ASCO: Copanlisib and Rituxan

There was a lot of CAR-T news coming out of ASCO -- much more than I have shared. And most of what I have shared is related to CAR-T in some way.

But one of the other big trends that I saw had to do with inhibitors -- treatments that inhibit cancer cells from growing and staying alive. For any cell to stay alive, there is a long path of reactions that need to take place -- genes telling enzymes and proteins to tell other enzymes and proteins to do certain tings, or stop doing certain things. Cancer happens when some part of that path goes wrong, and things that were supposed to stop don't stop, or things that were supposed to happen don't happen. Inhibitors are designed to stop something form happening, so the pathway gets blocked, and the cancer cell dies.

There are four inhibitors approved for use with Follicualr Lymphoma: Umbralisib (approved earlier this year), Idelalisib, Duvalisib, and Copanlisib (which I wrote about January). All are PI3K inhibitors (meaning they try to stop the same path, though by targeting slightly different things in that path), and all have been approved for different FL populations. 

A lot of the research on PI3K inhibitors has looked at their usefulness as part of combination therapies -- mixing the inhibitor with something else. Combinations of all kinds are important treatment options for FL, and they recognize how complex a disease it is -- cancer cells are tricky, and probably need more than one to get at them in order to be successful. Combinations are often more effective than the individual parts.

The problem, of course, is safety. Two different treatments might get at cancer cells in different ways (making them potentially twice as effective), but they also each come with their own side effects (making them potentially twice as dangerous). Like any treatment, the PI3K inhibitor combinations have to show that their improved effectiveness is balanced by their safety.

The ASCO presentation called "Copanlisib + rituximab versus rituximab + placebo in patients with relapsed follicular (FL) or marginal zone lymphoma (MZL): Subset analysis from the phase III CHRONOS-3 trial" seems to show just that. 

The presentation reports on results from a phase 3 clinical trial called CHRONOS-3 that looks at Copanlisib and Rituxan by comparing them to Rituxan and a placebo (in other words, comparing them to just Rituxan on its own). 

The title calls this a "subset analysis." That means the research are reporting on a smaller group within the larger group of patients who are in the trial. In this case, the smaller group includes patients with indolent NHL, including Follicular Lymphoma patients, as well as Marginal Zone Lymphoma patients. (In case you're curious, the others not included in this presentation were patients with small lymphocytic lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.)

The effectiveness was very good.  The Overall Response Rate for the C + R group was 82.4% (including a 37.6% Complete Response), and for the Rituxan group it was 50.8% (with an 18.3% CR). The median Progression Free Survival was 22.2 months for C + R and 15.4 months for R.

More importantly, safety was also good, though (maybe not suprisingly) the C + R group had more side effects, with the most common grade 3 or worse (that is, serious) being hyperglycemia (56.4%), hypertension (39.7%), and diarrhea (4.9%). The C + R group had more serious side effects (47.2%) than the R group (18.5%). And 2% of C + R patients had a grade 5 side effects (the most serious) versus 0.7% in the R group.

Given the way things are described in this presentation, it seems like the Copanlisib + Rituxan combination is probably going to be marketed as a treatment for patients who have already tried at least a couple of other more aggressive treatments, especially those who might not physically be able to handle something more aggressive and harder on the body. The makers of Copanlisib filed for FDA approval for relapsed indolent NHL (including FL), so if it is approved, it would cover a wider range than the one I mention. But that seems to be what it's being aimed at. (They are also seeking approval from the European Medicines Agency, but only for Marginal Zone Lymphoma, not FL -- not sure why.)

As I said, this was one of many presentations on inhibitors. I'm sure we'll see more approval applications for them in the months and years to come.