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Follicular Lymphoma: Optimizing Novel Agent Therapy

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Jan 25, 2018



Transcript: 

Ian W. Flinn, MD, PhD: There are some ongoing trials that are looking at copanlisib. They look at a variety of different designs. What is your knowledge about that?

Grzegorz S. Nowakowski, MD: Yes, there are a number of randomized studies that are trying to combine copanlisib with different agents and evaluate the activity of copanlisib in this setting. The CHRONOS-3 study randomizes patients between rituximab alone or rituximab plus copanlisib. It’s a very interesting study in the relapsed/refractory setting, and hopefully we’ll learn the value of combination in this setting. CHRONOS-4 is also a very interesting design because it builds on this concept of adding targeted agents to chemotherapy, and it’s actually using investigator choice–either BR [bendamustine and rituximab] plus copanlisib or R-CHOP plus copanlisib versus BR or R-CHOP– depending on the pattern of practice. And I think this study will be very interesting to watch. I’ll be curious to know over time what toxicities we’ll see in this combination. Hopefully they are very limited. But I think adding, in general, targeted agents to a chemotherapy or chemoimmunotherapy backbone makes a lot of sense, and I’m interested in the results of this study.

Ian W. Flinn, MD, PhD: There are a couple of other PI3 kinase inhibitors in development. One is duvelisib, which is a delta inhibitor. It also has inhibition of the gamma isoform. That may broaden its ability to diseases outside of follicular lymphoma and chronic lymphocytic leukemia. The pivotal trial has been completed, which was in chronic lymphocytic leukemia, but there was also the DYNAMO study that showed similar response rates and duration of remissions to what we’ve seen with the other PI3 kinase inhibitors. So I think there’s a lot happening in the PI3 kinase space, and it’s going to be interesting to see how this all sorts out. Of course, there’s also umbralisib, which may have a totally different safety profile, and that’s going to be interesting when we see the same efficacy with that drug.

Grzegorz S. Nowakowski, MD: Yes, it’s really exciting to see that we’re able to now capitalize on years of basic research, which was done regarding the importance of the PI3 kinase pathway in lymphoma.

Ian W. Flinn, MD, PhD: I think it’s wonderful to have all these choices, but it does complicate just some very simple decision making about what the best sequence is. Loretta, tell us how we’re going to be doing this in the years to come.

Loretta J. Nastoupil, MD: I think efficacy drives a lot of our decisions, but we can’t forget about toxicity. I think, as oncologists who have had many decades of experience with chemotherapy, we’re all quite comfortable with the safety profile of chemotherapy, and we’re also quite comfortable choosing chemotherapy based on patient characteristics. Again, with the addition of new CD20 antibodies, maybe we’re learning a little bit more. With the novel agents, I would say we have less experience. And so, as we have longer duration of therapy on these studies, some of the toxicity profiles tend to play out. There might be some differentiated toxicity, I think, that will factor into some of our treatment decisions. Before the era of the checkpoint inhibitors, I can tell you that we were all very nervous about colitis, pneumonitis, and transaminitis. Not that we’re not nervous about those anymore, but I think we have more experience in terms of how to identify them and how to manage them across some of these agents. But I still think that the goals of care are to provide patients a durable remission without impacting their quality of life. How you get there, I think, is still going to be individualized. What we’re missing, and we haven’t mentioned today, are biomarkers that will help us choose therapy given the biology of the tumor. And I just think we’re not there yet.

Ian W. Flinn, MD, PhD: You brought up some of the toxicity issues that we see with some of the different drugs. I think Anas talked a little about some of this, such as the hyperglycemia and hypertension. For the most part, it sounds like these things are manageable with copanlisib. Does that really affect how you select any of these therapies, Anas?

Anas Younes, MD: No. These are on-target effects, so they are predictable. Actually, as you said, they’re both transient. If you don’t check the glucose level of these patients, you would never probably notice it. They would just check because it was on a clinical trial. It happens where they peak and then they go down within 4 hours or so, and the blood pressure would also normalize within a few hours. This is an on-target effect. They do not require intervention, that’s the most important thing. You don’t want to see someone whose glucose level goes to 500 mg/dl and give them insulin. This is exactly what you don’t want to do because they may end up having hypoglycemia. It’s awareness, as Loretta said. You have to be aware of the side effects, how to manage them. There’s no need to intervene most of the time. So, that would not affect my decision because I know how to deal with it.

Loretta J. Nastoupil, MD: I want to add one more thing to the sequencing component. One emerging trend that I’m seeing is the reexposure to chemotherapy. For instance, patients get bendamustine-rituximab in frontline and then they get bendamustine with a CD20 antibody in second line. With the availability of these novel agents, I struggle with that decision and with who is appropriate for that. And again, I think there are probably a number of other options that may be better than rechanneling with bendamustine.

Ian W. Flinn, MD, PhD: I worry about the effect on stem cells with bendamustine. It feels like going back to the fludarabine days and the damage to the stem cell compartment and cumulative toxicity that can occur. I think that’s a good rationale for hopefully moving on to a new and better agent.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: There are some ongoing trials that are looking at copanlisib. They look at a variety of different designs. What is your knowledge about that?

Grzegorz S. Nowakowski, MD: Yes, there are a number of randomized studies that are trying to combine copanlisib with different agents and evaluate the activity of copanlisib in this setting. The CHRONOS-3 study randomizes patients between rituximab alone or rituximab plus copanlisib. It’s a very interesting study in the relapsed/refractory setting, and hopefully we’ll learn the value of combination in this setting. CHRONOS-4 is also a very interesting design because it builds on this concept of adding targeted agents to chemotherapy, and it’s actually using investigator choice–either BR [bendamustine and rituximab] plus copanlisib or R-CHOP plus copanlisib versus BR or R-CHOP– depending on the pattern of practice. And I think this study will be very interesting to watch. I’ll be curious to know over time what toxicities we’ll see in this combination. Hopefully they are very limited. But I think adding, in general, targeted agents to a chemotherapy or chemoimmunotherapy backbone makes a lot of sense, and I’m interested in the results of this study.

Ian W. Flinn, MD, PhD: There are a couple of other PI3 kinase inhibitors in development. One is duvelisib, which is a delta inhibitor. It also has inhibition of the gamma isoform. That may broaden its ability to diseases outside of follicular lymphoma and chronic lymphocytic leukemia. The pivotal trial has been completed, which was in chronic lymphocytic leukemia, but there was also the DYNAMO study that showed similar response rates and duration of remissions to what we’ve seen with the other PI3 kinase inhibitors. So I think there’s a lot happening in the PI3 kinase space, and it’s going to be interesting to see how this all sorts out. Of course, there’s also umbralisib, which may have a totally different safety profile, and that’s going to be interesting when we see the same efficacy with that drug.

Grzegorz S. Nowakowski, MD: Yes, it’s really exciting to see that we’re able to now capitalize on years of basic research, which was done regarding the importance of the PI3 kinase pathway in lymphoma.

Ian W. Flinn, MD, PhD: I think it’s wonderful to have all these choices, but it does complicate just some very simple decision making about what the best sequence is. Loretta, tell us how we’re going to be doing this in the years to come.

Loretta J. Nastoupil, MD: I think efficacy drives a lot of our decisions, but we can’t forget about toxicity. I think, as oncologists who have had many decades of experience with chemotherapy, we’re all quite comfortable with the safety profile of chemotherapy, and we’re also quite comfortable choosing chemotherapy based on patient characteristics. Again, with the addition of new CD20 antibodies, maybe we’re learning a little bit more. With the novel agents, I would say we have less experience. And so, as we have longer duration of therapy on these studies, some of the toxicity profiles tend to play out. There might be some differentiated toxicity, I think, that will factor into some of our treatment decisions. Before the era of the checkpoint inhibitors, I can tell you that we were all very nervous about colitis, pneumonitis, and transaminitis. Not that we’re not nervous about those anymore, but I think we have more experience in terms of how to identify them and how to manage them across some of these agents. But I still think that the goals of care are to provide patients a durable remission without impacting their quality of life. How you get there, I think, is still going to be individualized. What we’re missing, and we haven’t mentioned today, are biomarkers that will help us choose therapy given the biology of the tumor. And I just think we’re not there yet.

Ian W. Flinn, MD, PhD: You brought up some of the toxicity issues that we see with some of the different drugs. I think Anas talked a little about some of this, such as the hyperglycemia and hypertension. For the most part, it sounds like these things are manageable with copanlisib. Does that really affect how you select any of these therapies, Anas?

Anas Younes, MD: No. These are on-target effects, so they are predictable. Actually, as you said, they’re both transient. If you don’t check the glucose level of these patients, you would never probably notice it. They would just check because it was on a clinical trial. It happens where they peak and then they go down within 4 hours or so, and the blood pressure would also normalize within a few hours. This is an on-target effect. They do not require intervention, that’s the most important thing. You don’t want to see someone whose glucose level goes to 500 mg/dl and give them insulin. This is exactly what you don’t want to do because they may end up having hypoglycemia. It’s awareness, as Loretta said. You have to be aware of the side effects, how to manage them. There’s no need to intervene most of the time. So, that would not affect my decision because I know how to deal with it.

Loretta J. Nastoupil, MD: I want to add one more thing to the sequencing component. One emerging trend that I’m seeing is the reexposure to chemotherapy. For instance, patients get bendamustine-rituximab in frontline and then they get bendamustine with a CD20 antibody in second line. With the availability of these novel agents, I struggle with that decision and with who is appropriate for that. And again, I think there are probably a number of other options that may be better than rechanneling with bendamustine.

Ian W. Flinn, MD, PhD: I worry about the effect on stem cells with bendamustine. It feels like going back to the fludarabine days and the damage to the stem cell compartment and cumulative toxicity that can occur. I think that’s a good rationale for hopefully moving on to a new and better agent.

Transcript Edited for Clarity 
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