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Frontline Clinical Trials in Renal Cell Carcinoma

Panelists: Robert A. Figlin, MD, Cedars-Sinai Medical Center; Thai H. Ho, MD, PhD, Mayo Clinic Arizona; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center; Michael B. Atkins, MD, Georgetown Lombardi Comprehensive Cancer Center; Sandy Srinivas, MD, Stanford University Medical Center
Published Online: Thursday, Aug 10, 2017



Transcript:

Robert A. Figlin, MD: Let’s turn our attention to some really interesting emerging opportunities for our kidney cancer patients. We’ve had a spectacular decade of therapeutics, and it really appears that that’s going to continue.

Let’s start with a conversation around the clinical trial called the CABOSUN trial. This was a randomized phase II trial in the frontline setting that compared sunitinib to cabozantinib. Can you summarize those results for us and give us a sense of, as we start to talk about emerging therapies, how you think that data may play out over time?

Sandy Srinivas, MD: CABOSUN is a phase II trial, like you said. It was done by the Cooperative Group here in the United States. It was a small trial. It was 150 patients randomized to the cabozantinib or sunitinib, and they did demonstrate that cabozantinib had a superior progression-free survival of around 8.2 months compared to 5.6 with sunitinib. The response rate was doubled in the cabozantinib arm compared to sunitinib. This may be an opportunity to bring a drug on, first-line, if the data can be confirmed by the independent investigators.

Some of the issues with this trial is it was surprising how poorly sunitinib did. It was a little unexpected that sunitinib would only have a PFS of around 5 months. We expect, at least in the intermediate- and poor-risk group, to have a PFS of around 8 months. So, it was a little surprising.

There were some differences in dosing. Like we had been talking about earlier, most of us give sunitinib as 2 weeks on, 1 week off. In this trial, sunitinib was given as 4 weeks on, 2 weeks off, so there may be some dosing issues as to why sunitinib didn’t do as well. But nonetheless, I think cabozantinib did remarkably well. In the METEOR trial, we know that it met PFS, OS, and objective response rates. This is an opportunity where it might be a great move to get this drug into the frontline setting, especially for some patients, such as bone metastases patients, which has been a very challenging group to take care of.

Robert A. Figlin, MD: We’re starting to see changes in our frontline thinking. CABOSUN is an example, which was unexpected, where we saw a next-generation TKI outperforming an older-generation TKI. At the 2017 ASCO Annual Meeting and at the Genitourinary Cancers Symposium, we started to see combinations of immuno-oncology treatments, or I-Os, and targeted therapy. How do you think about that from the perspective of safety, efficacy, and some of the things that you’re seeing in early phase I and phase II trials that are leading to the pivotal trials that are taking place? Where are you with that?

Martin H. Voss, MD: There has certainly been a lot of excitement to take the treatment to the next level. We had 10 years of targeted therapy that have been effective in improving outcomes for our patients across the board, then the arrival of immuno-oncology—which created a lot of excitement—and then the natural next step of bringing the 2 together. We’re coming out with new trials now in early phase development—a total of 5 trials now in the phase III setting already for frontline treatment—combining either immunotherapy with immunotherapy or immunotherapy with VEGF-directed therapies.

The rationale for that, because of just trying to do more and being more aggressive, is pushing on the gas pedal here. But secondly, there is preclinical rationale for all of these combinations, to some extent, in that we have data that suggest that the targeted agents that are not immunotherapies can modulate the immune microenvironment in some way that might be favorable in terms of response to checkpoint inhibitor therapy.

Getting back to your question on efficacy and tolerance, obviously, the question is at hand. We’re being more aggressive to show more effective therapies, but at the same time, giving 2 medications jointly brings about greater chance for toxicity. We have some combinations that actually have not made it past the phase I stage. I was an investigator on a clinical trial that was meant to investigate a combination of a TKI, pazopanib, with pembrolizumab, a PD-1 inhibitor. It was designed to have a phase I portion to then go into a big randomized segment. It never did so because the toxicity proved unmanageable, and there was a high rate of hepatic toxic events in the first cohorts that we treated. It wasn’t for a lack of trying. We actually changed the design of the trial around to have a sequence approach where patients would get a lead off of the TKI first—and we would hope that whatever low-grade inflammation was around the liver would actually subside—and then we would add the I-O drug only in those patients who were tolerating the TKI well. Even for that, and there are data from the 2017 ASCO Annual Meeting, we found that there was a high rate of dose-limiting toxicities in patients once they went on the combination—not hepatic, but other toxicities ensued.

This is one example where a combination was not more effective in terms of its development because it proved too toxic. But we have other combinations that have proven quite manageable and that have made it into a phase I, then into the phase II and phase III studies—some of which even skipped phase II altogether. It went straight from phase I to phase III because the feeling was that they were manageable and so effective that they were worth being tested in a registration trial.

Transcript Edited for Clarity

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Transcript:

Robert A. Figlin, MD: Let’s turn our attention to some really interesting emerging opportunities for our kidney cancer patients. We’ve had a spectacular decade of therapeutics, and it really appears that that’s going to continue.

Let’s start with a conversation around the clinical trial called the CABOSUN trial. This was a randomized phase II trial in the frontline setting that compared sunitinib to cabozantinib. Can you summarize those results for us and give us a sense of, as we start to talk about emerging therapies, how you think that data may play out over time?

Sandy Srinivas, MD: CABOSUN is a phase II trial, like you said. It was done by the Cooperative Group here in the United States. It was a small trial. It was 150 patients randomized to the cabozantinib or sunitinib, and they did demonstrate that cabozantinib had a superior progression-free survival of around 8.2 months compared to 5.6 with sunitinib. The response rate was doubled in the cabozantinib arm compared to sunitinib. This may be an opportunity to bring a drug on, first-line, if the data can be confirmed by the independent investigators.

Some of the issues with this trial is it was surprising how poorly sunitinib did. It was a little unexpected that sunitinib would only have a PFS of around 5 months. We expect, at least in the intermediate- and poor-risk group, to have a PFS of around 8 months. So, it was a little surprising.

There were some differences in dosing. Like we had been talking about earlier, most of us give sunitinib as 2 weeks on, 1 week off. In this trial, sunitinib was given as 4 weeks on, 2 weeks off, so there may be some dosing issues as to why sunitinib didn’t do as well. But nonetheless, I think cabozantinib did remarkably well. In the METEOR trial, we know that it met PFS, OS, and objective response rates. This is an opportunity where it might be a great move to get this drug into the frontline setting, especially for some patients, such as bone metastases patients, which has been a very challenging group to take care of.

Robert A. Figlin, MD: We’re starting to see changes in our frontline thinking. CABOSUN is an example, which was unexpected, where we saw a next-generation TKI outperforming an older-generation TKI. At the 2017 ASCO Annual Meeting and at the Genitourinary Cancers Symposium, we started to see combinations of immuno-oncology treatments, or I-Os, and targeted therapy. How do you think about that from the perspective of safety, efficacy, and some of the things that you’re seeing in early phase I and phase II trials that are leading to the pivotal trials that are taking place? Where are you with that?

Martin H. Voss, MD: There has certainly been a lot of excitement to take the treatment to the next level. We had 10 years of targeted therapy that have been effective in improving outcomes for our patients across the board, then the arrival of immuno-oncology—which created a lot of excitement—and then the natural next step of bringing the 2 together. We’re coming out with new trials now in early phase development—a total of 5 trials now in the phase III setting already for frontline treatment—combining either immunotherapy with immunotherapy or immunotherapy with VEGF-directed therapies.

The rationale for that, because of just trying to do more and being more aggressive, is pushing on the gas pedal here. But secondly, there is preclinical rationale for all of these combinations, to some extent, in that we have data that suggest that the targeted agents that are not immunotherapies can modulate the immune microenvironment in some way that might be favorable in terms of response to checkpoint inhibitor therapy.

Getting back to your question on efficacy and tolerance, obviously, the question is at hand. We’re being more aggressive to show more effective therapies, but at the same time, giving 2 medications jointly brings about greater chance for toxicity. We have some combinations that actually have not made it past the phase I stage. I was an investigator on a clinical trial that was meant to investigate a combination of a TKI, pazopanib, with pembrolizumab, a PD-1 inhibitor. It was designed to have a phase I portion to then go into a big randomized segment. It never did so because the toxicity proved unmanageable, and there was a high rate of hepatic toxic events in the first cohorts that we treated. It wasn’t for a lack of trying. We actually changed the design of the trial around to have a sequence approach where patients would get a lead off of the TKI first—and we would hope that whatever low-grade inflammation was around the liver would actually subside—and then we would add the I-O drug only in those patients who were tolerating the TKI well. Even for that, and there are data from the 2017 ASCO Annual Meeting, we found that there was a high rate of dose-limiting toxicities in patients once they went on the combination—not hepatic, but other toxicities ensued.

This is one example where a combination was not more effective in terms of its development because it proved too toxic. But we have other combinations that have proven quite manageable and that have made it into a phase I, then into the phase II and phase III studies—some of which even skipped phase II altogether. It went straight from phase I to phase III because the feeling was that they were manageable and so effective that they were worth being tested in a registration trial.

Transcript Edited for Clarity
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