Tycel Phillips, MD, highlighted the key findings of the phase 2 CITADEL-204 trial.
Tycel Phillips, MD
BTK inhibitor–naïve patients with relapsed/refractory marginal zone Lymphoma (MZL) achieved rapid and durable responses with single-agent parsaclisib, as demonstrated in the CITADEL-204 trial (NCT03144674). According to lead study author Tycel Phillips, MD, this could potentially be a groundbreaking advancement in the limited MZL treatment paradigm, though additional research is needed.
In the open-label, phase 2 CITADEL-204 trial, investigators sought to determine the safety and efficacy of parsaclisib in adult patients with MZL who received at least 1 prior line of systemic therapy but were BTK inhibitor-naïve. One hundred BTK inhibitor–naïve patients were randomized 1:1 to receive 20 mg of parsaclisib once daily for 8 weeks followed by either 20 mg of parsaclisib once weekly or 2.5 mg daily, continuously. The daily-dosing group was selected as the preferred regimen, and all subsequent patients were enrolled to that cohort.
The primary end point was objective response rate (ORR); overall survival (OS), safety, and tolerability were key secondary objectives.
By independent review, results showed that the ORR was 57.0% (46.7-66.9) in all treated patients and 56.9% (44.7−68.6) in the daily-dosing group. The ORR was 70.0% (60.0-78.8) in all treated patients and 68.1% (56.0-78.6) in the daily-dosing group via investigator assessment. Similar rates of response were observed in patients with nodal, extranodal, and splenic MZL.
Treatment-emergent AEs occurred in over 10% of patients and included diarrhea, cough, rash, anemia, nausea, pruritus, and constipation.
“From this research, we learned that parsaclisib appears to be safe, tolerable, and effective in patients with MZL. In addition, the results that we have seen thus far seem to be favorable when compared with ibrutinib (Imbruvica),” Phillips said. “True to the design of the molecule, we did notice a marked decrease in transaminitis when compared with some of the other delta inhibitors in the space. Ultimately, this could be a very exciting advancement for patients with MZL.”
In an interview with OncLive, Phillips, an associate professor of hematology, medical oncology, and internal medicine at the University of Michigan Cancer Center, highlighted the key findings of the phase 2 CITADEL-204 trial.
Phillips: Notably, MZL is a low-grade lymphoma. For the longest time, the only approved agent was single-agent rituximab (Rituxan). Since then, many of the treatment options have piggybacked off of follicular lymphoma.
Over the past 2 years, there were regulatory approvals for ibrutinib (Imbruvica) and the combination of rituximab and lenalidomide (Revlimid). To date, these are the only therapies that have received a true FDA approval for the management of patients with MZL. Since this is a smaller niche of patients, they tend to respond well to the therapies available.
Parsaclisib is a second-generation PI3K inhibitor that was specifically designed to reduce the incidence of transaminitis, which could be noted as a class effect for this treatment. The treatment dose was found to be 20 mg; however, several other doses were explored as well. This research also explored parsaclisib in combination with a JAK inhibitor. For the most part, the treatment was well tolerated in patients.
To mitigate some of the class effects, they did make some alterations to the dosing of the regimen in the original phase 1/2 study. Notably, most patients derived the best response within the first 8 weeks of treatment. After this, they adjusted the treatment and had patients go on a quasi-maintenance therapy; therefore, patients received 20 mg of parsaclisib once weekly, instead of daily dosing. With the switch to maintenance, they did notice a decrease in several AEs, such as such as rash, pruritus, and pneumonitis. However, they needed more information, including the optimal dose of maintenance for this patient population. After this research, there were several copycat trials in patients with MZL, follicular lymphoma, and mantle cell lymphoma.
This trial evaluated patients with relapsed/refractory MZL who received at least 1 prior line of therapy. Since there was already an approval for ibrutinib in patients with MZL, the study was designed to evaluate the role of parsaclisib in patients with ibrutinib-naïve MZL or those who were relapsed/refractory to ibrutinib. The vast majority of patients on our study were enrolled to the ibrutinib-naïve arm. There were some enrollments to the ibrutinib-exposed arm; however, enrollment was much slower. As such, most results that were presented during the 2020 ASH Annual Meeting & Exposition came from the ibrutinib-naïve arm.
During the meeting, we highlighted the responses that were discovered in the first 8 weeks, as well as the AEs that occurred in result of the transition to maintenance therapy. In this study, maintenance therapy was administered at 2.5 mg daily versus 20 mg weekly. This dosing was chosen based on some of the other studies that evaluated this agent. There was a difference in the maintenance dosing due to the response; I don't know if anybody has a better explanation or rationale. Ultimately, the responses were great, the agent was well tolerated, and some of the information that we believed was true, such as the 8-week response, came to fruition. These were some of the key takeaways from this research.
As we gather more data, the new takeaways will be the mature responses, responses that are observed in different MZL subtypes, as well as long-term AE data. Notably, the AEs associated with PI3K inhibitors, in general, are one of the greatest roadblocks. When comparing the data of parsaclisib to some of the other approved agents in this space, there seems to be some similarities. Due to this, we are hopeful that more agents will be approved in the future.
This is an exciting time for patients with MZL because, historically, very few clinical trials included these patients in their research. Since the CITADEL-204 trial is a very specific study in MZL, if the data is found to be positive in the next steps, this could potentially be a new treatment. Additionally, we are hopeful that this research will help us better understand how to manage the AEs that are associated with delta inhibitors in this space.
Phillips TJ, Corradini P, Gurion R, et al. Phase 2 Study Evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory marginal zone lymphoma (CITADEL-204). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-9, 2020; virtual. Abstract 338.