Parsaclisib Elicits Impressive Activity in Relapsed/Refractory MCL

The potent, highly selective, next-generation PI3Kδ inhibitor parsaclisib demonstrated activity and an acceptable safety profile in patients with Bruton tyrosine kinase (BTK) inhibitor-naïve relapsed/refractory mantle cell lymphoma (MCL). Findings from the primary analysis of the phase 2 CITADEL-205 study (NCT03235544) presented during presented during the 2021 ASH Annual Meeting and Exposition.¹

Results showed that patients in the daily dosing group (n = 77) achieved an objective response rate (ORR) of 70.1% (95% CI, 58.6%-80.0%); 16% of responses were complete responses (CRs). 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 dosing group was 13.6 months (95% CI, 10.0-16.9).

Patients in this cohort received pasaclisib 20 mg once daily for 8 weeks followed by 2.5 mg daily continuously.

“Parsaclisib was structurally designed to optimize both selectivity and potency, and to avoid the hepatotoxicity associated with the early-generation PI3K inhibitors,” said Amitkumar Mehta, MD, the associate director of the hematology and oncology fellowship program and an associate professor of medicine at the University of Alabama Birmingham. “Parsaclisib has more than a 10,000-fold greater selectivity for the PI3Kδ isoforms [compared with] the α, β, and ϒ isoforms.”

CITADEL-205 enrolled a total of 108 adult patients with BTK inhibitor-naïve relapsed/refractory MCL who had previously received 1 to 3 prior systemic therapies. Eligible patients needed to have an ECOG performance status 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 manner to either the daily dosing group or the weekly dosing group (n = 31). The weekly dosing group received parsaclisib 20 mg once daily for 8 weeks followed by 20 mg once weekly. The data cutoff for the primary analysis was June 15, 2021. Following an interim analysis, daily dosing was the recommended dose and enrollment to the weekly cohort was closed.

The primary end point of the trial was ORR. Secondary end points included DOR, PFS, overall survival (OS), complete response rate (CRR), best percentage change in target lesion size from baseline, and safety/tolerability. Response was assessed by CT/MRI using Lugano criteria, radiology-based end points were determined by an independent review committee, and adverse events (AEs) were assessed using CTCAE v4.03. Data presented at the meeting included all treated patients in the daily dosing group and those who crossed over from 20 mg once weekly to 2.5 mg one daily.

The median age of the daily dosing cohort was 72.0 years (range, 51-90) and 78% of patients in this group were men. The median time since MCL diagnosis was 3.5 years (range, 0.1-16.9) and nearly all (95%) of patients had an ECOG performance status of 1 or less. Patients had a median of 1 (range, 1-3) prior lines of therapy 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 dosing group vs 8.3 months (range, 0.1-30.0) among all patients treated in the study (n = 108). The median duration 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-dosing arm discontinued treatment for reasons including progressive disease (39%), AE (30%), withdrawal/physician decision (3%), and death (1%).

The ORR among all treated patients was 68.5% (95% CI, 58.9%-77.1%), including an 18% CR rate. Nineteen percent of all treated patients achieved stable disease. Most (89%) responders experienced their first response at the first disease assessment (8 weeks). Evaluable patients (n = 94) experienced regression at target legions at a rate of 96% and 84% of these patients had a greater than 50% reduction in best percentage change from baseline.

Among all responders (n = 74) the median DOR was 13.7 months (95% CI, 9.0-19.9). All treated patients experienced a median PFS of 12.0 months (95% CI, 8.3-16.9).

The median overall survival (OS) was not reached (NR; 95% CI, 25.6-NE) among all treated patients and was also NR (95% CI, 24.4-NE) in the daily dosing group. There were 31 and 20 deaths reported among all treated patients and the daily dosing group, respectively. The 6-month OS rates were 90% (95% CI, 80%-90%) and 90% (95% CI, 80%-95%), respectively. Both groups had a 12-month survival rate of 80% (95% CI, 70%-90%).

In terms of safety, treatment emergent AEs (TEAEs) of any grade occurred in 91% of all treated patients vs 90% in the daily dosing group. TEAEs grade 3 or greater were present in 62% and 64% of all patients and the daily dosing group, respectively. Common TEAEs of any grade in the daily dosing group consisted of diarrhea (40%), pyrexia (17%), constipation (14%), and asthenia (13%).

Serious TEAEs occurred in 43.0% and 45.5% of all treated patients and the daily dosing group, respectively. Serious TEAEs in the daily dosing arm included diarrhea (13%), colitis (6.5%), hypokalemia, pyrexia, and rash (all 3%). A single death occurred due to TEAEs, the death was attributed by the investigator to be related to treatment with parsaclisib.

TEAEs resulted in dose interruptions in 47% and 51% of all patients treated and the daily dosing group, respectively. Dose reduction (8% vs 9%) and discontinuation (25% vs 30%) were not as prevalent. The median time to onset of grade 3 or greater diarrhea among the 14 patients who experienced it as a TEAE was 4.3 months (range, 1.0-11.0); events improved to grade 2 or less in a median time of 11.0 days (95% CI, 5.0-25.0).

Common hematologic TEAEs of any grade among all patients treated were decreased neutrophil count (54%), decreased platelet count (33%), decreased hemoglobin (31.5%), alanine aminotransferase elevation (31%), and elevated aspartate transaminase (26%). The rates of hematologic TEAEs were similar in the daily dosing group: 61%, 32.5%, 32.5%, 31%, and 25%, respectively.

“Parsaclisib represents a potentially new treatment option for BTK inhibitor-naïve relapsed/refractory MCL,” said Mehta.

Reference

1. Mehta A, Trněný 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 from a phase 2 study (CITADEL-205) Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 382.