FDA Considers Parsaclisib for Approval in FL, MZL, and MCL

The FDA has accepted a new drug application for the investigational PI3Kδ inhibitor, parsaclisib, for the treatment of patients with relapsed or refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL), according to a press release issued by the Incyte Corporation.¹

Priority review was granted to parsaclisib for the FL and MCL indications with a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2022. For the MZL indication, the FDA will conduct a standard review and the PDUFA data has been set to August 30, 2022.

Data from multiple clinical trials support the NDA, including the phase 2 CITADEL-203 (NCT03126019) trial, CITADEL-204 (NCT03144674), and CITADEL-205 (NCT03235544), which assessed the use of parsaclisib to treat relapsed or refractory non-Hodgkin lymphomas (NHLs). In all studies, the agent was well tolerated and had a manageable safety profile. Further, parsaclisib led to durable responses and showed survival benefit.

"Non-Hodgkin lymphomas are some of the most common cancers in the United States, and the FDA’s acceptance of this NDA represents an important milestone for Incyte and for NHL patients who have not responded to or who have progressed on initial therapies," said Peter Langmuir, MD, group vice president, Oncology Targeted Therapies, Incyte, in a press release. "We look forward to working with the FDA to bring this innovative therapy to patients who may benefit."

According to data presented during the 62nd American Society of Hematology Annual Meeting and Exposition, secondary end points explored across the 3 clinical trials included objective response rate (ORR); duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety/tolerability.²

In CITADEL-203, 118 patients with FL were treated with either the parsaclisib 20 mg once weekly (weekly dose) and 95 received parsaclisib 2.5 mg once daily (daily dose). The ORR observed in the daily dose cohort was 75% (95% CI, 65%-83%) compared with 73% (95% CI, 64%-81%) in the weekly dose cohort. The median DOR observed with the daily dose of parsaclisib was 14.7 months (95% CI, 12.0-17.5) compared with 15.9 months (95% CI, 12.0-NE) in the weekly dose cohort. In terms of survival, the median PFS observed with daily dosed parsaclisib was 15.8 months (95% CI, 13.8-19.1) versus 15.8 months (95% CI, 13.2-19.3) with the weekly dose. OS data had not reached maturity at the time of the analysis.^2,3

One-hundred six patients from the study were evaluable for safety. The most common treatment-emergent adverse events (TEAEs) observed were diarrhea (27.4% of patients), nausea (22.6%), cough (18.9%), and fatigue (15.1%).

Patients with MZL in the CITADEL-204 were also treated with either a weekly dose (n = 100) or a daily dose (n = 72). The ORR observed with the daily dose was 56.9% (95% CI, 44.7%-68.6%) compared 57.0% (95% CI, 46.7%-66.9%). The median DOR in the daily dose cohort was not reached (95% CI, 8.1 to not evaluable [NE]) versus 2.0 months (95% CI, 9.3-NE) in the weekly dose cohort. The median PFS was not reached (11.0-NE) with daily parsaclisib compared with 19.4 months (95% CI, 13.7-NE) with the weekly dose. OS data were not mature.^2,4

Safety assessed in 99 patients from the CITADEL-204 study showed that the most common TEAEs were diarrhea (36.4% of patients), cough (18.2%), and rash (14.1%).⁴

Finally, patients with MCL treated in the CITADEL-205 study were categorized based on whether they were naïve to treatment with a Bruton’s tyrosine kinase inhibitor or they were previously treated with ibrutinib (Imbruvica). In the treatment-naïve group, 77 patients received daily parsaclisib and 108 received the weekly dose. The ORR in the daily dose cohort was 71% (95% CI, 60%-81%) compared with 70% (95% CI, 61%-79%) with the weekly dose. The median DOR with daily parsaclisib was 9.0 months (95% CI, 6.7-14.7) versus 14.7 months (7.7-NE) with weekly parsaclisib. The median PFS with daily parsaclisib was 11.1 months (95% CI, 8.3-NE) compared with 11.1 months (95% CI, 8.3-19.2) with the weekly dose of parsaclisib. OS was not reached at either dosing schedule.^2,5

In the ibrutinib pretreated group, 41 patients received daily parsaclisib and 53 patients received weekly therapy. The ORR observed with the daily dose was 29% (95% CI, 16%-46%) compared with 25% (95% CI, 14%-38%) at the weekly dose. The median DOR observed was 3.7 months (95% CI, 1.9-NE) with daily parsaclisib versus 3.7 months (95% CI, 1.9-NE) with weekly parsaclisib.

In terms of survival in the previously treated CITADEL-205 population, treatment with daily parsaclisib showed a median PFS of 3.7 months (95% CI, 1.8-4.1) compared with 3.7 months (95% CI, 1.8-3.9) with the weekly dose. The median OS was 11.2 months (95% CI, 7.9-NE) with daily treatment compared with 11.2 months (95% CI, 7.9-17.1) with weekly treatment.

Safety evaluated in 47 patients from CITADEL-205 showed that the most common TEAEs were anemia (19.1%), diarrhea (19.1%), neutropenia (14.9%), asthenia and cough (12.8% each), decreased appetite, dyspnea, fatigue, pyrexia and rash (10.6% each).⁵

Following results from these 3 studies, daily dosing was chosen as the preferred dosing schedule for parsaclisib in relapsed or refractory NHLs.²

_References:

_{1. Incyte announces acceptance of NDA for parsaclisib for three types of relapsed or refractory non-Hodgkin lymphomas. News release. November 1, 2021. Accessed November 1, 2021. https://bit.ly/3Bu2QDj}

_{2. Incyte announces parsaclisib treatment results in high rate of rapid and durable responses in patients with relapsed or refractory b-cell non-hodgkin lymphomas. News release. December 7, 2021. Accessed November 1, 2021. https://bit.ly/3BGalHq}

_{3. Lynch RC, Paneesha S, Avigdor A, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory follicular lymphoma (CITADEL-203). Blood. 2020;136(suppl 1): 36-37. doi: 10.1182/blood-2020-134869}

_{4. Phillips TJ, Corradini P, Gurion C, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory marginal zone lymphoma (CITADEL-204). Blood. 2020;136(suppl 1):27-28. doi: 10.1182/blood-2020-134451}

_{5. Zinzani PL, Delwail V. Paneesha S, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory mantle cell lymphoma previously treated with ibrutinib (CITADEL-205). Blood. 2020;136(suppl 1): 43-44. doi: 10.1182/blood-2020-134609}