Follicular Lymphoma: Optimizing Copanlisib



Bruce Cheson, MD: We’ve mentioned the word biomarkers a few times here. Are there any biomarkers available that will predict either response or toxicity in copanlisib?

Anas Younes, MD: Unfortunately, none that you can use in the clinical practice today. There were some correlative studies performed in the context of the trial that led to its approval. Not surprisingly, that PI3 kinase activation measured by gene signature correlated with the response. That’s not surprising. But we don’t have selection biomarkers that you can test up front and say, “I’m going to give you copanlisib now, because the chance you respond is 100%” or, “No, copanlisib is not going to work for you, I’d rather give you something else.” We’re not there yet.

Bruce Cheson, MD: How far away are we?

Anas Younes, MD: The company did really extensive biomarker studies in the context of the trial. And, as I recall, they could not find a clear-cut biomarker that can be translated into, let’s say, a companion diagnostic or exact patients. So, at least in the context of copanlisib, the good news is that it has a good response rate. It’s not 10%, where you have to select patients. It’s about a 60% response rate. But I’m not so sure this will be the next step in the development of this agent.

Bruce Cheson, MD: I think the next step in developing these agents are the phase III clinical trials, and there are a number of them going on with this drug: CHRONOS-2, CHRONOS-3, and CHRONOS-4. Could you review those for us?

Nathan Fowler, MD: The CHRONOS-2 study is copanlisib vs placebo in relapsed low-grade lymphomas. The CHRONOS-3 study, a little more advanced, is copanlisib plus rituximab. And the CHRONOS-4 study is copanlisib with R [rituximab]-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone] versus R-CHOP alone, and these studies are going to be in low-grade lymphomas.

Bruce Cheson, MD: Are there any other studies that you could think of doing that might further inform us about the role of this drug in the context of how we currently treat our patients? I have one thought, that we’re missing the most commonly used chemotherapy drug here, and that’s bendamustine. Is there a trial you might design that would answer that question about its contribution?

Anas Younes, MD: One of the CHRONOS trials actually included either/or, R-CHOP or R-bendamustine. And then, for practical reasons, they switched to R-CHOP, because there were very few patients. But I agree you, it would be good to test it in the context of commonly used regimens like R-bendamustine.

Bruce Cheson, MD: Now, all of these studies are in patients with relapsed/refractory disease. One thing we learned from the idelalisib experience was that toxicities were much worse when the drug was used in younger patients and in less heavily pretreated patients, probably because of a more intact immune system. Do we have any data that suggest this drug might be safe in the frontline setting?

Nathan Fowler, MD: None that I’m aware of. I don’t know of any frontline studies using this drug. One of the issues with follicular lymphoma, as we pointed out earlier in our discussion, is that many patients can have very heterogeneous outcomes. In fact, some patients with standard chemotherapy will probably never relapse. At least not in a long, long, long time.

Bruce Cheson, MD: Not in our lifetime.

Transcript Edited for Clarity

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