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Other Clinical Trials in Renal Cell Carcinoma

Insights From: Brian Rini,MD, Cleveland Clinic Main Campus; David F. McDermott, MD, Harvard Cancer Center
Published: Monday, Dec 10, 2018



Transcript: 

David F. McDermott, MD: It’s interesting. We’ve gotten combination therapies and shown positive results with PD-1 [programmed cell death protein 1] based combinations in the front line. But we knew very little about what PD-L1 [programmed death-ligand 1]/PD-1 combinations or PD-L1 alone would get you in the front line. We did the KEYNOTE-427 study, which looked at pembrolizumab at its standard dose in 2 cohorts: patients with clear cell disease and patients with non–clear cell kidney cancer.

We’ve seen the results in clear cell kidney cancer, and the results were actually better than we thought. The response rate for patients with clear cell kidney cancer—the trial was 110 patients—was in the mid-30% range. It was actually higher in patients who had intermediate and poor risk disease, where it was 42%, and higher in patients with PD-L1–positive tumors, where it was 50%. We had a sense that this agent actually worked in the first-line setting. It was less toxic than some of the other combinations because it’s single agent, so there aren’t 2 different toxicities to deal with.

It was a relatively clean therapy and a relatively effective treatment. I think it’s not clear that single-agent PD-1 will become something that we apply in the clinic, but it’ll give us a sense of how active these combinations are. We now have a standard of what to expect with a single agent, so folks can decide if combinations are worth it for their patients. It also gives us a sense that since single-agent therapy is active in patients with metastatic disease who have been untreated, we should try to move these single agents into the adjuvant setting. There are several large adjuvant trials looking at immune checkpoint blockade. This gives more incentive to enroll patients in those trials because we know these drugs are probably pretty active.

We’ve also attempted to try to overcome resistance pathways by combining PD-1 blockade with other immune therapies. We’ve shown effectiveness combining PD-1 with CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] through ipilimumab and nivolumab, but we’re now combining PD-1 with other immune therapies: for example, IDO [indoleamine 2,3-dioxygenase] inhibition with epacadostat. It’s not entirely clear how well that strategy is going to work in kidney cancer. We recently did a large randomized phase III trial in melanoma comparing PD-1/epacadostat with PD-1 alone. That trial showed no impact of the IDO inhibitor—no negative effect, but no positive effect—on efficacy outcomes in that trial. That’s made us question, going back, if we have the right patients.

We saw very interesting data with that combination in the phase I study, but it didn’t hold up in phase III. Maybe we need to go back to the drawing board and, before we start these phase III trials, figure out which group needs an IDO inhibitor, a VEGF inhibitor, or a CTLA-4 inhibitor before applying these strategies broadly. Because if we try to do that, we might see more negative trials like we did in melanoma.

Brian Rini, MD: The CLEAR study looked at lenvatinib plus pembrolizumab, another TKI/I-O [tyrosine kinase inhibitor/immune-oncology] combination; lenvatinib/everolimus, which is TKI plus mTOR inhibitor that was approved on the basis of a randomized phase II trial; and Sutent [sunitinib] as a control. It’s a little bit different in that it has 3 arms. It’s testing that lenvatinib/everolimus combination, which was approved although very toxic. I think most interestingly, it’s testing lenvatinib plus pembrolizumab, which is clearly going to be active. Once all the dust settles, we’ll have to figure out how to use all these combinations and discover which one’s best, but we await further data.

Transcript Edited for Clarity 
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Transcript: 

David F. McDermott, MD: It’s interesting. We’ve gotten combination therapies and shown positive results with PD-1 [programmed cell death protein 1] based combinations in the front line. But we knew very little about what PD-L1 [programmed death-ligand 1]/PD-1 combinations or PD-L1 alone would get you in the front line. We did the KEYNOTE-427 study, which looked at pembrolizumab at its standard dose in 2 cohorts: patients with clear cell disease and patients with non–clear cell kidney cancer.

We’ve seen the results in clear cell kidney cancer, and the results were actually better than we thought. The response rate for patients with clear cell kidney cancer—the trial was 110 patients—was in the mid-30% range. It was actually higher in patients who had intermediate and poor risk disease, where it was 42%, and higher in patients with PD-L1–positive tumors, where it was 50%. We had a sense that this agent actually worked in the first-line setting. It was less toxic than some of the other combinations because it’s single agent, so there aren’t 2 different toxicities to deal with.

It was a relatively clean therapy and a relatively effective treatment. I think it’s not clear that single-agent PD-1 will become something that we apply in the clinic, but it’ll give us a sense of how active these combinations are. We now have a standard of what to expect with a single agent, so folks can decide if combinations are worth it for their patients. It also gives us a sense that since single-agent therapy is active in patients with metastatic disease who have been untreated, we should try to move these single agents into the adjuvant setting. There are several large adjuvant trials looking at immune checkpoint blockade. This gives more incentive to enroll patients in those trials because we know these drugs are probably pretty active.

We’ve also attempted to try to overcome resistance pathways by combining PD-1 blockade with other immune therapies. We’ve shown effectiveness combining PD-1 with CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] through ipilimumab and nivolumab, but we’re now combining PD-1 with other immune therapies: for example, IDO [indoleamine 2,3-dioxygenase] inhibition with epacadostat. It’s not entirely clear how well that strategy is going to work in kidney cancer. We recently did a large randomized phase III trial in melanoma comparing PD-1/epacadostat with PD-1 alone. That trial showed no impact of the IDO inhibitor—no negative effect, but no positive effect—on efficacy outcomes in that trial. That’s made us question, going back, if we have the right patients.

We saw very interesting data with that combination in the phase I study, but it didn’t hold up in phase III. Maybe we need to go back to the drawing board and, before we start these phase III trials, figure out which group needs an IDO inhibitor, a VEGF inhibitor, or a CTLA-4 inhibitor before applying these strategies broadly. Because if we try to do that, we might see more negative trials like we did in melanoma.

Brian Rini, MD: The CLEAR study looked at lenvatinib plus pembrolizumab, another TKI/I-O [tyrosine kinase inhibitor/immune-oncology] combination; lenvatinib/everolimus, which is TKI plus mTOR inhibitor that was approved on the basis of a randomized phase II trial; and Sutent [sunitinib] as a control. It’s a little bit different in that it has 3 arms. It’s testing that lenvatinib/everolimus combination, which was approved although very toxic. I think most interestingly, it’s testing lenvatinib plus pembrolizumab, which is clearly going to be active. Once all the dust settles, we’ll have to figure out how to use all these combinations and discover which one’s best, but we await further data.

Transcript Edited for Clarity 
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