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Making Decisions for Second-Line Therapy 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: Monday, Aug 27, 2018



Transcript: 

Thomas E. Hutson, DO, PharmD: There are many types of progression that can influence a physician’s choice of therapy after progression. For instance, there may be slow progression in known sites of disease where the patient is asymptomatic, and the progression events are picked up on serial CT scans. There may be spread of cancer, and that spread may either be rapid spread or slow spread to new sites of disease. Historically, we have used those different types of progression to choose between continuing with use of VEGF inhibitors or changing mechanism of action to mTOR inhibitors. That has become somewhat of a moot point in the United States, where we have the availability of many agents beyond mTOR inhibition, but it’s still a very valid point in some areas of the world.

Nizar M. Tannir, MD, FACP: There are different scenarios for progression. Patients can progress in the preexisting tumor sites. Let’s say the patient had lung metastasis and was treated with an agent. For the sake of this illustration, let’s say they were treated with a tyrosine kinase inhibitor. At progression, the patient may either have progression in the lung with metastasis or they could develop metastasis in new organs. Or they could develop metastasis or progression in the preexisting tumor sites and in new sites. We believe that each one of these scenarios could represent a different biology.

For the patient who has progression in a site, maybe we can continue with the same therapy that we used in the first place. And maybe if it is a single site, we can target that with local therapy. We sometimes do that. If the patient is progressing in different sites, that calls for a different agent. The rate of progression obviously presents a different biological paradigm. A patient who progresses right through first-line therapy is different from a patient who responds to first-line therapy and then, months or years later, shows progression. So we approach these scenarios differently and are trying to understand the different biological mechanisms for these different scenarios.

Chung-Han Lee, MD, PhD: The triggers that we often use to switch therapies are really 2-fold. First is efficacy—as a reason to switch. Whether or not people develop progressive disease is clearly an indication to switch. Second is whether or not they develop intolerable toxicity. For patients who are on any of these agents, because it’s necessary to maintain the use of these agents, tolerability is critical. If the side effects can’t be managed by either dose reduction or supportive measures, that would be another indication to either potentially give them a treatment break or, if a treatment break is insufficient, potentially change to a different TKI or a different therapy.

Thomas E. Hutson, DO, PharmD: Personally, the factors I use to choose among therapy are based upon the way a patient’s progression develops. If a patient is able to be on a therapy for quite a long time with a reasonable quality of life and slow progression in known sites of disease, sometimes I will continue the patient on the same therapy that they’re progressing on. Other times, I will change the therapy to a similar agent or a class-related therapy. For instance, I may go from one VEGF inhibitor to a second VEGF inhibitor. If I have a patient who has rapid progression of disease with new sites of disease and/or is symptomatic, I will likely change mechanism of action or, alternatively, since we do have newer agents that are very active in the refractory patient and produce very quick responses, such as cabozantinib or lenvatinib/everolimus, I may choose to use one of them as the next line of therapy.

Transcript Edited for Clarity 
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Transcript: 

Thomas E. Hutson, DO, PharmD: There are many types of progression that can influence a physician’s choice of therapy after progression. For instance, there may be slow progression in known sites of disease where the patient is asymptomatic, and the progression events are picked up on serial CT scans. There may be spread of cancer, and that spread may either be rapid spread or slow spread to new sites of disease. Historically, we have used those different types of progression to choose between continuing with use of VEGF inhibitors or changing mechanism of action to mTOR inhibitors. That has become somewhat of a moot point in the United States, where we have the availability of many agents beyond mTOR inhibition, but it’s still a very valid point in some areas of the world.

Nizar M. Tannir, MD, FACP: There are different scenarios for progression. Patients can progress in the preexisting tumor sites. Let’s say the patient had lung metastasis and was treated with an agent. For the sake of this illustration, let’s say they were treated with a tyrosine kinase inhibitor. At progression, the patient may either have progression in the lung with metastasis or they could develop metastasis in new organs. Or they could develop metastasis or progression in the preexisting tumor sites and in new sites. We believe that each one of these scenarios could represent a different biology.

For the patient who has progression in a site, maybe we can continue with the same therapy that we used in the first place. And maybe if it is a single site, we can target that with local therapy. We sometimes do that. If the patient is progressing in different sites, that calls for a different agent. The rate of progression obviously presents a different biological paradigm. A patient who progresses right through first-line therapy is different from a patient who responds to first-line therapy and then, months or years later, shows progression. So we approach these scenarios differently and are trying to understand the different biological mechanisms for these different scenarios.

Chung-Han Lee, MD, PhD: The triggers that we often use to switch therapies are really 2-fold. First is efficacy—as a reason to switch. Whether or not people develop progressive disease is clearly an indication to switch. Second is whether or not they develop intolerable toxicity. For patients who are on any of these agents, because it’s necessary to maintain the use of these agents, tolerability is critical. If the side effects can’t be managed by either dose reduction or supportive measures, that would be another indication to either potentially give them a treatment break or, if a treatment break is insufficient, potentially change to a different TKI or a different therapy.

Thomas E. Hutson, DO, PharmD: Personally, the factors I use to choose among therapy are based upon the way a patient’s progression develops. If a patient is able to be on a therapy for quite a long time with a reasonable quality of life and slow progression in known sites of disease, sometimes I will continue the patient on the same therapy that they’re progressing on. Other times, I will change the therapy to a similar agent or a class-related therapy. For instance, I may go from one VEGF inhibitor to a second VEGF inhibitor. If I have a patient who has rapid progression of disease with new sites of disease and/or is symptomatic, I will likely change mechanism of action or, alternatively, since we do have newer agents that are very active in the refractory patient and produce very quick responses, such as cabozantinib or lenvatinib/everolimus, I may choose to use one of them as the next line of therapy.

Transcript Edited for Clarity 
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