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Future Directions for Research in mRCC

Insights From: Thomas E. Hutson, DO, PharmD, Baylor University Medical Center; Chung-Han Lee, MD, PhD, Memorial Sloan Kettering Cancer Center; Nizar M. Tannir, MD, FACP, The University of Texas MD Anderson Cancer Center
Published: Friday, Sep 28, 2018



Transcript: 

Nizar M. Tannir, MD, FACP: We have come a long way with treatment for renal cell carcinoma, at least for the most common type of RCC—clear-cell renal cell carcinoma. Although we now have 12 therapies that are FDA approved, that are on the market and help many of our patients, we still have a long way to go. We need to improve our predictive biomarkers to be able to select the appropriate therapy for the right patient. We’re still not there yet. We’re still not there in being able to identify which patients are going to respond to which drug.

It’s also important to identify new targets and develop new therapies to improve the outcomes of those patients. We are not yet curing patients with renal cell carcinoma—not everybody, anyway. There are newer drugs that are coming, and there is a class of new immune therapies that can potentially be added or combined with immune checkpoint inhibitors. There are 2 such drugs that I’ve been involved in developing, that are promising. One is NKTR-214, which is a piglet IL-2 or CD122 agonist immune therapy that has a strong biological rationale for being combined with immune checkpoint inhibitors such as PD-1—for example, nivolumab. A presentation at this ASCO Annual Meeting is reporting on results of this combination in many solid tumor types, including renal cell carcinoma. Another agent that is also promising and has shown preliminary activity and tolerable safety is piglet interleukin-10 (IL-10).

There are also some newer targeted agents that are being tested. I’d like to mention one that we are developing with Calithera Biosciences—a first-in-class tumor metabolic agent that inhibits the enzyme glutaminase, that converts glutamine to glutamate. This combination of cabozantinib, which we spoke about earlier, and this drug, CB-839, has been given a breakthrough status designation by the FDA. Hopefully this will bring us a new class of agents in the fight against renal cell carcinoma.

Chung-Han Lee, MD, PhD: Right now, there are multiple combinations that are still being explored for advanced RCC. At this point, we’ve probably used every single permutation with a TKI and a PD-1 inhibitor, and that may not be the future direction of future studies that come down the line. However, there are multiple immune checkpoint inhibitors. Whether or not those immune checkpoint inhibitors can be combined with PD-1, or a TKI, in addition to PD-1, remains to be seen. Furthermore, there have also been multiple vaccine studies that may provide some additional benefit. Those types of trials have been rather disappointing thus far, but that’s not to exclude it as a possibility in the future.

Thomas E. Hutson, DO, PharmD: In the past, in kidney cancer, our new drug development has outpaced our ability to understand how to optimally use the agents we have. Again, I think we’re in a setting where this is happening. Certainly, the appropriate sequence, whether or not one can be rechallenged with immunotherapy, and the decision to stop immunotherapy after maximal response or give it indefinitely are key questions that are not only based on efficacy and toxicity, but also economics. Can we combine agents in a way that will allow our patients to, at some point, reach a stopping point—to allow them to no longer be a cancer patient, and to be able to take a break from therapy, which is extremely important as we move forward?

Transcript Edited for Clarity 
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Transcript: 

Nizar M. Tannir, MD, FACP: We have come a long way with treatment for renal cell carcinoma, at least for the most common type of RCC—clear-cell renal cell carcinoma. Although we now have 12 therapies that are FDA approved, that are on the market and help many of our patients, we still have a long way to go. We need to improve our predictive biomarkers to be able to select the appropriate therapy for the right patient. We’re still not there yet. We’re still not there in being able to identify which patients are going to respond to which drug.

It’s also important to identify new targets and develop new therapies to improve the outcomes of those patients. We are not yet curing patients with renal cell carcinoma—not everybody, anyway. There are newer drugs that are coming, and there is a class of new immune therapies that can potentially be added or combined with immune checkpoint inhibitors. There are 2 such drugs that I’ve been involved in developing, that are promising. One is NKTR-214, which is a piglet IL-2 or CD122 agonist immune therapy that has a strong biological rationale for being combined with immune checkpoint inhibitors such as PD-1—for example, nivolumab. A presentation at this ASCO Annual Meeting is reporting on results of this combination in many solid tumor types, including renal cell carcinoma. Another agent that is also promising and has shown preliminary activity and tolerable safety is piglet interleukin-10 (IL-10).

There are also some newer targeted agents that are being tested. I’d like to mention one that we are developing with Calithera Biosciences—a first-in-class tumor metabolic agent that inhibits the enzyme glutaminase, that converts glutamine to glutamate. This combination of cabozantinib, which we spoke about earlier, and this drug, CB-839, has been given a breakthrough status designation by the FDA. Hopefully this will bring us a new class of agents in the fight against renal cell carcinoma.

Chung-Han Lee, MD, PhD: Right now, there are multiple combinations that are still being explored for advanced RCC. At this point, we’ve probably used every single permutation with a TKI and a PD-1 inhibitor, and that may not be the future direction of future studies that come down the line. However, there are multiple immune checkpoint inhibitors. Whether or not those immune checkpoint inhibitors can be combined with PD-1, or a TKI, in addition to PD-1, remains to be seen. Furthermore, there have also been multiple vaccine studies that may provide some additional benefit. Those types of trials have been rather disappointing thus far, but that’s not to exclude it as a possibility in the future.

Thomas E. Hutson, DO, PharmD: In the past, in kidney cancer, our new drug development has outpaced our ability to understand how to optimally use the agents we have. Again, I think we’re in a setting where this is happening. Certainly, the appropriate sequence, whether or not one can be rechallenged with immunotherapy, and the decision to stop immunotherapy after maximal response or give it indefinitely are key questions that are not only based on efficacy and toxicity, but also economics. Can we combine agents in a way that will allow our patients to, at some point, reach a stopping point—to allow them to no longer be a cancer patient, and to be able to take a break from therapy, which is extremely important as we move forward?

Transcript Edited for Clarity 
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