Follicular Lymphoma: Complexities in Combinations


Bruce Cheson, MD: We’ve studied the SYK/JAK inhibitor, cerdulatinib, and we’ve treated a few patients and seen some responses, but it’s still way too early. We’re combining all of these agents. It’s like the old days. We took all the chemotherapy drugs and did things like ProMACE-MOPP and ProMACE-CytaBOM. Now we’re doing that with all of these targeted drugs, and there are hundreds of studies of doublets and triplets of checkpoint inhibitors and BCR signaling. How do we pick what drugs to use? How should we pick what drugs to use? How can we pick what drugs to combine with what drugs? Right now, it’s totally empiric.

Nathan Fowler, MD: It’s very empiric. Unfortunately, because there are no good models to predict toxicity with some of these novel—novel combinations, we’ve seen many studies in the past 5 years that have been terminated due to excess toxicity.

Bruce Cheson, MD: Several of them were mine.

Nathan Fowler, MD: Yes, and ours too. We had lenalidomide/idelalisib, which was closed. Just this last month, we saw letters from the FDA going out regarding combinations of pembrolizumab and lenalidomide in myeloma, with which, unfortunately, there was excess mortality in the combination arms.

Bruce Cheson, MD: And that’s had spinoff to the durvalumab.

Nathan Fowler, MD: Correct. I think it’s a good thing to do and it’s a safe thing to do, but across the field right now, we’re seeing a reevaluation of these combination immunotherapy studies in B-cell malignancies, as well as in myeloma, until we can really figure out how to predict toxicity and reduce risk for patients.

Bruce Cheson, MD: You’ve thought about this a lot.

Anas Younes, MD: I think it’s a very good point. The biggest challenge that we have is how to prioritize. How do we pick, as investigators, the next combinations? There are plenty of them floating around. It’s a phenomenal number of combinations you can test, and not just 2 novel agents. These are me-too drugs, multiple checkpoint inhibitors plus a certain drug. How do you choose which one you want to work with?

The best idea, and I think it’s not easy, is to step back and perform these synergy analyses in independent laboratories and then prioritize which ones have the highest chance of being beneficial or synergistic. There’s no question that there are many combinations that will give you some benefit. But is it the right combination that we want to prioritize?

I think there may be one better than others, and we should seek it as a group or as a community and say, “This is a combination that we want to pursue. Thank you for offering combination C, because I want to focus on combination A.” Otherwise, it’s going to be messy. We’ll be doing a lot of trials, competing with each other, and we will not be able to finish these trials because of the competition.

Bruce Cheson, MD: There’s another risk we’re running into here. Do you remember the old days, when you were young and you were very young? I was at a cooperative group meeting when I was still at the NIH and I was listening to them. They had already done studies with doxorubicin in large cell lymphoma and epirubicin in large cell lymphoma and there was another “rubicin,” so I got up and I said, “Really guys? Can’t you think of anything different?” Now we have 5, 6, or 7 BTK inhibitors and 4 or 5 PI3K inhibitors. We’ve got a swath of anti-CD20s. I don’t want us to get in that position again, where we’re just doing me-too studies because a different company will give us their targeted agent rather than the other one. I think it’s a risk we run into.

Transcript Edited for Clarity

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