Parsaclisib Offers New Hope for Patients With BTK Inhibitor-Naïve Relapsed/Refractory MCL

Amitkumar Mehta, MD

Parsaclisib is known to be a potent and highly selective first-in-class PI3Kδ inhibitor, which represents a new potential treatment option for patients with BTK inhibitor-naïve relapsed/refractory mantle cell lymphoma (MCL). Encouraging findings were observed for the next-generation therapy in the phase 2 CITADEL-205 study (NCT03235544).

These findings, which were recently presented during the 2020 American Society of Hematology (ASH) Annual Meeting, demonstrated that patients with relapsed/refractory MCL who were treated with a daily dose of parsaclisib induced significant activity and tolerability. Patients who had not received prior therapy with a BTK appeared to have a higher response rate compared with those who had prior exposure to BTK inhibition.

The open-label multicenter study included 2 cohorts of patients in order to evaluate the safety and efficacy of parsaclisib in both those who had or had not received a prior BTK inhibitor. Treatment was administered at either 20 mg once daily for 8 weeks followed by either 2.5 mg once daily continuously or 20 mg given once weekly.

In an interview with Targeted Oncology, Amitkumar Mehta, MD, an associate professor at the University of Alabama at Birmingham Comprehensive Cancer Center, discussed the findings for the PI3Kδ inhibitor parsaclisib as treatment of patients with relapsed/refractory MCL.

TARGETED ONCOLOGY: What was the rationale for this study?

Mehta: As we know that in mantle cell lymphoma, there have been a lot of treatments, especially the BTK inhibitors, that have been landmark in [terms of] responses in MCL, especially in the relapsed/refractory setting. Frontline MCL is still tricky. There are so many regimens and people don't have a preference. If you ask 5 different lymphoma experts, you will find 5 different treatments. BTK inhibitors are a landmark in MCL, now CAR T is also coming up, but we also know that BTK inhibitors have many side effects, especially atrial fibrillation, and bleeding issues. We need something in that setting that is highly active, probably has a different safety profile, and is tolerable from the patient's perspective.

That was the main rationale, and we saw the indication that PI3K is highly active in MCL. It's very active in the B-cell lymphoma setting, therefore we explored it in relapsed/refractory MCL.

TARGETED ONCOLOGY: How was the study designed, and what were the objectives?

Mehta: It's a phase 2 study design, so it was explored in 2 different regimens. One of the reasons for that is to see whether we can improve on tolerance and whether we see any difference in responses. The patients were randomized in a 1:1 ratio in 2 different subsets. One is what we call a weekly group, and these patients started at 20 mg daily for 8 weeks. Before the junction after 8 weeks, they are either randomized to a weekly regimen, so 20 mg weekly or 2.5 mg daily. The primary end point of the study was overall response rate. There were multiple secondary end points in that setting, but we also wanted to explore which regimen is tolerable with optimal responses.

TARGETED ONCOLOGY: What did the findings from this study ultimately show?

Mehta: We enrolled about 108 patients, and in the early part of the study, we realized that the daily group, which is after 8 weeks of 20 mg daily dose, and then those patients were taking 2.5 mg daily. We saw that the responses were very impressive, a 71% response rate, and it was overall well tolerated. We also saw that in the first assessment, 87% of patients had response in their shrinkage of the tumor size, so overall, we were very thrilled to see the response.

TARGETED ONCOLOGY: What do we know about the durability of the agent today?

Mehta: To date, we have seen that the median duration of response is 9 months, and median progression-free survival is 11.1 months. The data cutoff that we had was in July 2020, and at that time, about 35% of patients were still on the treatment.

TARGETED ONCOLOGY: We know PI3K inhibitors are not without their own set of toxicities, but how do they differ from those with BTK inhibitors?

Mehta: Parsaclisib is a highly specific PI3Kδ inhibitor, so if you compare all other PI3Kδ inhibitors, parsaclisib is very highly specific, and it was designed to reduce the transaminitis as a side effect. We saw that the transaminitis were very, very low, especially grade 3/4 in 3% to 4%, but we did see diarrhea, which is 1 of the side effects that we know is a class effect. We saw in about 13% of patients that we have grade 3 or more diarrhea, and for about half of the patients, that was a reason for discontinuation.

TARGETED ONCOLOGY: Was there anything about the analysis that surprised you?

Mehta: No. I was very impressed in a way that we have another agent which is active, and if you look at the BTK inhibitor data at the initial part, especially ibrutinib, the response rates are almost in alignment with BTK inhibitor. We are very excited that we have another agent with a similar response rate and overall well tolerated, that we can explore in that space and an alternative to BTK inhibitors with their side effects.

TARGETED ONCOLOGY: What are the implications of these data, and what does it mean in terms of sequencing therapy in MCL?

Mehta: That's still up in the air right now for MCL, especially with the CAR T approval when the label is so nonspecific for relapsed/refractory MCL. I think in that setting, the BTK inhibitor has been a landmark as I was saying, but if you look at the other data where we are looking at parsaclisib in those patients who have failed BTK inhibitor, and interestingly, what we found was that the response rates were not as high. They were very, very poor responses, and median progression-free survival was also very, very small in those patients. I think that gives us an indication that those patients who cannot tolerate BTK inhibitors are those patients who cannot be put on BTK inhibitors for a wide variety of reasons. This agent, with a similar efficacy and a different safety profile, can be a good alternative in this setting.

TARGETED ONCOLOGY: Are there any next steps planned for this research?

Mehta: We want to see whether it is safe enough to move in a frontline setting, and that's something that I've been thinking a lot. We will see whether that pans out down the line. As I was mentioning that in the frontline setting of MCL, there are so many regimens, and it's a very heterogeneous disease. Some patients are very indolent, some are very aggressive, so if we can prognostically identify those patients who can benefit, we have targeted agents early in the course. That's something that we should explore in medicine, especially the high-risk and TP53-mutated patients.

TARGETED ONCOLOGY: Is there anything else that is important to highlight from this research?

Mehta: One other thing that I would like to explore in future is the minimal residual disease (MRD) assessment, and this patient's MRD has been evolved as a major. There are a couple of clinical trials also going on based on the MRD-negativity that whether there is a role of transplant or not. That's something that is an area of interest from my side down the line to see whether even if you move in a frontline setting or relapsed setting, whether we are achieving MRD-negativity with this agent and compare all across with the targeted agents, we'll see that we can improve the PFS down the line.