Smith Discusses Importance of Adherence When Integrating Pirtobrutinib Into Clinical Practice

Leslie Smith, DNP, RN, APRN-CNS, BMTCN, AOCNS

Pirtobrutinib (Jaypirca) has expanded options for patients with mantle cell lymphoma (MCL) as the first noncovalent Bruton tyrosine kinase (BTK) inhibitor approved by the FDA. On January 27, 2023, the oral treatment was approved for patients who have already undergone at least 2 systemic treatments, including BTK inhibition.

In the phase 1/2 BRUIN trial (NCT03740529) 120 patients who previously received treatment with a covalent BTK inhibitor, ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa), experienced an overall response rate (ORR) of 50% (95% CI, 41%-59%) with 13% of responders having a complete response. The median duration of response (DOR) was 8.3 months (95% CI, 5.7-not estimable) and median time to response was 1.8 months (0.8-4.2).

“We talk a lot about adherence [as a challenge] and patients need to take [pirtobrutinib] every day at the same time,” Leslie Smith, DNP, RN, APRN-CNS, BMTCN, AOCNS, said. “They can take it with or without food and they shouldn’t miss a dose, it is important. The patient should also be educated about the potential for pancytopenia that [may] occur, [as well as] fatigue and other events....Pirtobrutinib is a promising third line agent for MCL for [individuals] who have refractory relapsed disease, so it’s important to emphasize that to patients.”

In an interview with Oncology Nursing News^®, Smith, a clinical nurse specialist at the National Institutes of Health, discussed the agent’s efficacy as seen in the BRUIN trial and offered her perspective on how this agent differs from approved BTK inhibitors.

Oncology Nursing News^®: Can you discuss the treatment landscape of MCL? How might pirtobrutinib be factored into the fold?

Smith: I work at a research hospital, and we have research studies that are looking at different agents to treat MCL. Patients who are being treated for MCL generally need to receive a BTK inhibitor at some point and the 3 original ones are ibrutinib, acalabrutinib, and zanubrutinib. Chemotherapy and radiation therapy can also be the standard of care.

I have not used pirtobrutinib yet, because it’s so new and [patients] who come to our institution are enrolled in a clinical trial. But, for this particular drug, patients usually need to have at least 2 lines of systemic therapy. Second line therapy generally is where you see the BTK inhibitor [given] if the patient is relapsing, or not showing a response, or they can participate in a clinical trial.

Pirtobrutinib is approved as a third line noncovalent BTK inhibitor at this point per the [National Comprehensive Cancer Network] NCCN guidelines. [Of note],dose modification and [reductions are permitted] with adverse events, so [patients] should be honest with their prescriber/hematologist. [Pirtobrutinib] can be just as effective as the 200-mg dose. The biggest challenge is adherence not just for this drug, but every oral drug.

What findings from BRUIN stood out to you and what were the limitations of the study?

BRUIN enrolled 120 patients with MCL that had previously been treated with another BTK inhibitor. Patients had [a] median of 3 lines of prior therapy and 93% had 2 or more prior lines of therapy. The most common BTK inhibitor was ibrutinib followed by acalabrutinib and then zanubrutinib and 83%, so a large percentage of these patients, had discontinued their last BTK inhibitor because of refractory or progressive disease. In this trial pirtobrutinib was administered orally at 200 mg once daily and was continued until disease progression or unacceptable toxicity.

In the BRUIN trial, [investigators] were looking at ORRs and DOR. The ORR was 50% with a CR rate of 13%. The [median] DOR was 8.3 months and the estimated DOR at 6 months was 65%.

[A] limitation of the trial was the small population, MCL is not a very common type of lymphoma and [therefore] the trial had a small population of patients with MCL. In addition, some of these patients had also received CAR T-cell therapy as well, and [had] experienced progression subsequent to that.

Could you discuss what makes pirtobrutinib unique from ibrutinib, acalabrutinib, and zanubrutinib? What is significant about the approval of a noncovalent BTK inhibitor?

In normal B cells, you have the B-cell receptor pathway which is crucial for the normal lifespan of the B cell. In lymphoma, the continuous stimulation of the B-cell receptor pathway leads to continued growth and proliferation of the lymphoma cancer. BTK is a [signaling] protein that is found early in the pathway of the B-cell receptor pathway. Ibrutinib, zanubrutinib, and acalabrutinib bind to BTK and inhibit this continued signaling so [that] the lymphoma cell will not have the opportunity to reproduce, and it will die. But they bind irreversibly to BTK, which means that once they bind, they never let go and what can happen is the lymphoma cell can mutate to get around this irreversible binding.

Pirtobrutinib is a noncovalent reversible binder [and it] can jump off the BTK protein and therefore not allow the lymphoma cell to mutate. It also is in the blood longer so you have a longer DOR.

What stands out to you the most looking at the safety profile of this agent?

In the BRUIN trial, the most common AEs were fatigue, musculoskeletal pain, diarrhea, edema, pneumonia, bruising and dyspnea. Like any other BTK inhibitor, patients will become pancytopenic; in the trial greater than 10% of patients had decreased neutrophil counts, lymphocyte counts, and platelet counts. In the prescribing information from the manufacturer, they include warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and atrial flutter, like all the other BTK inhibitors, and then [a] risk for second primary malignancies.

However, in the trial [with pirtobrutinib] no cardiac arrhythmias were seen like they were with the other BTK inhibitors.

Reference

Jaypirca. Prescribing information. Eli Lilly and Company; 2023. Accessed January 30, 2023. https://pi.lilly.com/us/jaypirca-uspi.pdf