Insights From: Bruce Cheson, MD, Lombardi Comprehensive Cancer Center; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Anas Younes, MD: There are multiple PI3 kinase inhibitors that are being tested in clinical trials. The only one that is approved by the FDA right now is idelalisib. But just because they’re PI3 kinase inhibitors, that doesn’t mean that they have the same toxicity profile, because the root of administration, dose, schedule, and the chemical structure can play a role in predicting better or worse safety profiles. So, copanlisib is a pan-PI3 kinase inhibitor that preferentially inhibits 2 isoforms: the alpha and delta. It’s given by intravenous infusion, so you give it once a week for 3 consecutive weeks, and then a 1-week break. By doing so, you’re bypassing the gut as an oral administration, and you’re giving it intermittently once a week. It’s not continuous dosing, plus it has a different chemical structure compared to idelalisib. All of those facts may have contributed to what seems to be, for now, a better safety profile compared to idelalisib and a better safety profile in the 3 things that I mentioned: a very low incidence of pneumonitis, transaminitis, and colitis. These incidences occur in about 1.5% of patients, compared to sometimes 10% or so with the idelalisib and other PI3 kinase inhibitors.
Bruce Cheson, MD: There are now several new PI3 kinase inhibitors in clinical development. One of these is copanlisib, which is a pan-PI3 kinase inhibitor. Idelalisib is a delta isoform specific inhibitor. Copanlisib is a pan inhibitor—alpha, beta, gamma, delta—but mostly the alpha-delta. Now, the delta is probably most important in the activity of PI3 kinase inhibitors in lymphoma. There are those who feel that the alpha may also contribute to some activity. I think that’s not as clear. One of the major differences is the administration of the drugs. Idelalisib is a pill, twice a day, for as long as it works. On the other hand, copanlisib is intravenous weekly for 3 weeks and then a week off, potentially indefinitely. So, this will have a number of differences. When you look at the activity of these 2 drugs, they’re fairly comparable. They have around a 60% response rate with a median progression-free survival of 11 to 12 months. The biggest difference is in the mode of administration, the schedule of administration, and in the toxicity profile.
Now the safety profiles of copanlisib and idelalisib are fairly different. Idelalisib has itis associated with it. It has pneumonitis, it has colitis, and it has transaminitis. It stimulates an inflammatory reaction in those organs that cause the resulting toxicity. Early on, you can get simple diarrhea, which is easy to take care of. But around 7, 8, or 9 months is when you can get a colitis, which can be very, very difficult. The transaminitis tends to be transient. You hold the drug, it gets better, and you give it again. It frequently doesn’t come back, or if it does, you hold the drug and when it comes back to normal, you give a lower dose. Frequently, you can move along. Sometimes, you can’t. Sometimes, you have to discontinue the drug, particularly for the colitis, which can be life-threatening.
Copanlisib is given intravenously and bypasses the GI tract as a result, so you don’t see that as frequently, although you do see the pneumonitis, transaminitis, and even occasionally colitis, but far less frequently than with idelalisib. What you do see is hyperglycemia and hypertension. They’re relatively manageable, but I want to stress this. With the first publication of idelalisib, we didn’t see the colitis. We didn’t see a lot of this stuff. Why didn’t we? Because the median follow-up was 6 months in that publication. And the colitis and other effects don’t occur until 7, 8, or 9 months. So, as we were following the patients further and further along, all of a sudden, these toxicities appeared. The initial data of copanlisib have a median follow-up of probably 6 months or less. Are we going to see more toxicities the longer we follow patients on treatment with this drug? That remains to be seen, but we have to keep our eyes open.
Now whether or not the differences in PI3 subset targeting will have any clinical implications is unclear. Whether or not targeting the alpha will improve on just targeting the delta isoform, we don’t know. But based on the clinical results that we have to date, they are fairly comparable between idelalisib and copanlisib with response rates around 60% and progression-free survival in the range of 11 to maybe 12 months.