Parsaclisib Displays Efficacy in Relapsed/Refractory MCL

Treatment with the PI3Kδ inhibitor parsaclisib led to responses with a manageable safety profile in patients with relapsed/refractory mantle cell lymphoma (MCL), according to findings from the phase 2 CITADEL-205 trial (NCT03235544) published in eClinicalMedicine.¹

At the January 15, 2021, data cutoff, patients who were BTK inhibitor naïve who received daily parsaclisib monotherapy (n = 77) experienced an objective response rate (ORR) of 70.1% (95% CI, 58.6%-80.0%), including a 15.6% (95% CI, 8.3%-25.6%) complete response (CR) rate, and a median duration of response (DOR) of 12.1 months (95% CI, 9.0-not evaluable [NE]) by independent review committee (IRC). BTK inhibitor–naïve patients who received the agent on a weekly basis (n = 31) achieved an ORR of 64.5% (95% CI, 45.4%-80.8%), with a CR rate of 22.6% (95% CI, 9.6%-41.1%).

The ORR among all BTK inhibitor–naïve patients (n = 108) was68.5% (95% CI, 58.9%-77.1%), with a CR rate of 17.6% (95% CI, 10.9%-26.1%). Notably, CITADEL-205 also included a cohort of patients who previously received the BTK inhibitor ibrutinib (Imbruvica; n = 53), however, enrollment to this cohort was subsequently closed after findings from an interim analysis showed that parsaclisib conferred limited clinical benefit. The ORR by IRC in the BTK inhibitor–experienced cohort was 30.2% (95% CI, 18.3%-44.3%), with 1 patient achieving a CR.

“Data from our study suggest that although parsaclisib demonstrated limited clinical benefit in patients who had previously received BTK inhibitor treatment, patients without prior BTK therapy achieve rapid and durable responses indicating that parsaclisib may provide an effective treatment option for this patient population,” study authors wrote.

Parsaclisib in combination with ruxolitinib (Jakafi) was previously under evaluation for the treatment of patients with myelofibrosis in the phase 3 LIMBER-304 trial (NCT04551053). However, the study was discontinued after findings from a preplanned interim analysis showed that it was unlikely to meet its primary end point of targeted reduction in spleen volume in the intent-to-treat population. The agent’s manufacturer noted that the decision was not due to safety concerns.²

CITADEL-205 was a multicenter, open-label study that enrolled adult patients with relapsed/refractory MCL who displayed overexpression of cyclin D1 or translocation (11;14). Eligible patients needed to have received 1 to 3 prior lines of treatment for MCL and experienced documented failure after attaining a minimum of a partial response (PR), have an ECOG performance status of 2 or less, and adequate hematological, hepatic, and renal function. Those with a history of central nervous system lymphoma, had previously received a PI3Kδ or pan-PI3K inhibitor, or had undergone allogenic stem cell transplantation within 6 months or autologous stem cell transplantation within 3 months were excluded from the study.¹

Investigators planned to randomly assign patients in a 1:1 fashion to receive either 20 mg of oral parsaclisib once daily for 8 weeks followed by 20 mg once weekly (weekly dosing group) or oral parsaclisib at a dose of 20 mg daily for 8 weeks followed by 2.5 mg daily. After examining initial safety and efficacy results from this trial and others, the daily dosing schedule was selected by investigators for additional study. Patients in both the BTK inhibitor–naïve and –experienced cohorts were allocated to the daily dosing group; those in the weekly dosing group were allowed to switch regimens or continue with the weekly dosing schedule. Treatment with parsaclisib continued until disease progression, death, unacceptable toxicity, or withdrawal.

The primary end point was ORR. Secondary end points included CR rate by IRC, best percentage change in target lesion size from baseline, duration of response (DOR) by IRC, progression-free survival (PFS) by IRC, overall survival (OS), and safety and tolerability. Blood biomarkers at baseline and on-treatment were also profiled as an exploratory end point.

At baseline, the median age in the overall population was 72.0 years (range, 43-90), with 78.7% of patients being at least 65 years old. Most patients were White (81.5%), male (79.6%), had an ECOG performance status of 0 (58.3%), had Mantle Cell Lymphoma International Prognostic Index high-risk disease (55.2%), and had Ann Arbor stage IV disease (63.9%). The median time to diagnosis was 3.6 years (range, 0.1-20.9).

The median number of previous lines of therapy was 1.0 (range, 1-3). Patients previously were treated with anti-CD20 monoclonal antibodies (97.2%), nitrogen mustard analogues (95.4%), vinca alkaloids and analogs (72.2%), anthracyclines and related substances (69.4%), and glucocorticoids (68.5%). Fifty percent of patients relapsed following treatment with their most recent therapy, 43.5% were refractory, and 6.5% had an unknown response.

Additional findings from the study revealed that stable disease was the best overall response in 20.8% of patients in the BTK inhibitor–naïve daily dosing group. Three patients experienced progressive disease and 4 patients were not assessed. The investigator-assessed objective response and CR rates in this cohort were 81.8% (95% CI, 71.4%-89.7%) and 27.3% (95% CI 17.7%-38.6%), respectively.

Patients in the BTK inhibitor–naïve daily dosing group with evaluable tumors at baseline and at least 1 post baseline assessment (n = 69) achieved tumor regression at a rate of 95.7%, with 84.8%(n = 56/66) achieving a reduction in target lesion size from baseline above 50%. By IRC assessment, the median change from baseline in target lesion size was -75.1% (range, –100.0%-73.0%). The median time to response for patients with a CR or PR was 8.1 weeks, with 88.9%(n = 48/54) experiencing a response by the time of the first planned assessment at week 8.

The median PFS in the daily dosing group was13.6 months (95% CI, 10.0-16.9); the estimated 6- and 12-month PFS rates were 69.0% (95% CI, 56.5%-78.6%) and 52.1% (95% CI 38.6%-64.0%), respectively. The median OS was not yet reached, however, the estimated 6- and 12-month OS rates were 89.4% (95% CI, 79.8%-94.5%) and 78.5% (95% CI, 67.3%-86.2%), respectively.

Regarding safety, all treated patients in the BTK inhibitor–naïve cohort experienced any grade treatment-emergent adverse effects (TEAEs) at a rate of 90.7%, including 62.0% who suffered a grade 3 or worse TEAE. The most common any grade TEAEs were diarrhea (34.3%), pyrexia (17.6%), and constipation (13.0%). Grade 3 or higher TEAEs included diarrhea (13.9%), neutropenia (8.3%), hypokalemia (3.7%), and colitis (3.7%). Serious TEAEs (42.6%), parsaclisib discontinuation due to TEAEs (25.0%), and treatment-related TEAEs (66.7%) were all present.

In the BTK inhibitor–naïve daily dosing group, any grade TEAES and grade 3 or higher TEAEs occurred at rates of 89.6% and 63.6%, respectively. The most common any grade TEAEs were diarrhea (40.3%), pyrexia (16.9%), and constipation (14.3%). All 8 fatal TEAEs occurred in the daily dosing group, with 3 being reported in the same patient for a total of 5 deaths.

At data cutoff, 3 BTK inhibitor–experienced patients remained on treatment, all in the daily dosing group. Nine BTK inhibitor-naïve patients remained on treatment in the weekly dosing group and 21 were still being treated in the daily dosing group.

“Considering that the treatment landscape for relapsed/refractory MCL has moved increasingly to the use of BTK inhibitors as the preferred second-line therapy, the role of PI3K inhibitors, including parsaclisib, in the treatment of [patients with] relapsed/refractory MCL, [requires] further investigation,” investigators wrote in conclusion.

References

1. Zinzani PL, Trněný M, Ribrag V, et al. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory mantle cell lymphoma (CITADEL-205): a phase 2 study. EClinicalMedicine. Published online August 10, 2023. doi:10.1016/j.eclinm.2023.102131
2. Incyte provides update on interim analysis of phase 3 LIMBER-304 study of parsaclisib and ruxolitinib in patients with myelofibrosis. News release. Incyte. March 3, 2023. Accessed September 1, 2023. https://investor.incyte.com/news-releases/news-release-details/incyte-provides-update-interim-analysis-phase-3-limber-304-study