Efficacy and Safety of Pirtobrutinib Continue to Reshape MCL Treatment Paradigm

Although BTK inhibitors have become ingrained in the treatment of patients with mantle cell lymphoma (MCL), the continued investigation of the noncovalent inhibitor pirtobrutinib (Jaypirca) could continue to reshape how these agents are utilized for this patient population, according to Jean L. Koff, MD, MS.

“What we've seen throughout the clinical trials for pirtobrutinib s that it's well tolerated. It has a low rate of discontinuation due to drug-related toxicity, which is a great aspect to have in a new drug,” Koff said in an interview with OncLive^®. “We can regard pirtobrutinib as a new standard-of-care patients with MCL who received a prior covalent BTK inhibitor.”

In the interview, Koff expanded on factors to consider when selecting between the covalent BTK inhibitors approved for patients with MCL, how the approval of pirtobrutinib has affected the MCL treatment paradigm, and the ongoing investigation of pirtobrutinib in earlier treatment settings.

Koff is an associate professor in the Department of Hematology and Medical Oncology and a clinical investigator in the Bone Marrow and Stem Cell Transplant Center at Emory University School of Medicine, as well as a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive: When choosing between covalent BTK inhibitors for the frontline treatment of patients with MCL, what factors do you take into account?

Koff: The first question [when determining therapy for previously] untreated patients with MCL is thinking about whether their ultimate goal is getting an autologous stem cell transplant [ASCT]. [The role of ASCT] is evolving, as well. We also think along the lines of whether patients are candidates for aggressive induction regimens, or if they would be better suited for less-aggressive regimens.

In terms of the selection of BTK inhibitors in the frontline and maintenance setting, the data that we use to inform that selection comes from the [phase 3] TRIANGLE trial [NCT02858258], which incorporated ibrutinib [Imbruvica] into [standard chemoimmunotherapy] and then as single-agent maintenance with or without ASCT. Because there have been a lot of data that's come out showing that newer covalent BTK inhibitors—acalabrutinib [Calquence] and zanubrutinib [Brukinsa]—seem to be as effective as ibrutinib in many different spaces and are able to be better tolerated by patients in many lymphoma subtypes including MCL, we are now selecting these newer covalent BTK inhibitors over ibrutinib.

Although ibrutinib was the drug that was incorporated into the regimens in TRIANGLE, the National Comprehensive Cancer Network Guidelines have a category 2B recommendation to select a newer-generation BTK inhibitor in place of ibrutinib.

How has the FDA approval of pirtobrutinib impacted the treatment paradigm for relapsed/refractory MCL?

This was a very exciting approval for our patients with MCL. Historically, patients whose disease progresses after receiving a covalent BTK inhibitor have not had a whole lot of options in terms of treatment strategies, and their outcomes have been poor.

The outcomes with pirtobrutinib in patients who have progressed on a covalent BTK inhibitor were very encouraging. [In the phase 1/2 BRUIN trial (NCT03740529), which supported pirtobrutinib’s FDA approval], patients with MCL [treated with 200 mg of pirtobrutinib per day experienced] an overall response rate of 50%. Importantly, [pirtobrutinib] is also a well-tolerated drug with minimal or at least manageable toxicities. This is an important treatment agent to have in our armamentarium when we're treating patients with MCL who have progressed after a prior covalent BTK inhibitor.

What is the safety profile of pirtobrutinib, and what should community oncologists be aware of?

Most of the adverse effects [AEs] that we saw in relation to pirtobrutinib [during the BRUIN trial] were more constitutional symptoms such as fatigue, as well as some gastrointestinal AEs such as diarrhea. In terms of AEs of interest that we think about in terms of BTK inhibitors in general. [whether they be] covalent or noncovalent [agents], we do see some infections [with pirtobrutinib], which is common in patients who are getting almost any type of treatment for lymphoma. However, in terms of severe infections that we could relate to pirtobrutinib, this number was low. There was some bruising in these patients, but no patients had severe bruising or hemorrhage.

In terms of atrial fibrillation or flutter, this rate was very low in terms of what could be associated with the pirtobrutinib. Blood pressure is another AE event that we monitor in patients getting BTK inhibitors, and the rate of pirtobrutinib-related hypertension was very low with no severe-grade high blood pressure.

What could be the implications of the phase 3 BRUIN MCL-321 trial (NCT04662255) if pirtobrutinib demonstrates superior efficacy vs covalent BTK inhibitors in the BTK inhibitor–naive population?

This is a trial that is comparing pirtobrutinib vs covalent BTK inhibitors [in patients who received at least 1 prior line of systemic therapy but no prior approved or investigational BTK inhibitor], What we would like to see is an improvement in efficacy in terms of how many patients respond and how long they're able to stay on treatment.

The other ways that pirtobrutinib could be superior to other BTK inhibitors would be in the AE profile. If we do find [improved safety] in a comparative study, then pirtobrutinib may be poised to overtake covalent BTK inhibitors in treating BTK inhibitor–naive MCL.

[An important question] to consider is whether patients who have received pirtobrutinib and progressed will then respond to a covalent BTK inhibitor. When we're treating MCL, it's not a question of whether patients respond to just 1 therapy. [Finding] the sequence of therapies that will provide the longest time before a patient needs a new therapy [is important].