Matthew Stuart McKinney, MD, Assistant Professor of Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, overviews the phase 2 CITADEL-203 study on parsaclisib in patients with relapsed or refractory (R/R) follicular lymphoma (FL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

I'm Matt McKinney, MD. I'm an assistant professor of medicine at Duke University Medical Center within the Duke Cancer Institute.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr McKinney: FL is the second most common type of non-Hodgkin lymphoma (NHL) that we see in adults in the US.

While some cases of aggressive lymphoma are curable, FL generally is incurable with any measures that we currently have. These patients continue to relapse with subsequent lines of either chemotherapy or targeted therapy. There is a role for new agents to be developed in the field.

One active pathway in FL is the PI 3-kinase pathway, which is a signaling pathway that results in cell proliferation and cell survival. We already know that PI 3-kinase inhibitors can effectively slow the growth of FL cells.

Then, there are examples of several already FDA-approved available therapies including idelalisib, copanlisib, which is an IV weekly medication, duvelisib, which has in the past had FDA approval but was recently taken off of the market due to concerns of side effects versus efficacy, and more recently, there was approval of umbralisib.

I think all of these agents do have disadvantages and so within this landscape, we sought to study a very specific PI 3-kinase delta inhibitor called parsaclisib, which is this agent.

The other interesting thing that was a design part of the study was that parsaclisib was dosed for 8 weeks at a higher dose and then on study patients either went to weekly or lower dose daily dosing, with idea that we could maybe mitigate some side effects of PI 3-kinase inhibition, both by more specific delta inhibition, as well as modified dosing within the timeframe where we see most of these side effects in our patients.

OLN: Could you briefly describe the study and its findings?

Dr McKinney: CITADEL-203 was a single-arm phase 2 trial that had 2 dosing regimens, one was parsaclisib dose 20 mg per day for 8 weeks, followed by weekly dosing of the same 20 mg again given weekly.

The other cohort of patients initially treated was 20 mg a day for a total of 8 weeks, followed by a lower daily dose of 2.5 mg, with an idea that we could potentially mitigate some of the safety concerns with the PI 3-kinase inhibition in these patients.

After an initial analysis, the daily dosing was chosen for the majority of the patients. We have data presented on the efficacy and toxicity in 103 of those patients.

OLN: Were any of the outcomes particularly surprising?

Dr McKinney: It's helpful to understand what we saw in the study.

In the daily dosing cohort, the primary assessment or primary objective of the study was overall response rates (ORR). In the daily dosing cohort, we saw an ORR of right around 75%, or three-quarters of patients, with almost all patients having some degree of tumor shrinkage by protocol-mandated CT scans.

What I think was surprising is that we saw within that group, a cohort of 20% of patients had complete responses (CR). Often with targeted inhibitors in the field of FL and other diseases like CLL (chronic lymphocytic leukemia), SLL (small lymphocytic leukemia), CRs can be relatively rare. I think these results compared favorably to what we've seen with other PI 3-kinase agents in terms of efficacy.

Also, looking at some of the safety analysis, there seem to be lower rates of severe side effects like diarrhea and pneumonitis than we'd otherwise expect, with similar PI 3-Kinase approaches in a follicular lymphoma, third line population.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr McKinney: The hope was that parsaclisib would have an FDA indication for some of these indolent lymphoma subtypes, particularly FL. The initial goal of the trial was to help in the US a new drug application or NDA, which did actually exist. Unfortunately, it has been recently removed due to concerns about confirmatory studies and also as a business decision with Incyte.

I think parsaclisib, having used it on a number of patients on trial, is a very exciting active agent. We've used it successfully in many patients now with very good results in terms of lymphoma with relatively manageable toxicities.

On the 203 trial, only about 20% of patients had to come off of study due to an adverse effect, which compares favorably to other targeted oral inhibitors across the board in many different indications.

I'm hopeful that some of these real-world applications, either single-agent parsaclisib perhaps in the third-line or so setting in diseases like FL or marginal zone lymphoma (MZL) may become available or studies that look at it in combination with other agents.

Potentially newer agents in FL are also particularly exciting and I think likely to be beneficial for many of our patients.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what will be your next steps?

Dr McKinney: We're always looking for newer ways to diagnose and prognosticate as well as treat FL. We're really looking at, are there other combination studies that are out there or do we need to look at other modalities?

Bispecific CD19 or CD20 antibody therapies are very exciting.

The CAR-T space has recently expanded to FL treatment paradigm with FDA approval of axicabtagene ciloleucel, which is already one of the more effective therapies across any line of FL.

In the realm of targeted small molecule oral inhibitors, branching out either with parsaclisib is an option or other combinations is very exciting in the field and  hopefully will help us extend the lives of patients, and also potentially help us find a cure for this disease.