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Immune-Related Response Criteria in NSCLC

Panelists:Benjamin Levy, MD, Mount Sinai Health Systems, ; John W. Longshore, PhD, Carolinas Pathology Group; Gregory J. Riely, MD, PhD, Weill Cornell Medical College; Mark A. Socinski, MD, University of Pittsburgh; Thomas E. Stinchcombe, MD, University of North Carolina at Chapel Hill; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Friday, Jun 10, 2016


Transcript:

Mark A. Socinski, MD:
Jared, we talked earlier a little bit about immune-related response criteria, and specifically as they relate to this issue of pseudoprogression. Thoughts?

Jared Weiss, MD: So, I think there are two closely related phenomena going on here in terms of the patterns of response and progression that we see here. One is actually not all that new, which is the phenomenon of mixed progression, where there can be some lesions responding, some lesions not. And I think that kind of situation is very analogous to what we discussed earlier in the context of the EGFR inhibitors: that you have to look at which lesions you think are threatening your patient and which are not. The phenomenon of so-called pseudoprogression, I think, is rather overstated in lung cancer. This came from the melanoma literature. Some of the patients in the first phase I study of ipilimumab were taken off study and put on hospice for apparent progression, and are still living and doing well today. But, in lung cancer, this is a different disease with a different biology. In lung cancer, this phenomena where the tumor appears to be growing and then later shrinks is actually rather rare.

The overwhelming majority, if you take a glance at the spider plots for all of the major agents out there, it looks like it’s probably under 5% of apparent progression; that’s pseudoprogression as opposed to real. And so I think that the greatest danger here in our world is not taking a patient off a drug who’s benefitting. That danger is real. But I think the greater danger in real-world use is keeping patients on too long, leading to symptomatic deterioration where a patient’s PFS event may well be death, or if it’s not, that they’re too sick to benefit from third-line agents, including promising trials. That said, I think when you have that rare patient who is feeling wonderful, who says, ‘Doctor, I feel so much better than before you started this,’ and none of the progression is rapid or dramatic, none of it is hurting them, none of them is near something scary, I think there’s nothing wrong with going one more scan and giving that patient a shot at being a participant.

Mark A. Socinski, MD: Yes. I think it really needs to be symptom-driven. I think you have to understand that. There have been many things over the years. We had to become dermatologists when the EGFR TKIs came out. Then we had to become nephrologists with the hypertension and proteinuria with the antiangiogenic agents. Now, we’ve got to become endocrinologists. Ben, tell us about immune-related processes.

Benjamin P. Levy, MD: I think that this is really forcing us to engage in a more multidisciplinary approach…

Mark A. Socinski, MD: It’s called a consult.

Benjamin P. Levy, MD: Exactly, with our other physicians. These classes of drugs obviously bring tremendous excitement, but they also bring a tremendous different AE profile that we need to be comfortable with—and endocrinopathies derangements, and thyroid function, pneumonitis—which is quite low in the report, but still needs to be on the radar—and colitis, hepatitis. Anything ‘itis' is something that we need to keep in mind, and I think we’re still learning on how to optimally manage some of these AEs in terms of pneumonitis and colitis and whether we should re-challenge patients after we manage it with steroids. But I’ve engaged my pulmonologists, I’ve engaged my gastroenterologists, and we’ve had very good discussions, most of the time over the phone, about how to manage these. And I think we’re still learning. It’s an iterative process of trying to understand how best to manage these AEs.

Mark A. Socinski, MD: It’s amazing to me. You almost get lulled into complacency with these drugs because 90% to 95% of the patients do extremely well. And then you have this small percentage that you have to be vigilant about and understand all these ‘itises’ that can occur. And you’d rather recognize it when they’re grade 1 or 2, not grade 3 or 4. So, it’s a real challenge, I think, in this population. I think community doctors need to be aware of the very different toxicity profile.

Gregory J. Riely, MD, PhD: I’ll just add that the endocrinopathies you described, hypothyroidism, it sounds a lot like a patient who has progressive cancer when you listen to them and they tell you about their significant fatigue, and everything is just much worse. And if you’re not thinking hypothyroidism is a common event and you’re not screening for it, you might miss that. I think your team, the nurses who you work with, we all attribute fatigue to growing cancer. I think it’s something we have to be on the lookout for.

Thomas E. Stinchcombe, MD: Along those lines, we just built in thyroid checking every 6 weeks or 12 weeks. It might not be the right decision.

Mark A. Socinski, MD: You can over-check.

Thomas E. Stinchcombe, MD: We probably do over-check, but like you said, it’s a very subtle thing that can sort of slip up on you.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
Jared, we talked earlier a little bit about immune-related response criteria, and specifically as they relate to this issue of pseudoprogression. Thoughts?

Jared Weiss, MD: So, I think there are two closely related phenomena going on here in terms of the patterns of response and progression that we see here. One is actually not all that new, which is the phenomenon of mixed progression, where there can be some lesions responding, some lesions not. And I think that kind of situation is very analogous to what we discussed earlier in the context of the EGFR inhibitors: that you have to look at which lesions you think are threatening your patient and which are not. The phenomenon of so-called pseudoprogression, I think, is rather overstated in lung cancer. This came from the melanoma literature. Some of the patients in the first phase I study of ipilimumab were taken off study and put on hospice for apparent progression, and are still living and doing well today. But, in lung cancer, this is a different disease with a different biology. In lung cancer, this phenomena where the tumor appears to be growing and then later shrinks is actually rather rare.

The overwhelming majority, if you take a glance at the spider plots for all of the major agents out there, it looks like it’s probably under 5% of apparent progression; that’s pseudoprogression as opposed to real. And so I think that the greatest danger here in our world is not taking a patient off a drug who’s benefitting. That danger is real. But I think the greater danger in real-world use is keeping patients on too long, leading to symptomatic deterioration where a patient’s PFS event may well be death, or if it’s not, that they’re too sick to benefit from third-line agents, including promising trials. That said, I think when you have that rare patient who is feeling wonderful, who says, ‘Doctor, I feel so much better than before you started this,’ and none of the progression is rapid or dramatic, none of it is hurting them, none of them is near something scary, I think there’s nothing wrong with going one more scan and giving that patient a shot at being a participant.

Mark A. Socinski, MD: Yes. I think it really needs to be symptom-driven. I think you have to understand that. There have been many things over the years. We had to become dermatologists when the EGFR TKIs came out. Then we had to become nephrologists with the hypertension and proteinuria with the antiangiogenic agents. Now, we’ve got to become endocrinologists. Ben, tell us about immune-related processes.

Benjamin P. Levy, MD: I think that this is really forcing us to engage in a more multidisciplinary approach…

Mark A. Socinski, MD: It’s called a consult.

Benjamin P. Levy, MD: Exactly, with our other physicians. These classes of drugs obviously bring tremendous excitement, but they also bring a tremendous different AE profile that we need to be comfortable with—and endocrinopathies derangements, and thyroid function, pneumonitis—which is quite low in the report, but still needs to be on the radar—and colitis, hepatitis. Anything ‘itis' is something that we need to keep in mind, and I think we’re still learning on how to optimally manage some of these AEs in terms of pneumonitis and colitis and whether we should re-challenge patients after we manage it with steroids. But I’ve engaged my pulmonologists, I’ve engaged my gastroenterologists, and we’ve had very good discussions, most of the time over the phone, about how to manage these. And I think we’re still learning. It’s an iterative process of trying to understand how best to manage these AEs.

Mark A. Socinski, MD: It’s amazing to me. You almost get lulled into complacency with these drugs because 90% to 95% of the patients do extremely well. And then you have this small percentage that you have to be vigilant about and understand all these ‘itises’ that can occur. And you’d rather recognize it when they’re grade 1 or 2, not grade 3 or 4. So, it’s a real challenge, I think, in this population. I think community doctors need to be aware of the very different toxicity profile.

Gregory J. Riely, MD, PhD: I’ll just add that the endocrinopathies you described, hypothyroidism, it sounds a lot like a patient who has progressive cancer when you listen to them and they tell you about their significant fatigue, and everything is just much worse. And if you’re not thinking hypothyroidism is a common event and you’re not screening for it, you might miss that. I think your team, the nurses who you work with, we all attribute fatigue to growing cancer. I think it’s something we have to be on the lookout for.

Thomas E. Stinchcombe, MD: Along those lines, we just built in thyroid checking every 6 weeks or 12 weeks. It might not be the right decision.

Mark A. Socinski, MD: You can over-check.

Thomas E. Stinchcombe, MD: We probably do over-check, but like you said, it’s a very subtle thing that can sort of slip up on you.

Transcript Edited for Clarity
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