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Managing Checkpoint Inhibitor Therapy in RCC

Panelists:Robert A. Figlin, MD, Cedars-Sinai Medical Center; Sandy Srinivas, MD, Stanford University Medical Center; Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Mar 17, 2016


Transcript:

Robert A. Figlin, MD:
Sandy, I want to put you on the spot and ask you: we’ve spent the last decade talking to kidney cancer patients about how to prepare for chronic administration of targeted therapy with a progression-free survival benefit. And now we turn the page and we have an agent that produces about 1 in 5 responses, no change in progression-free survival when compared to a control, but a survival benefit. I want to hear from you what you actually say to patients when they’re about to start checkpoint inhibitors. What do you tell them the goals are? How do you figure out how long to treat? How do you use imaging to decide when and if to stop? These are some of the questions that are still evolving in terms of our use of checkpoint inhibitors in kidney cancer.

Sandy Srinivas, MD: I think we don’t have answers to all of the questions that you are asking. But what I tell patients is that this is a drug that we don’t know if it’s going to work for you because, as you said earlier, we don’t have a way to pick who it’s going to be effective for. We don’t have a biomarker. On the CheckMate trial, PD-L1 staining on the tissue was not predictive for who was going to respond, though it was prognostic. So I tell people, ‘We don’t know if it’s going to work for you, but if it does, you’re likely to have a response for a prolonged period of time.’ I also say that the side effects are minimal compared to the TKIs, but, again, it’s important to figure out how to recognize those side effects and how to manage them. So, in terms of overall survival, I think it’s patients who stay on it for a longer time that definitely derive the benefit, and we should be careful not to take patients off prematurely of the drug.

Robert A. Figlin, MD: Is this because of pseudoprogression or because of the possible things that Martin talks about,that infiltrating the tumor with activated cells may show us a conclusion that doesn’t lead to an interpretation of long-term benefit for the patient?

Sandy Srinivas, MD: I think both. On the CheckMate trial, even though the PFS itself was not that different, they did their landmark analysis at six months, and if you look at that difference, it did favor nivolumab. So many patients on the trial were allowed to stay on beyond progression, and I think that certainly contributed to the impact on overall survival and didn’t make a difference on progression-free survival.

Robert A. Figlin, MD: Nizar, we’re talking about immune-related side effects. And although the overall side effect profile for this checkpoint inhibitor is quite favorable, some patients have challenges with respect to kidney function, liver function, that need to be picked up early. How do you use that in your clinic? Do you see the patient every two weeks? Does your staff get trained about how to pick up the autoimmune side effects associated with checkpoint inhibitor therapy? How have you started to evolve in a practical way that can inform the practicing physician who’s delivering these drugs for kidney cancer?

Nizar M. Tannir, MD, FACP: This is very important. Obviously, this is good therapy for our patients and we want to make sure we identify a problem, an adverse event, if a patient is experiencing a symptom early on. So it has to be recognized. So we do teach. We have trained our research nurse and our clinic nurses and midlevel providers to recognize these. Obviously, as was mentioned, the immune-related adverse events related to the immune checkpoint inhibitors involve several organs. The most serious one would be obviously liver toxicity, so it is important to check their liver function tests every two weeks. We do that. We do also check endocrine function. Organ toxicity can result from even just monotherapy of nivolumab, looking at liver toxicity by liver function tests, looking at if a patient develops diarrhea that’s immune-related colitis. So if this is more than a grade 1, even if it’s a grade 1, the patient has to be watched very closely because a grade 1 toxicity can quickly become a grade 3 and land the patient in the hospital. Obviously, if they develop grade 3 toxicity—colitis, pneumonitis, or hepatitis—they need to be on steroids and in the hospital. And unfortunately for that patient, if they develop a grade 3 toxicity, that’s the end of their treatment with the immune checkpoint inhibitors.

Now, the good news is it may be all they need. If they received several infusions, and they develop a grade 3 toxicity and now they’re on steroids, then once you take off the steroids, if the adverse event resolves to baseline, those patients may not require any more therapy. And we’ve seen patients who stopped receiving the nivolumab who continued to have a response. So it’s important to be a team and work together; the physician, the midlevel providers, the research nurse, and the clinic nurse. We actually place a call to the patient at home. We may not see them every two weeks, but we certainly are calling them to make sure that they are not having symptoms such as fatigue, because that could indicate adrenal insufficiency. So we frequently check cortisol levels, thyroid levels, and, in males, testosterone levels. And so these are important. If they develop the endocrine deficiencies, they do not need to stop the immune therapy, but they need to obviously be treated. They have to have replacement with hydrocortisone for adrenal insufficiency, or thyroid. And actually frequently, we may see, initially, thyroiditis. The patient may have thyrotoxicosis on the way to developing hypothyroidism and then future requirement.

They’re interesting and they’re challenging at the same time, these adverse events. Unlike, for example, the TKIs, where you stop the drug and the hypertension, fatigue, and diarrhea may resolve completely. With immune checkpoint inhibitors, some of these toxicities, especially, for example, the endocrine deficiencies, could last for a long time. And probably 50% or so of patients, if they develop those toxicities, may end up having to receive supplementation for thyroid, hydrocortisone, or testosterone for a long time. So I think patients need to be educated and informed about this, so that they understand that this could become a chronic thing.

Robert A. Figlin, MD: Martin, there are some things that you’d like to add. But one of the things I’d like to ask you is, when we used to think about high-dose IL-2, we always thought that steroid therapy would ablate high-dose IL-2’s possible efficacy. Do we do know that to be true for checkpoint inhibition? And do you stop it or you continue it? Do you restart it later? Your thoughts?

Martin H. Voss, MD: So it’s never been formally investigated for kidney cancer, specifically. But in the whole field of targeted immunotherapy, we benefit greatly from the experience that our melanoma colleagues have who are a few years ahead of us and are already using these agents in standard practice. And it’s never been shown to my knowledge in melanoma that administration of steroids impacts upon the clinical effectiveness of these agents towards the cancer. And that’s what I tell my patients. Certainly, I haven’t had the impression that patients who have required steroids are the ones that do not respond to these therapies.

In my experience, when these toxicities do occur and steroids are needed, there’s not much debate as to whether or not to administer them. Typically, we know that, like Nizar said, these toxicities can get worse quickly. And one thing I wanted to add is with this new host of immune-related adverse events that can really affect any organ, we’re finding ourselves to be relying on our colleagues and consultants more heavily than we ever have. I now work a lot with endocrinologists; I talk more to the gastroenterologists. In many ways, we are becoming rheumatologists and using medications we haven’t used before. Patients who are refractory to steroids, or respond and have side effects to a steroid medications—but cannot be weaned off of them—are treated with other immunosuppressive agents like TNF-alpha inhibitors or mycophenolate. There’s a lot to learn outside of oncology now for us. And I think that is now going to apply to any medical oncologist because these agents are going to be used widely.

Robert A. Figlin, MD: Sandy, your thoughts?

Sandy Srinivas, MD: I just wanted to add one more thing to what has already been said, that unlike chemotherapy, especially as we see patients who have been on these checkpoint inhibitors for a long time, the toxicity doesn’t necessarily have to happen early on. We have had patients who have been on it for two years now complaining of cough and shortness of breath. So I think it’s really important to keep in mind that these immune-related side effects can happen any time during the course of therapy, and just because somebody has been on it for six months, they may not necessarily be home free.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Sandy, I want to put you on the spot and ask you: we’ve spent the last decade talking to kidney cancer patients about how to prepare for chronic administration of targeted therapy with a progression-free survival benefit. And now we turn the page and we have an agent that produces about 1 in 5 responses, no change in progression-free survival when compared to a control, but a survival benefit. I want to hear from you what you actually say to patients when they’re about to start checkpoint inhibitors. What do you tell them the goals are? How do you figure out how long to treat? How do you use imaging to decide when and if to stop? These are some of the questions that are still evolving in terms of our use of checkpoint inhibitors in kidney cancer.

Sandy Srinivas, MD: I think we don’t have answers to all of the questions that you are asking. But what I tell patients is that this is a drug that we don’t know if it’s going to work for you because, as you said earlier, we don’t have a way to pick who it’s going to be effective for. We don’t have a biomarker. On the CheckMate trial, PD-L1 staining on the tissue was not predictive for who was going to respond, though it was prognostic. So I tell people, ‘We don’t know if it’s going to work for you, but if it does, you’re likely to have a response for a prolonged period of time.’ I also say that the side effects are minimal compared to the TKIs, but, again, it’s important to figure out how to recognize those side effects and how to manage them. So, in terms of overall survival, I think it’s patients who stay on it for a longer time that definitely derive the benefit, and we should be careful not to take patients off prematurely of the drug.

Robert A. Figlin, MD: Is this because of pseudoprogression or because of the possible things that Martin talks about,that infiltrating the tumor with activated cells may show us a conclusion that doesn’t lead to an interpretation of long-term benefit for the patient?

Sandy Srinivas, MD: I think both. On the CheckMate trial, even though the PFS itself was not that different, they did their landmark analysis at six months, and if you look at that difference, it did favor nivolumab. So many patients on the trial were allowed to stay on beyond progression, and I think that certainly contributed to the impact on overall survival and didn’t make a difference on progression-free survival.

Robert A. Figlin, MD: Nizar, we’re talking about immune-related side effects. And although the overall side effect profile for this checkpoint inhibitor is quite favorable, some patients have challenges with respect to kidney function, liver function, that need to be picked up early. How do you use that in your clinic? Do you see the patient every two weeks? Does your staff get trained about how to pick up the autoimmune side effects associated with checkpoint inhibitor therapy? How have you started to evolve in a practical way that can inform the practicing physician who’s delivering these drugs for kidney cancer?

Nizar M. Tannir, MD, FACP: This is very important. Obviously, this is good therapy for our patients and we want to make sure we identify a problem, an adverse event, if a patient is experiencing a symptom early on. So it has to be recognized. So we do teach. We have trained our research nurse and our clinic nurses and midlevel providers to recognize these. Obviously, as was mentioned, the immune-related adverse events related to the immune checkpoint inhibitors involve several organs. The most serious one would be obviously liver toxicity, so it is important to check their liver function tests every two weeks. We do that. We do also check endocrine function. Organ toxicity can result from even just monotherapy of nivolumab, looking at liver toxicity by liver function tests, looking at if a patient develops diarrhea that’s immune-related colitis. So if this is more than a grade 1, even if it’s a grade 1, the patient has to be watched very closely because a grade 1 toxicity can quickly become a grade 3 and land the patient in the hospital. Obviously, if they develop grade 3 toxicity—colitis, pneumonitis, or hepatitis—they need to be on steroids and in the hospital. And unfortunately for that patient, if they develop a grade 3 toxicity, that’s the end of their treatment with the immune checkpoint inhibitors.

Now, the good news is it may be all they need. If they received several infusions, and they develop a grade 3 toxicity and now they’re on steroids, then once you take off the steroids, if the adverse event resolves to baseline, those patients may not require any more therapy. And we’ve seen patients who stopped receiving the nivolumab who continued to have a response. So it’s important to be a team and work together; the physician, the midlevel providers, the research nurse, and the clinic nurse. We actually place a call to the patient at home. We may not see them every two weeks, but we certainly are calling them to make sure that they are not having symptoms such as fatigue, because that could indicate adrenal insufficiency. So we frequently check cortisol levels, thyroid levels, and, in males, testosterone levels. And so these are important. If they develop the endocrine deficiencies, they do not need to stop the immune therapy, but they need to obviously be treated. They have to have replacement with hydrocortisone for adrenal insufficiency, or thyroid. And actually frequently, we may see, initially, thyroiditis. The patient may have thyrotoxicosis on the way to developing hypothyroidism and then future requirement.

They’re interesting and they’re challenging at the same time, these adverse events. Unlike, for example, the TKIs, where you stop the drug and the hypertension, fatigue, and diarrhea may resolve completely. With immune checkpoint inhibitors, some of these toxicities, especially, for example, the endocrine deficiencies, could last for a long time. And probably 50% or so of patients, if they develop those toxicities, may end up having to receive supplementation for thyroid, hydrocortisone, or testosterone for a long time. So I think patients need to be educated and informed about this, so that they understand that this could become a chronic thing.

Robert A. Figlin, MD: Martin, there are some things that you’d like to add. But one of the things I’d like to ask you is, when we used to think about high-dose IL-2, we always thought that steroid therapy would ablate high-dose IL-2’s possible efficacy. Do we do know that to be true for checkpoint inhibition? And do you stop it or you continue it? Do you restart it later? Your thoughts?

Martin H. Voss, MD: So it’s never been formally investigated for kidney cancer, specifically. But in the whole field of targeted immunotherapy, we benefit greatly from the experience that our melanoma colleagues have who are a few years ahead of us and are already using these agents in standard practice. And it’s never been shown to my knowledge in melanoma that administration of steroids impacts upon the clinical effectiveness of these agents towards the cancer. And that’s what I tell my patients. Certainly, I haven’t had the impression that patients who have required steroids are the ones that do not respond to these therapies.

In my experience, when these toxicities do occur and steroids are needed, there’s not much debate as to whether or not to administer them. Typically, we know that, like Nizar said, these toxicities can get worse quickly. And one thing I wanted to add is with this new host of immune-related adverse events that can really affect any organ, we’re finding ourselves to be relying on our colleagues and consultants more heavily than we ever have. I now work a lot with endocrinologists; I talk more to the gastroenterologists. In many ways, we are becoming rheumatologists and using medications we haven’t used before. Patients who are refractory to steroids, or respond and have side effects to a steroid medications—but cannot be weaned off of them—are treated with other immunosuppressive agents like TNF-alpha inhibitors or mycophenolate. There’s a lot to learn outside of oncology now for us. And I think that is now going to apply to any medical oncologist because these agents are going to be used widely.

Robert A. Figlin, MD: Sandy, your thoughts?

Sandy Srinivas, MD: I just wanted to add one more thing to what has already been said, that unlike chemotherapy, especially as we see patients who have been on these checkpoint inhibitors for a long time, the toxicity doesn’t necessarily have to happen early on. We have had patients who have been on it for two years now complaining of cough and shortness of breath. So I think it’s really important to keep in mind that these immune-related side effects can happen any time during the course of therapy, and just because somebody has been on it for six months, they may not necessarily be home free.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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