Parsaclisib, a potent, highly selective, next-generation PI3KÎ´ inhibitor, has demonstrated activity and an acceptable safety profile in patients with relapsed / naive mantle cell lymphoma-refractory Bruton’s tyrosine kinase inhibitor.
Parsaclisib, a potent, highly selective, next-generation PI3KÎ´ inhibitor, has demonstrated activity and an acceptable safety profile in patients with tyrosine kinase inhibitor (BTK) naÃ¯ve mantle cell lymphoma (MCL) by relapse / refractory of Bruton. Results of the primary analysis of the CITADEL-205 phase 2 study (NCT03235544) presented at the 2021 ASH Annual Meeting and Exhibition.1
Results showed that patients in the daily dose group (n = 77) achieved an objective response rate (ORR) of 70.1% (95% CI, 58.6% to 80.0%); 16% of responses were complete responses (CR). The median duration of response (DOR) among the 54 responders in this group was 12.1 months (95% CI, 9.0 – not estimable [NE]). The median progression-free survival (PFS) of the daily dose group was 13.6 months (95% CI, 10.0-16.9).
Patients in this cohort received 20 mg of pasaclisib once daily for 8 weeks, followed by 2.5 mg daily continuously.
“Parsaclisib was structurally engineered to optimize both selectivity and potency, and to avoid hepatotoxicity associated with first generation PI3K inhibitors,” said Amitkumar Mehta, MD, associate director of the scholarship program in hematology and oncology and associate professor of medicine at the University of Alabama at Birmingham. âParsaclisib has more than 10,000 times the selectivity for PI3KÎ´ isoforms [compared with] the Î±, Î² and isoforms.
CITADEL-205 enrolled a total of 108 adult patients with relapsed / refractory MCL to BTK inhibitors who had received 1 to 3 previous systemic treatments. Eligible patients had to have an ECOG performance index of 2 or less and documented cyclin D1 overexpression or t (11:14) translocation. No prior PI3K or BTK inhibitors were permitted.
The study allocated patients in a 1: 1 fashion to either the daily dosing group or the weekly dosing group (n = 31). The weekly dose group received 20 mg of parsaclisib once daily for 8 weeks, followed by 20 mg once weekly. The data cut-off date for the main analysis was June 15, 2021. Following an interim analysis, the daily dosage was the recommended dose and the recruitment into the weekly cohort was closed.
The primary endpoint of the trial was ORR. Secondary endpoints included ORD, PFS, overall survival (OS), complete response rate (CRR), best percent change in target lesion size from baseline, and safety / tolerability. Response was assessed by computed tomography / MRI using the Lugano criteria, radiology-based endpoints were determined by an independent review committee, and adverse events (AEs) were assessed at the CTCAE v4.03 help. Data presented at the meeting included all treated patients in the daily dose group and those who went from 20 mg once weekly to 2.5 mg once daily.
The median age of the daily dosing cohort was 72.0 years (range, 51-90) and 78% of patients in this group were males. The median time from diagnosis of MCL was 3.5 years (range: 0.1-16.9) and almost all (95%) of the patients had an ECOG performance index of 1 or less. Patients had a median of 1 (range, 1-3) prior lines of treatment and 54.5% had a high-risk MIPI score.
The median duration of treatment was 7.9 months (range, 1.7-27.4) in the daily dose group versus 8.3 months (range, 0.1-30.0) among all treated patients in the study (n = 108). The median length of follow-up was 18.2 months (range, 11.6-35.9) and 22.9 months (range, 11.6-35.9), respectively. Most patients (73%) in the daily dose group discontinued treatment for reasons such as disease progression (39%), AE (30%), decision to withdraw / doctor (3 %) and death (1%).
The ORR among all treated patients was 68.5% (95% CI, 58.9% -77.1%), including a CR rate of 18%. Nineteen percent of all treated patients achieved stable disease. Most (89%) of responders experienced their first response at the first assessment for disease (8 weeks). Evaluable patients (n = 94) regressed to target legions at a rate of 96%, and 84% of these patients experienced a greater than 50% reduction in best percent change from baseline.
Among all responders (n = 74), the median DOR was 13.7 months (95% CI, 9.0-19.9). All treated patients had a median PFS of 12.0 months (95% CI: 8.3-16.9).
Median overall survival (OS) was not achieved (NR; 95% CI, 25.6-NE) ââin all treated patients and was also NR (95% CI, 24.4-NE) in the daily treatment group. There were 31 and 20 reported deaths among all treated patients and the daily treatment group, respectively. The rates of OS at 6 months were 90% (95% CI, 80% to 90%) and 90% (95% CI, 80 to 95%), respectively. Both groups had an 80% 12-month survival rate (95% CI, 70% to 90%).
In terms of safety, treatment-emergent AEs (ADRs) of any grade occurred in 91% of all treated patients versus 90% in the daily dose group. Grade 3 or greater ATEs were present in 62% and 64% of all patients and in the daily dose group, respectively. Common side effects of any grade in the daily dose group were diarrhea (40%), pyrexia (17%), constipation (14%), and asthenia (13%).
Serious ATEs occurred in 43.0% and 45.5% of all treated patients and in the daily dose group, respectively. Serious ADEs in the daily administration arm included diarrhea (13%), colitis (6.5%), hypokalemia, pyrexia, and rash (all 3%). Only one death occurred due to TIA, the death was attributed by the investigator to treatment with parsaclisib.
ADEs resulted in dose interruptions in 47% and 51% of all treated patients and in the daily treatment group, respectively. Dose reduction (8% vs. 9%) and discontinuation (25% vs. 30%) were not as frequent. The median time to onset of grade 3 or greater diarrhea among the 14 patients who experienced it as an ADE was 4.3 months (range 1.0-11.0); events improved to grade 2 or less within a median of 11.0 days (95% CI, 5.0-25.0).
Common hematologic adverse reactions of any grade in all treated patients were decreased neutrophil count (54%), decreased platelet count (33%), decreased hemoglobin (31.5%), an increase in alanine aminotransferase (31%) and an increase in aspartate transaminase (26%). Hematologic TIE rates were similar in the daily dose group: 61%, 32.5%, 32.5%, 31%, and 25%, respectively.
âParsaclisib represents a potential new treatment option for relapsed / refractory MCL to naive BTK inhibitors,â Mehta said.
- Mehta A, TrnÄnÃ½ M, Walewski J, et al. Efficacy and safety of parsaclisib in patients with relapsed or refractory mantle cell lymphoma not previously treated with a BTK inhibitor: primary analysis of a phase 2 study (CITADEL-205) Document presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 382.