In short videos with accompanying text, Dr. Brian Koffman, the Executive Vice President (EVP) and Chief Medical Officer (CMO) of the CLL Society, takes us through his “Top 12” abstracts from ASCO or the American Society of Clinical Oncology Annual Meeting held virtually in May, 2020.
#7
ASCO 2020: Tolerability and durable responses of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies
In my ASH interview with Dr. Pagel, we shared the rationale behind an intermittent dosing schedule to lower the toxicity and allow patients to enjoy the benefits for longer of ME-401, a PI3Kδ inhibitor that is a potentially potent agent in chronic lymphocytic leukemia.
The intermittent schedule was devised to avoid the problems with long term daily use of PI3Kδ inhibitors that can lead to serious adverse events including auto-immune problems. These events usually don’t become problematic until months after starting the medication. Therefore, the intermittent schedule chosen for this trial was “ME-401 at 60 mg/day for two 28-day cycles, followed by 7 days of therapy every 28-day cycle until disease progression or intolerance. Pts received ME-401 monotherapy (n = 21) or a combination with rituximab (n = 36) given at 375 mg/m2 for 8 doses in Cycles 1-6.”
While this trial looked at several types of slow growing or indolent lymphomas, we will focus mostly on the updated data on the 10 CLL patients who received ME-401 with or without the monoclonal antibody rituximab.
Takeaways:
- When looking at all 57 patients in the trial, the serious adverse events commonly seen with other PI3Kδ inhibitors were relatively rare, perhaps due to the intermittent dosing, with only 2 patients with severe diarrhea, 2 with colitis, 1 with a severe rash, 1 with non-infectious inflammation of the lungs, and 1 with significantly elevated liver enzymes.
- The overall response rate (ORR) in CLL was 89%, with 1 patient reaching a complete response (CR) when ME-401 was combined with rituximab. Responses seem durable, but the numbers are too small for any accurate predictions.
Conclusions:
This innovative dosing scheduling may make it possible to maintain the efficacy while limiting the toxicities of ME-401.
The next question is, could the same regimen work with other PI3Kδ inhibitors such as the two already approved in CLL, namely duvelisib and idelalisib?
The P13Kδ inhibitors block the B cell receptor (BCR) just like the better known BTK inhibitors, ibrutinib and acalabrutinib. However, they have been largely sidelined due to the great success of the BTK inhibitors and venetoclax and due to their toxicities with long term daily use.
Intermittent dosing with ME-401 may be clearing a path for these P13δ inhibitors to better add to our therapy options in managing CLL.
Stay strong. We are all in this together.
Brian
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
