, FACP, Cedars-Sinai Medical Center;Daniel J. George, MD, Duke University Medical Center;Thomas Hutson, DO, PharmD, Baylor Charles A. Sammons Cancer Center;David F. McDermott, MD, Dana Farber Harvard Cancer Center;Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center;Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center
Published: Wednesday, Aug 17, 2016


Transcript:

Robert A. Figlin, MD:
Let’s dive into a little bit of the cabozantinib and the lenvatinib data. So, Nizar, let’s take cabozantinib first. The argument that one makes about cabozantinib, it’s a potent VEGFR inhibitor but also has the ability to modulate through inhibition of resistance pathways AXL and MET. There’s a strong scientific rationale for why cabozantinib might be effective. Additionally, we have a press release on a trial called CABOSUN, which suggests that even in the frontline setting, there may be a benefit for cabozantinib compared to sunitinib—although we’ll not see the data for a bit of time until it’s presented at an international meeting. There’s clearly scientific rationale for why cabozantinib might have a positive effect. So, talk more about the results of the trial, the toxicity profile, and how you think we should be thinking about this approach when patients come to us ready for second-line therapy.

Nizar M. Tannir, MD: I think we have to talk a little bit about the science. We had published in Oncogene last year around the time when the phase III data, METEOR, was presented at ESMO (European Society for Medical Oncology) in Vienna. Patients who had prior sunitinib, for example, we show that there is upregulation of these pathways—mechanism of resistance pathways that you mentioned—c-MET, AXL, and the drug cabozantinib, particularly, can show benefit when you give it post a VEGF TKI. But, as you mentioned, cabozantinib first-line therapy, there’s no prior VEGF blockade. So, we know that tumors that are poor risk have higher expression of c-MET and AXL, and a drug that blocks VEGFR, AXL, and c-MET I think is doing something. The reason cabozantinib is a unique TKI compared to the first generation of sunitinib/pazopanib/axitinib is that it has that, again, multi-pathway inhibition. And finally I think we would like to think that c-MET and AXL are important. Although, you talk about biomarkers, we still do not know who the patients who responded to cabozantinib are, so it’s not about just c-MET expression in a tumor from a nephrectomy specimen.

Back to the phase III data of METEOR, this is a large trial. It was a 658-patient trial in the salvage setting rather than second-line setting. And the difference between it and the lenvatinib plus everolimus is that that trial was a second-line therapy trial, allowing only one prior VEGFR TKI. Whereas, METEOR allowed any number of prior TKI activity, although about 70% of the patients had only one. So, it was a trial with a primary endpoint of PFS, but it was powered enough to also address the OS, which was a secondary endpoint. Also, the presentation from last year and the New England Journal of Medicine publication that came out in September last year with a primary endpoint PFS being superior to everolimus, showed a 7.4 versus 3.8 months’ median PFS when comparing the two. And although the initial publication had a trend of improvement of overall survival—which was a secondary endpoint—now we’re going to hear on Sunday morning from Tony Choueiri about the overall survival analysis. And there was a press release from the METEOR, from Exelixis, saying that the OS secondary endpoint was also met. It was powered, and it did deliver.

So, here is an agent that, unlike the previous TKIs, delivers on objective response rate, PFS, and OS. You have a trifecta. When you talk to patients, they like to see their tumors shrinking in CT and say we can get cancer control. I think this is a drug that’s for real, and it’s an added tool or added agent to our armamentarium for our patients.

I think a lot of people say, about the tolerability, this is a tolerable agent. How do you compare it to, say, nivolumab? And true, it does have adverse events like the other TKIs; 60% of the patients on cabozantinib on the METEOR trial had to have dose reduction. And the median dose for patients ultimately was 44 mg, but only 10% discontinued therapy because of toxicity. I think it takes some learning, and if you have treated patients with sunitinib or pazopanib before, you know how to manage fatigue, diarrhea, hand-foot syndrome, etc.

In my opinion, if community oncologists have confidence in managing and embracing a new therapy, they’ll be able to keep their patient on therapy for a long time and manage it. As Dan mentioned, have your PharmD or nurse in the clinic teaching those patients. And I think it’s true, the first month is the crucial month where education is important and to be proactive. Tell them how to manage diarrhea with the anti-diarrhea medication, probiotic, etc. So, that’s the nutshell on the METEOR and the results. It’s delivered on all three endpoints.

Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Let’s dive into a little bit of the cabozantinib and the lenvatinib data. So, Nizar, let’s take cabozantinib first. The argument that one makes about cabozantinib, it’s a potent VEGFR inhibitor but also has the ability to modulate through inhibition of resistance pathways AXL and MET. There’s a strong scientific rationale for why cabozantinib might be effective. Additionally, we have a press release on a trial called CABOSUN, which suggests that even in the frontline setting, there may be a benefit for cabozantinib compared to sunitinib—although we’ll not see the data for a bit of time until it’s presented at an international meeting. There’s clearly scientific rationale for why cabozantinib might have a positive effect. So, talk more about the results of the trial, the toxicity profile, and how you think we should be thinking about this approach when patients come to us ready for second-line therapy.

Nizar M. Tannir, MD: I think we have to talk a little bit about the science. We had published in Oncogene last year around the time when the phase III data, METEOR, was presented at ESMO (European Society for Medical Oncology) in Vienna. Patients who had prior sunitinib, for example, we show that there is upregulation of these pathways—mechanism of resistance pathways that you mentioned—c-MET, AXL, and the drug cabozantinib, particularly, can show benefit when you give it post a VEGF TKI. But, as you mentioned, cabozantinib first-line therapy, there’s no prior VEGF blockade. So, we know that tumors that are poor risk have higher expression of c-MET and AXL, and a drug that blocks VEGFR, AXL, and c-MET I think is doing something. The reason cabozantinib is a unique TKI compared to the first generation of sunitinib/pazopanib/axitinib is that it has that, again, multi-pathway inhibition. And finally I think we would like to think that c-MET and AXL are important. Although, you talk about biomarkers, we still do not know who the patients who responded to cabozantinib are, so it’s not about just c-MET expression in a tumor from a nephrectomy specimen.

Back to the phase III data of METEOR, this is a large trial. It was a 658-patient trial in the salvage setting rather than second-line setting. And the difference between it and the lenvatinib plus everolimus is that that trial was a second-line therapy trial, allowing only one prior VEGFR TKI. Whereas, METEOR allowed any number of prior TKI activity, although about 70% of the patients had only one. So, it was a trial with a primary endpoint of PFS, but it was powered enough to also address the OS, which was a secondary endpoint. Also, the presentation from last year and the New England Journal of Medicine publication that came out in September last year with a primary endpoint PFS being superior to everolimus, showed a 7.4 versus 3.8 months’ median PFS when comparing the two. And although the initial publication had a trend of improvement of overall survival—which was a secondary endpoint—now we’re going to hear on Sunday morning from Tony Choueiri about the overall survival analysis. And there was a press release from the METEOR, from Exelixis, saying that the OS secondary endpoint was also met. It was powered, and it did deliver.

So, here is an agent that, unlike the previous TKIs, delivers on objective response rate, PFS, and OS. You have a trifecta. When you talk to patients, they like to see their tumors shrinking in CT and say we can get cancer control. I think this is a drug that’s for real, and it’s an added tool or added agent to our armamentarium for our patients.

I think a lot of people say, about the tolerability, this is a tolerable agent. How do you compare it to, say, nivolumab? And true, it does have adverse events like the other TKIs; 60% of the patients on cabozantinib on the METEOR trial had to have dose reduction. And the median dose for patients ultimately was 44 mg, but only 10% discontinued therapy because of toxicity. I think it takes some learning, and if you have treated patients with sunitinib or pazopanib before, you know how to manage fatigue, diarrhea, hand-foot syndrome, etc.

In my opinion, if community oncologists have confidence in managing and embracing a new therapy, they’ll be able to keep their patient on therapy for a long time and manage it. As Dan mentioned, have your PharmD or nurse in the clinic teaching those patients. And I think it’s true, the first month is the crucial month where education is important and to be proactive. Tell them how to manage diarrhea with the anti-diarrhea medication, probiotic, etc. So, that’s the nutshell on the METEOR and the results. It’s delivered on all three endpoints.

Transcript Edited for Clarity
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