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Follicular Lymphoma: Defining Copanlisib

Panelists:Bruce Cheson, MD, Georgetown Lombardi Comprehensive Cancer Center; Nathan Fowler, MD, The University of Texas MD Anderson Cancer Center; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Oct 23, 2017



Transcript:

Bruce Cheson, MD: How does copanlisib differ from idelalisib in its mechanism of action?

Nathan Fowler, MD: There are several different isoforms of PI3 kinase. Idelalisib hits mainly the delta isoform, and the drug copanlisib is a pan-PI3 kinase inhibitor. It tends to hit alpha and delta isoforms, more so than the other isoforms. It also is given intravenously versus idelalisib, which is given orally. So, these differences, meaning the differences in the isoforms that they hit, also lead to a slightly different side effect profile with copanlisib compared to idelalisib.

Bruce Cheson, MD: But what’s the rationale for targeting both the alpha and the delta?

Nathan Fowler, MD: Let me back up a little bit. PI3 kinase is a regulator of multiple cellular processes, everything from survival to chemoresistance to genomic stability. It looks like alpha is probably involved, or is more prevalent, in resistant follicular lymphomas, and so maybe hitting the alpha is going to be better when you’re looking at patients who have progressed after multiple lines of therapy. It may also be involved, as I mentioned, in chemoresistance and in cellular signaling within the microenvironment.

Bruce Cheson, MD: The CHRONOS-1 study was, in large, partly responsible for this accelerated approval. What were the data from that study?

Anas Younes, MD: It was a single-arm phase II trial. In a way, you can say it was double refractory. So, patients were required to have at least 2 prior regimens—failed alkylating agents and rituximab—and were treated with single-agent copanlisib. The response rate is pretty good: close to 60% percent, I think, about 58%. The CR rate with these agents is usually not high, but that’s OK because the PFS is pretty good: about 1 year, and it sometimes exceeds 1 year. It’s the same thing for duration of response. So, as a single-agent in the third-line space, it looks like rituximab did as a single agent in the old days. A 50% response rate for rituximab with about 1 year PFS. So, it’s pretty good.

Bruce Cheson, MD: These are people who already failed rituximab.

Anas Younes, MD: Exactly, right.

Bruce Cheson, MD: But how do these results compare with idelalisib?

Anas Younes, MD: Almost the same, actually. It’s very comparable to idelalisib. But the difference is really the safety profile, that’s what the major difference is between them.

Bruce Cheson, MD: What’s the difference in the safety profile?

Nathan Fowler, MD: We saw with idelalisib that there was a significant portion of patients who developed both acute and late colitis. There are also a couple of cases of pneumonitis, and with some of the randomized studies there appeared to be a significant signaling with regards to significant infections.

With copanlisib, we see a slightly lower incidence of colitis, but we do see transient hyperglycemia and hypertension, which we did not see in the idelalisib studies. Luckily, most of the cases of hyperglycemia resolved. Most of the patients did not require significant intervention. In fact, many times, we really don’t recommend insulin because the drug will still be on board and patients can develop delayed hypoglycemia. So, again, hypertension is fairly transient, around 2 hours, and hyperglycemia is also transient and not too significant. In most patients, it lasted around 5 to 8 hours.

I think this probably has to do with the different isoforms. The infectious risk, to be fair, is hard to know until we see more data with copanlisib. The infectious risk with idelalisib really didn’t come out, we didn’t truly understand it, until we ran randomized studies, and that’s when we saw an increased risk compared to non-idelalisib arms.

Bruce Cheson, MD: The other issue with idelalisib was that the median time to follow-up in the Gopal study, which was the major publication, was 6 months. And we didn’t see the colitis and all of that until after. The median follow-up in the CHRONOS study is about the same, if I’m not mistaken. So, I think we need longer follow-up to make sure. The publication would suggest that even though you are seeing colitis, you are seeing pneumonitis, and you’re seeing dermatitis and transaminitis—all the “itises”—it seems to be, and hopefully is, at a lower frequency than the other therapies. The schedule of administration difference though, as you said, is 1 pill twice a day versus days 1, 8, 15, and a week off indefinitely. Do you envision that being an issue with patient compliance or something else?

Nathan Fowler, MD: It’s a very interesting question. I think with compliance, it’s hard to know. Sometimes, with having a scheduled visit once a week—where you set it up on a Monday during lunch, you’re coming every Monday, and it becomes a routine thing—maybe the compliance is actually better with a drug that’s given at the doctor’s office on a routine schedule than with oral drugs. We’ve seen it with many other oral drugs across the spectrum of diseases—I can think of HIV, for example—where, unfortunately, sometimes with an oral drug that’s given daily, there are a lot of missed doses. With regards to the usage of the drug, I think that’s going to be hard to know.

We talked earlier about academic medical centers, where many patients are coming in from out of town. Clearly a drug that’s given weekly is difficult. If you’re traveling from Little Rock, Arkansas, to New York City to get your drug, it’s pretty much inconceivable that you can indefinitely make that trip weekly. So, an oral drug in that kind of setting is clearly easier for patients. How this is going to translate into community practices, where patients are not traveling too far, is hard to know yet.

Anas Younes, MD: I think there are advantages and disadvantages for everything. The advantage of having an IV is that some patients like to see their physicians once a week. They feel more secure. You’re keeping an eye on them, because now they’re coming in every week. You’re checking on side effects. You’re asking them, “Do you have a cough? Do you have diarrhea?” So, you can detect toxicities early on and act on that early on. Whereas, if you give them pills to take home and they disappear for 2 months then come back, maybe it’s too late because they kept taking it, ignoring the side effects and symptoms. And then, they got more into trouble. So, yes, from a convenience point of view, the IV is a little bit more inconvenient. But I think from a safety point of view, with me, it actually adds some safety value for this drug.

Transcript Edited for Clarity 
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Transcript:

Bruce Cheson, MD: How does copanlisib differ from idelalisib in its mechanism of action?

Nathan Fowler, MD: There are several different isoforms of PI3 kinase. Idelalisib hits mainly the delta isoform, and the drug copanlisib is a pan-PI3 kinase inhibitor. It tends to hit alpha and delta isoforms, more so than the other isoforms. It also is given intravenously versus idelalisib, which is given orally. So, these differences, meaning the differences in the isoforms that they hit, also lead to a slightly different side effect profile with copanlisib compared to idelalisib.

Bruce Cheson, MD: But what’s the rationale for targeting both the alpha and the delta?

Nathan Fowler, MD: Let me back up a little bit. PI3 kinase is a regulator of multiple cellular processes, everything from survival to chemoresistance to genomic stability. It looks like alpha is probably involved, or is more prevalent, in resistant follicular lymphomas, and so maybe hitting the alpha is going to be better when you’re looking at patients who have progressed after multiple lines of therapy. It may also be involved, as I mentioned, in chemoresistance and in cellular signaling within the microenvironment.

Bruce Cheson, MD: The CHRONOS-1 study was, in large, partly responsible for this accelerated approval. What were the data from that study?

Anas Younes, MD: It was a single-arm phase II trial. In a way, you can say it was double refractory. So, patients were required to have at least 2 prior regimens—failed alkylating agents and rituximab—and were treated with single-agent copanlisib. The response rate is pretty good: close to 60% percent, I think, about 58%. The CR rate with these agents is usually not high, but that’s OK because the PFS is pretty good: about 1 year, and it sometimes exceeds 1 year. It’s the same thing for duration of response. So, as a single-agent in the third-line space, it looks like rituximab did as a single agent in the old days. A 50% response rate for rituximab with about 1 year PFS. So, it’s pretty good.

Bruce Cheson, MD: These are people who already failed rituximab.

Anas Younes, MD: Exactly, right.

Bruce Cheson, MD: But how do these results compare with idelalisib?

Anas Younes, MD: Almost the same, actually. It’s very comparable to idelalisib. But the difference is really the safety profile, that’s what the major difference is between them.

Bruce Cheson, MD: What’s the difference in the safety profile?

Nathan Fowler, MD: We saw with idelalisib that there was a significant portion of patients who developed both acute and late colitis. There are also a couple of cases of pneumonitis, and with some of the randomized studies there appeared to be a significant signaling with regards to significant infections.

With copanlisib, we see a slightly lower incidence of colitis, but we do see transient hyperglycemia and hypertension, which we did not see in the idelalisib studies. Luckily, most of the cases of hyperglycemia resolved. Most of the patients did not require significant intervention. In fact, many times, we really don’t recommend insulin because the drug will still be on board and patients can develop delayed hypoglycemia. So, again, hypertension is fairly transient, around 2 hours, and hyperglycemia is also transient and not too significant. In most patients, it lasted around 5 to 8 hours.

I think this probably has to do with the different isoforms. The infectious risk, to be fair, is hard to know until we see more data with copanlisib. The infectious risk with idelalisib really didn’t come out, we didn’t truly understand it, until we ran randomized studies, and that’s when we saw an increased risk compared to non-idelalisib arms.

Bruce Cheson, MD: The other issue with idelalisib was that the median time to follow-up in the Gopal study, which was the major publication, was 6 months. And we didn’t see the colitis and all of that until after. The median follow-up in the CHRONOS study is about the same, if I’m not mistaken. So, I think we need longer follow-up to make sure. The publication would suggest that even though you are seeing colitis, you are seeing pneumonitis, and you’re seeing dermatitis and transaminitis—all the “itises”—it seems to be, and hopefully is, at a lower frequency than the other therapies. The schedule of administration difference though, as you said, is 1 pill twice a day versus days 1, 8, 15, and a week off indefinitely. Do you envision that being an issue with patient compliance or something else?

Nathan Fowler, MD: It’s a very interesting question. I think with compliance, it’s hard to know. Sometimes, with having a scheduled visit once a week—where you set it up on a Monday during lunch, you’re coming every Monday, and it becomes a routine thing—maybe the compliance is actually better with a drug that’s given at the doctor’s office on a routine schedule than with oral drugs. We’ve seen it with many other oral drugs across the spectrum of diseases—I can think of HIV, for example—where, unfortunately, sometimes with an oral drug that’s given daily, there are a lot of missed doses. With regards to the usage of the drug, I think that’s going to be hard to know.

We talked earlier about academic medical centers, where many patients are coming in from out of town. Clearly a drug that’s given weekly is difficult. If you’re traveling from Little Rock, Arkansas, to New York City to get your drug, it’s pretty much inconceivable that you can indefinitely make that trip weekly. So, an oral drug in that kind of setting is clearly easier for patients. How this is going to translate into community practices, where patients are not traveling too far, is hard to know yet.

Anas Younes, MD: I think there are advantages and disadvantages for everything. The advantage of having an IV is that some patients like to see their physicians once a week. They feel more secure. You’re keeping an eye on them, because now they’re coming in every week. You’re checking on side effects. You’re asking them, “Do you have a cough? Do you have diarrhea?” So, you can detect toxicities early on and act on that early on. Whereas, if you give them pills to take home and they disappear for 2 months then come back, maybe it’s too late because they kept taking it, ignoring the side effects and symptoms. And then, they got more into trouble. So, yes, from a convenience point of view, the IV is a little bit more inconvenient. But I think from a safety point of view, with me, it actually adds some safety value for this drug.

Transcript Edited for Clarity 
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