Incyte Withdraws NDA for Parsaclisib in Relapsed/Refractory Follicular Lymphoma, MZL, MCL

The global biopharmaceutical company Incyte has decided to withdraw the new drug application (NDA) for parsaclisib for the treatment of patients with relapsed or refractory follicular lymphoma, marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL).¹

The decision follows discussions with the FDA regarding the confirmatory studies needed to support the accelerated approval of the agent in these indications. The company determined that these studies cannot be completed within a period that would support the investment.

“The withdrawal of the NDA is a business decision and is not related to any changes in either the efficacy or safety of parsaclisib,” the company stated in an update. “The decision impacts only follicular lymphoma, MZL, and MCL indications in the United States, and does not affect other ongoing clinical trials in the United States or other countries.”

The application seeking the approval of the PI3Kδ inhibitor was supported by data from several phase 2 trials, including CITADEL-203 (NCT03126019), CITADEL-204 (NCT03144674), and CITADEL-205 (NCT03235544).

The multicenter, open-label CITADEL-203 trial enrolled adult patients with histologically confirmed relapsed/refractory follicular lymphoma (grade 1, 2, or 3a) who had previously received at least 2 systemic therapies, not including PI3K inhibitors or BTK inhibitors.²

Study participants were allocated 1:1 to receive parsaclisib at a once daily dose of 20 mg for 8 weeks followed by a once weekly dose of 20 mg (weekly dosing group) or a once-daily dose of parsaclisib at 20 mg for 8 weeks followed by a once daily dose of 2.5 mg continuously (daily dosing group).

Sixty-one percent of patients were at least 65 years of age, and 77.5% had stage III/IV disease. The median number of prior lines of therapy received was 2 (range, 1-8), and 49% were refractory to the most recent therapy they had received.

As of the data cutoff date of January 15, 2021, a total of 126 patients were enrolled to the trial and 103 patients comprised the daily dosing group. Results presented during the 2021 ASH Annual Meeting indicated that parsaclisib elicited an objective response rate (ORR) of 75.4% per independent review committee (IRC) assessment in all treated patients; in the daily-dosing subset, the ORR achieved with the agent was 77.7%.

The complete response (CR) rate in all treated patients was 18% vs 19% in those who comprised the daily dosing group. Per investigator assessment, the ORR was 74.6% in the all patients who received treatment, and 75.7% in the daily-dosing subset.

Ninety-five percent of all evaluable patients (n = 113/119) experienced tumor regression, with 86% of patients experiencing a reduction of greater than 50% in best percentage change in tumor size from baseline.

The median duration of response (DOR) in the daily-dosing subset was 14.7 months (95% CI, 12.0-17.5), and the median progression-free survival (PFS) was 15.8 months (95% CI, 11.0–not evaluable [NE]).

At cutoff, 31% of patients were still receiving treatment. The median duration of treatment was 8.5 months in all treated patients and 8.4 months in the daily-dosing subset; the median duration of follow-up was 20.6 months (range, 5.7-34.1) and 17.6 months (range, 5.7-33.1), respectively.

The most common TEAEs observed in all treated patients and in the daily-dosing subset were diarrhea (38% vs 44%, respectively), nausea (25% vs 24%), cough (22% vs 24%), fatigue (18% vs 18%), pyrexia (18% vs 19%), rash (16% vs 14%), neutropenia (14% vs 16%), asthenia (13% vs 14%), and arthralgia (10% vs 11%). The most frequent TEAEs that were grade 3 or higher included diarrhea (12% vs 14%) and neutropenia (10% vs 11%). Serious TEAEs included diarrhea (7% vs 9%) and colitis (6% vs 8%).

TEAEs resulted in 2 deaths, and they were determined by the investigator to be associated with parsaclisib; these included 1 case of Stevens-Johnson syndrome and 1 case of pneumonia.

Approximately 50% of patients required dose interruptions and the most common TEAEs that led to this were diarrhea (18%) and neutropenia (7%); diarrhea (12%) and rash (3%) were the most common TEAEs to result in dose reduction, which was needed in approximately 20% of all patients. The primary reasons for discontinuation included disease progression (36.5%) and toxicities (21.0%). The most common treatment-emergent adverse effects (TEAEs) that resulted in discontinuation were diarrhea (8%) and colitis (5%).

The open-label phase 2 CITADEL-204 trial enrolled patients who were at least 18 years of age, had a confirmed MZL histology, previously received at least 1 line of systemic therapy including anti-CD20 treatment, experienced either progressive disease or inadequate response to their most recent regimen, and have an ECOG performance status ranging from 0 to 2.³

A total of 100 patients were enrolled to the trial, which was comprised of 2 cohorts. Those in cohort 1 received ibrutinib (Imbruvica), but this cohort closed due to feasibility issues. Those in cohort 2 were naïve to BTK inhibitors. Those within the latter cohort were allocated 1:1 to receive the weekly dose of parsaclisib (n = 28) or the daily dose (n = 72).

The primary end point of the trial was ORR, and key secondary end points comprised CR rate, DOR, PFS, overall survival (OS), best percentage in disease burden from baseline, as well as safety and tolerability.

The median age of all patients was 71.0 years (range, 35-95); in the daily-dosing subset, the median age was 72.0 years (range, 35-95). Moreover, 53% of patients were male, and 95% had an ECOG performance status of 0 or 1. Regarding MZL subtype, 31% had nodal disease, 34% had extranodal disease, and 35% had splenic disease.

Results from cohort 2, which were presented during the 2021 ASH Annual Meeting, showed that parsaclisib produced an IRC-assessed ORR of 58.3% (95% CI, 46.1%-69.8%) and an investigator-assessed ORR of 69.4% in the daily-dosing subset, along with a median DOR of 12.2 months (95% CI, 8.1-17.5), and a median PFS of 16.5 months (95% CI, 11.5-20.6).

Among all patients who received treatment, the IRC-assessed ORR with the agent was 58.0% (95% CI, 47.7%-67.8%) and the investigator-assessed ORR was 72.0%. The median DOR was 12.2 months (95% CI, 8.1-17.5) and the median PFS was 16.5 months (95% CI, 13.5-19.6).

The median OS had not yet been reached. All evaluable patients (n = 81/81) experienced regression in the target lesions or spleen, and 83% experienced a reduction in best percentage change from baseline of over 50%.

Regarding safety, 97% of those in the daily-dosing subset experienced any-grade TEAEs, the most common of which included diarrhea (47%), cough (23%), and rash (18%). Grade 3 or higher TEAEs were experienced by 63% of patients, and the most frequently experienced toxicities included diarrhea (12.0%) and neutropenia (9.0%).

Fifty-six percent of all patients experienced toxicities that resulted in dose interruption and 16.0% had effects that required dose reductions; these rates were 60% and 17%, respectively, in the daily-dosing subset. In the latter group, diarrhea was the most common TEAE to lead to dose interruption (15%), reduction (7%), and discontinuation (12.5%).

Forty-seven percent of patients experienced serious AEs, the most common of which was pneumonia (9.0%). Six percent of patients had fatal TEAEs that were deemed to be related to parsaclisib; 1 death was from febrile neutropenia and the other death was from sepsis.

Lastly, the phase 2 CITADEL-205 trial enrolled a total of 108 patients with relapsed/refractory MCL who were naïve to BTK inhibitors and who had previously received 1 to 3 systemic therapies.⁴ Eligible patients needed to have an ECOG performance status of 0 to 2 and documented cyclin D1 overexpression or t(11:14) translocation. Patients could not have received prior PI3K or BTK inhibitors.

Study participants were allocated 1:1 to receive parsaclisib at a daily (n = 77) or weekly dose (n = 31). The primary end point of the trial was ORR, and secondary end points comprised DOR, PFS, OS, CR rate, best percentage change in target lesion size from baseline, along with safety and tolerability.

The median age in the daily-dosing subset was 72.0 years (range, 51-90) and 78% were male. The median time since diagnosis was 3.5 years (range, 0.1-16.9), and 95% had an ECOG performance status of 0 or 1. The median number of prior lines of therapy received was 1 (range, 1-3) and 54.5% had a high-risk MIPI score.

The data cutoff date for the primary analysis was June 15, 2021. The median duration of treatment was 7.9 months (range, 1.7-27.4) in the daily-dosing subset and 8.3 months (range, 0.1-30.0) in all patients. 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.

Data showed that in the daily-dosing subset, parsaclisib induced an ORR of 70.1% (95% CI, 58.6%-80.0%), with a CR rate of 16%. The median DOR was 12.1 months (95% CI, 9.0-NE), and the median PFS was 13.6 months (95% CI, 10.0-16.9). In all patients, the ORR was 68.5% (95% CI, 58.9%-77.1%), with a CR rate of 18%. In this population, the median DOR was 13.7 months (95% CI, 9.0-19.9) and the median PFS was 12.0 months (95% CI, 8.3-16.9).

The median OS was not reached in both all treated patients (95% CI, 25.6-NE) and in the daily-dosing subset (95% CI, 24.4-NE). Deaths were reported in 31 and 20 patients, respectively. The OS rates at 6 months were 90% (95% CI, 80%-90%) and 90% (95% CI, 80%-95%), respectively; the 12-month OS rate in both groups was 80% (95% CI, 70%-90%).

Ninety percent of all treated patients experienced TEAEs vs 90% of those in the daily-dosing group; grade 3 or higher TEAEs were reported in 62% and 64% of patients, respectively. Common any-grade TEAEs within the daily-dosing group were diarrhea (40%), pyrexia (17%), constipation (14%), and asthenia (13%).

Serious TEAEs were experienced by 43.0% of all treated patients and 45.5% of those in the daily-dosing group, and these included diarrhea (13%), colitis (6.5%), hypokalemia (3%), pyrexia (3%), and rash (3%). One death due to toxicity associated with the agent was reported.

In all treated patients and the daily-dosing subset, dose interruptions were experienced by 47% and 51%, respectively, and dose reductions were required by 8% and 9% of patients, respectively.

References

1. Icyte provides update on parsaclisib and MCLA-145. News release. Incyte; January 25, 2022. Accessed January 26, 2022. https://bit.ly/3o0MJJu
2. Lynch RC, Avigdor A, McKinney MS, et al. Efficacy and safety of parsaclisib in patients with relapsed or refractory follicular lymphoma: primary analysis from a phase 2 study (CITADEL-203). Blood. 2021;138(suppl 1):813. doi:10.1182/blood-2021-147918
3. Phillips T, Avigdor A, Gurion R, et al. Efficacy and safety of parsaclisib in patients with relapsed or refractory marginal zone lymphoma: primary analysis from a phase 2 study (CITADEL-204). Blood. 2021;138(suppl 1):44. doi:10.1182/blood-2021-147778
4. Mehta A, Trnêny, 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). Blood. 2021;138(suppl 1):382. doi:10.1182/blood-2021-147867