Insights From: Bruce Cheson, MD, Lombardi Comprehensive Cancer Center; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Anas Younes, MD: There are 4 isoforms for PI3 kinase—alpha, beta, gamma, and delta—and there are drugs that you can selectively target 1 or more of these isoforms with. So, idelalisib targets delta, duvelisib targets gamma and delta, and copanlisib targets alpha and delta. There are other delta specific inhibitors beyond idelalisib. Those drugs have different safety profiles and different advantages and disadvantages. The advantage of combining alpha and delta, at least from preclinical experiments, is at least 2-fold. If you inhibit 1 isoform, the other may compensate for it. So, it can still activate downstream events by having alpha-selective receptors. And then, in some cases where patients had repeat biopsies and you measured gamma and alpha levels, it seems like at relapse, the alpha levels go up, suggesting that there may be a compensatory mechanism through alpha. So, again, in theory and from preclinical experiments, it seems that combining alpha and delta inhibition may be more effective up front and may inhibit this feedback mechanism through activation or increased level of the alpha.
That comes with some side effects because alpha inhibition can contribute to hyperglycemia, which is usually seen in patients treated with pan-PI3 kinase inhibitors, and to the transient hypertension that is also seen. So, these are on-target effects, but they’re transient. Just because you have hyperglycemia with these agents doesn’t mean that you’re going to have diabetes when you stop treatment. It’s just transient. It goes up and down, depending on the dose schedule that you use with these agents.
The potential for copanlisib and other PI3 kinase inhibitors in improving treatment outcome in the follicular lymphomas and, in my opinion, other lymphoid malignancies is combination. There are consistent data right now with idelalisib and copanlisib that the best response we can get is about 55% to 58% response rate. Most of these responses are partial responses, and they give you about a 1 year of mileage. The question is, how do you improve on that? And it’s going to be through rational design, mechanism-based combination strategies. So, you’ll see, in the future, multiple combinations with these PI3 kinase inhibitors in follicular lymphoma and other lymphoid malignancies.
Bruce Cheson, MD: There are several randomized phase III trials that have been conducted with copanlisib. There was the CHRONOS-2 trial, and this was in rituximab-refractory indolent lymphomas. Patients were randomized to copanlisib or placebo. Now personally, I find that study design to be questionable in treating somebody with a placebo when there are other drugs out there that might be of some clinical benefit. There is the CHRONOS-3 trial, which is in a similar population of patients, using rituximab with or without copanlisib. That study is still ongoing. The first study I mentioned, CHRONOS-2, is closed to accrual. And then there’s CHRONOS-4, which is bendamustine/rituximab or R-CHOP with or without copanlisib for relapsed/refractory follicular and low-grade lymphomas.
These are interesting studies. They’re important for defining the role of this new PI3 kinase inhibitors in our clinical panorama. With longer follow-up, that’s when we’re going to get a better idea of how the toxicities of this PI3K inhibitor stack up with idelalisib. Because the itis may not occur for months and months down the road. In fact, I had a patient on idelalisib who didn’t develop the colitis for 2-and-a-half years. So, you’ve got to keep your eyes out. You can’t be complacent in monitoring these patients. You have to actively investigate the toxicities, and hopefully, we won’t see them with copanlisib. Maybe the intravenous administration abrogates that problem, but time will tell with this drug, and hopefully it will provide additional benefit to patients with follicular and low-grade lymphomas.