Parsaclisib Leads to Significant ORR in R/R MCL Without Prior BTK Exposure

Patients with relapsed or refractory mantle cell lymphoma (MCL) treated with a daily dose of parsaclisib demonstrated significant activity and tolerability for the next-generation PI3Kδ inhibitor, according to findings from the phase 2 CITADEL-205 trial (NCT03235544).^1,2

Findings presented during the 2020 American Society of Hematology (ASH) Annual Meeting from the 2 cohorts of the study showed that patients who had not received prior treatment with a Bruton tyrosine kinase (BTK) inhibitor showed a higher response rate than patients who had prior exposure to BTK inhibition.

“Parsaclisib represents a potentially new treatment option for BTK inhibitor–naïve relapsed/refractory mantle cell lymphoma and a first-in-class PI3Kδ inhibitor for this patient population,” Amitkumar Mehta, MD, said during one of the ASH poster presentations for the trial.

The open-label, multicenter CITADEL-205 study consisted of 2 cohorts to evaluate the safety and efficacy of parsaclisib in both patients who had and had not been previously exposed to a BTK inhibitor.

In cohort 1, 53 patients who had previously received treatment with ibrutinib (Imbruvica) among 1 to 3 prior systemic therapies were evenly allocated to receive either a weekly or daily regimen of parsaclisib.² Cohort 2 included 108 patients who were BTK inhibitor–naïve but had received 1 to 3 prior systemic therapies, and these patients were also allocated to either a weekly or daily regimen of parsaclisib.1 All patients had an ECOG performance status of 0 to 2 and cyclin D1 overexpression or t(11;14) translocation.

Treatment with parsaclisib was administered at 20 mg once daily for 8 weekly followed by either 2.5 mg once daily given continuously or 20 mg given once weekly.

The daily regimen was selected during the course of the study as the preferred dosing regimen, and patients in the weekly group were allowed to switch to daily administration.

Objective response rate (ORR) was the primary end point for the study and secondary end points included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival, target lesion size change from baseline, safety and tolerability, and other radiology-based end points per the independent review committee (IRC).

Analyses presented at ASH in 2 poster presentations covered each cohort separately, including the total population of the cohort as well as for all patients who received the daily dose, including crossover.

Parsaclisib Without Prior BTK Exposure

Overall in cohort 2, the median age was 72 years (range, 43-90) and 80% of the participants were male. The majority of patients had Ann Arbor stage III to IV disease (73%), an ECOG performance status of 0 or 1 (93%), and high-risk disease by Mantle Cell Lymphoma International Prognostic Index (MIPI; 55%). Forty-four percent of patients were refractory to their most recent therapy and 31% had undergone prior hematopoietic stem cell transplantation. The median number of prior systemic therapies was 1 (range, 1-3).

A total of 77 patients were treated with the daily dose, including 31 who crossed over from the weekly dose group. These patients had similar baseline characteristics to the overall population.

As of data cutoff on July 13, 2020, 36% of patients were continuing treatment, including 35% of the daily group. Forty percent had discontinued due to progressive disease and 21% due to adverse events. The median duration of treatment was 7.3 months (range, 0.1-25.0) and the median duration of follow-up was 16.8 months (range, 5.5-29.8).

The ORR in the total population of cohort 2 by IRC was 70% (95% CI, 61%-79%) with CRs in 15% and partial responses (PRs) in 56%; 18% of patients had stable disease (SD). Four percent of patients had progressive disease, 5% were not evaluable, and 4% were not yet assessed.

In the daily-dose group, the ORR was 71% (95% CI, 60%-81%), consisting of CRs in 12% and PRs in 60%; 20% of patients had SD. Eighty-seven percent of responses occurred by the time of the first assessment. Four percent had progressive disease in the daily group and 5% were not evaluable.

By investigator assessment, the ORRs were 79% and 81% in the overall and daily dose populations, respectively.

“Parsaclisib demonstrated excellent activity in relapsed/refractory mantle cell lymphoma,” said Mehta, who is an associate professor at the University of Alabama at Birmingham Comprehensive Cancer Center.

Eighty-four percent of all treated patients and 87% of the daily-dose group had regression of their target lesions by IRC assessment.

The median DOR was 14.7 months (95% CI, 7.7-not evaluable [NE] in the overall group and 9.0 months (95% CI, 6.7-14.7) in the daily group.

The median PFS was 11.1 months in both the overall and daily group populations. The median OS was not reached in either population as of data cutoff. At 12 months, the OS rate was 77% for the overall group and 76% for the daily-dose group, and at 18 months the rates were 69% and 68%, respectively.

Treatment-emergent adverse events (TEAEs) were observed in 87% of all treated patients in cohort 2, including most frequently diarrhea (31%), pyrexia (18%), constipation (14%), asthenia (11%), and neutropenia (11%). Grade ≥3 TEAEs were reported in 57% of patients, including diarrhea in 13% and neutropenia in 8%.

New or worsening laboratory values included any-grade neutrophil decrease in 51%, alanine aminotransferase (ALT) elevation in 30%, and aspartate aminotransferase (AST) elevation in 24%. Neutrophil decrease was the only grade 4 event reported and there were 5 grade 4 events.

Serious TEAEs were observed in 39% of patients and included diarrhea 9%, colitis in 4%, hypokalemia in 4%, and pyrexia in 3%. Two deaths reported on the study were due to TEAEs including 1 patient who had leukocytosis, acute kidney injury, and AML, which was attributed to treatment by the investigator, and the second patient had endocarditis staphylococcal and septic shock, but neither of these events were considered related to parsaclisib.

TEAEs led to dose interruption in 41%, dose reduction in 5%, and treatment discontinuation in 22%. Fourteen of the 24 patient treatment discontinuations were due to diarrhea/colitis events. The median time to onset of grade 3 or higher diarrhea/colitis was .9 months and it took a median of 11.0 days for the event to improve to grade 2 or less.

“Treatment with parsaclisib had an acceptable safety profile that was generally well tolerated,” Mehta said.

Parsaclisib After BTK Inhibition

In cohort 1, 41 patients received the daily dose, including 12 patients who crossed over from the weekly dose group.

The median age of all patients in cohort 1 was 71 years (range, 48-89) and 77% were male. The majority of patients had Ann Arbor stage III to IV disease (81%), ECOG performance status of 0 or 1 (89%), and a high-risk MIPI score (55%).

Patients had received a median of 3 prior therapies in the cohort (range, 1-3) with 43% refractory to their last therapy; 36% of patients had undergone prior hematopoietic stem cell transplantation.

Parsaclisib was received for a median of 2.8 months (range, 0.1-19.6) and the median duration of follow-up was 14.0 months (range, 2.3-31.7). As of data cutoff, 5 patients (95%) were continuing treatment with 75% discontinuing due to disease progression and 8% due to adverse events.

The ORR was 25% (95% CI, 14%-38%) in the overall cohort by IRC, consisting of CRs in 2% and PRs in 23%; SD was reported in 19%. Progressive disease was reported in 21% but 4% were not evaluable and 32% had no post-baseline response data available yet.

In the daily group, the ORR was 29% (95% CI, 16%-46%) with CRs in 2% and PRs in 27%. Seventeen percent of patients had SD. Progressive disease was reported in 24%, 2% were not evaluable, and 27% had no response data available.

By investigator assessment, the ORRs were 36% and 44% in the overall and daily group populations, with CRs in 8% and 10%, respectively.

From baseline, 47% of patients in the cohort and 51% who received the daily dose of parsaclisib had tumor regressions in their target lesions.

The median PFS and DOR were both 3.7 months for both the daily group and the overall population of patients. Median OS was 11.2 months in both groups. At 1 year, the OS rate was 50% for all patients in the cohort and 49% for those who received the daily regimen, and at 18 months the OS rates were 32% and 37%, respectively.

“Parsaclisib demonstrated clinical activity in relapsed/refractory mantle cell [lymphoma] previously treated with ibrutinib,” Pier Luigi Zinzani, MD, PhD, of the Institute of Hematology and Medical Oncology at the University of Bologna in Italy, said during a presentation of the cohort findings.

Similar to the BTK inhibitor–naïve cohort, TEAEs of any grade were observed in 83% of all patients, but with this group the most common events were diarrhea (23%), anemia (19%), asthenia (15), and neutropenia (15%). Grade ≥3 events were reported in 53% and included anemia in 11%, neutropenia in 8%, and diarrhea in 6%.

New or worsening laboratory values included both ALT (15%) and AST (15%) elevation of any grade and neutrophil count decrease (32%), but also platelet decrease (21%) and hemoglobin decrease (40%) in the BTK-exposed population. Neutrophil decrease was again the only grade 4 event observed.

Serious TEAEs of any grade were reported in 43%, including most commonly diarrhea in 8% and pneumonia in 6%. TEAEs led to treatment interruption in 32%, reduction in 2%, and discontinuation in 9%. Three of the treatment discontinuations were due to diarrhea/colitis, which took a median of 7.1 months to develop at grade 3 severity or higher. Two deaths were reported in the cohort, including 1 patient with general health deterioration and respiratory tract infection and the other patient with dehydration and neutropenia; none of these events were attributed to treatment with parsaclisib.

_References:

_{1. Mehta A, Trnĕný M, Walewski J, et al. Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor (CITADEL-205). Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; Virtual. Abstract 1121.}

_{2. 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). Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; Virtual. Abstract 2044.}