CHICAGO—Updated data presented at the 2019 ASCO Annual Meeting from a phase Ib study of investigational ME-401, a selective oral inhibitor of PI3Kδ, demonstrated an 80 percent overall response rate in patients with relapsed or refractory (r/r) follicular lymphoma (FL) (n=50) (Abstract 7512).
Additionally, the data demonstrated comparable overall response rates, ranging from 75 percent to 83 percent, across patient groups receiving ME-401 as a monotherapy or in combination with rituximab, and in patient groups dosed with ME-401 once daily on a continuous schedule (CS) or on an intermittent schedule (IS) of once daily for the first 7 days of a 28-day cycle after 2 months of continuous dosing.
In addition, the research showed a lower rate of delayed, grade 3 adverse events (e.g., 8.7% diarrhea/colitis for IS dosing) observed in patients in the IS group, as well as durable responses in both CS and IS groups with no median yet reached.
“ME-401 is a second-generation PI3K inhibitor specific for the delta isoform that has excellent activity in CLL and FL,” noted Andrew D. Zelenetz, MD, PhD, principal investigator of the phase Ib study and Professor of Medicine at Weill Cornell Medical College, Medical Director of Quality Informatics at Memorial Sloan Kettering Cancer Center, and Chair of the National Comprehensive Cancer Network's Non-Hodgkin Lymphoma Guideline Panel. “This class of drugs has been associated with immune-related toxicities that are also seen with ME-401 dosed continuously.”
“However, we explored a novel dosing strategy with intermittent drug exposure (1 week on, 3 weeks off) that appears to markedly reduce toxicity and maintain efficacy. If validated, this could expand the role of PI3K in B-cell malignancies. A prospective randomized phase II trial is underway comparing intermittent to continuous dosing aiming to confirm these preliminary findings.”
A global phase II study has been initiated to evaluate the efficacy, safety, and tolerability of ME-401 as a single agent in patients with follicular lymphoma after failure of at least two prior systemic therapies, including chemotherapy and an anti-CD20 antibody. This study, now labeled the TIDAL study (Trials of PI3K DeltA in Non-Hodgkin's Lymphoma), is intended to support an accelerated approval marketing application with the FDA.
ME-401 Phase Ib Clinical Study
The ongoing phase Ib clinical study is evaluating ME-401 as a monotherapy and in combination with rituximab or with zanubrutinib in patients with r/r B-cell malignancies. Over 85 patients have been enrolled to date, including 54 patients with r/r FL reported on in the ASCO 2019 poster. Sixty-five percent (35/54) of r/r FL patients had two or more prior lines of therapy. Of the 50 evaluable r/r FL patients, 52 percent (26/50) were a group of FL patients with progression of disease within 24 months (POD24) of initial immunochemotherapy, which typically have a poor prognosis compared to other r/r FL patients.
ME-401 was administered once daily at 60 mg for 2 28-day cycles and then on an intermittent schedule of once-daily dosing for the first 7 days of each subsequent 28-day cycle (i.e., the intermittent schedule or IS). A previous cohort of monotherapy patients in the study was treated with ME-401 administered continuously once daily or were switched to the intermittent schedule in later cycles.
The overall response rate in patients with r/r FL was 80 percent (40/50), with 20 percent (10/50) achieving a complete response. Patients receiving monotherapy achieved a 79 percent (30/38) overall response rate and patients receiving ME-401 in combination with rituximab achieved an 83 percent (10/12) overall response rate. The group of patients receiving IS dosing achieved a 75 percent (15/20) overall response rate and patients receiving the CS dosing achieved an 83 percent (25/30) overall response rate. The response rate among POD24 patients was 92 percent (24/26).
The majority of responses, 88 percent (35/40), had an objective response by the first 2 treatment cycles and the achieved responses, to date, are durable; neither median duration of response nor median progression-free survival has been reached. Median follow-up for duration of response in the IS group is 8.8 months (range: 1.9-15.5) and 8.3 months in the CS group (range: 3.0-25.8). Median follow-up for progression-free survival is 5.5 months in the IS group (range: 0.9-15.5) and 6.5 months in the CS group (range: 0.9-25.8). Four patients in the IS group and two patients in the CS group that were switched to IS dosing experienced progressive disease and reverted to CS dosing to continue treatment.
ME-401 was generally well-tolerated and no grade 4 or grade 5 adverse events have been observed in the phase Ib study. Among drug-related grade 3 adverse events of special interest, the most common are diarrhea/colitis at 8.7 percent (2/23) on IS dosing and 16.1 percent (5/31) on CS dosing, and rash with none on IS dosing and 12.9 percent (4/31) on CS dosing. Four patients, each on the continuous schedule, discontinued due to an adverse event.
The rate of the development of delayed, grade 3 adverse events was improved in patients on the intermittent dosing schedule. There were no isolated grade 3 elevations in ALT and AST; such elevations were transient and in each case were associated with grade 3 diarrhea or rash.