Oncology Drug Crash Course: Pirtobrutinib (Jaypirca)

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Who Is This Drug Approved For?

Pirtobrutinib (Jaypirca) was approved by the FDA on January 27, 2023, under accelerated approval, for adult patients with relapsed or refractory mantle cell lymphoma (MCL) who previously received at least 2 lines of systemic therapy, including a Bruton tyrosine kinase inhibitor (BTKi).¹ MCL is a form of non-Hodgkin B-cell lymphoma that arises from the malignant transformation of B lymphocytes in the mantle zone of lymph node follicles.² Current National Comprehensive Cancer Network guidelines recommend pirtobrutinib for third-line and subsequent therapy in patients with intolerance to, or disease that is refractory to, prior covalent BTKis, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa).³

What Efficacy Data Back It Up?

The BRUIN trial (NCT03740529), a phase 1/2 study, supported the use of pirtobrutinib to treat MCL for patients with refractory or relapsed disease who had been previously treated with a BTK inhibitor.⁴ The single-arm, international, open-label study included 120 patients with MCL who received pirtobrutinib as monotherapy.^4-5 In phase 1 of the study, maximum tolerated dosing was established, and in phase 2, the overall response rate (ORR) and the duration of response was evaluated.5 The efficacy data showed that the treatment led to a 50% (n = 60) ORR, as either a partial (38%) response or a complete (13%) response to therapy, and the duration of response (DOR) at 6 months was estimated to be 65.3% (95% CI, 49.8%-77.1%).⁴

How It Works

Pirtobrutinib is a highly selective, noncovalent, reversible BTK inhibitor that binds to wild-type BTK signaling proteins and BTK harboring C481 mutations, thereby leading to inhibition of BTK activity in the signaling protein pathways.⁴ Pirtobrutinib was developed because of complex mechanisms and tolerability issues associated with covalent BTK inhibitors, which can lead to treatment failure and disease progression.5,6Resistance to covalent BTK inhibitors, while not completely understood, is believed to be mediated by C481 mutations. Pirtobrutinib, as a novel third-generation BTK inhibitor, works independently of C481 mutations in select B-cell malignancies.⁷

How It’s Administered

Pirtobrutinib is administered orally with water, once daily. It may be given with or without food but should be taken at the same time each day. The tablets should be swallowed whole, without crushing or chewing. If a dose is missed by more than 12 hours, the missed dose should not be given. Instead, the next scheduled dose is given. Doses should never be doubled.^4,8

Recommended Dosages

The recommended dosage of pirtobrutinib is 200 mg orally once daily until disease progression or unacceptable toxicity. Tablets are available in 50 mg and 100 mg dosage forms.⁴ Dosages may be modified for patients with severe renal impairment or concomitant use with strong CPY3A inhibitors or inducers. For example, for patients with an eGFR of 15 to 29 mL/min, the dose may be reduced from 200 mg to 100 mg once daily. If a patient’s current dose is 50 mg and they need another reduction, then pirtobrutinib should be discontinued. If the use of concomitant CPY3A inhibitors or inducers cannot be avoided, doses should be modified based on full prescribing information and clinical decision-making.

How to Manage Associated Adverse Events

The most clinically significant adverse reactions in clinical trial were infection, hemorrhage, cytopenia, atrial fibrillation, and second primary malignancies.⁴

Dosage modifications (Table⁴) are recommended for grade 3 or greater toxicities and generally include treatment interruptions (until recovery to grade 1 or baseline) followed by dosage modifications, with the first 3 occurrences. Discontinuation of pirtobrutinib is recommended with fourth occurrences.

What to Inform Patients Who Are About to Start Treatment

Patients should be advised to report signs of infection, such as fever, chills, weakness, flu-like symptoms, burning with urination, or any other sign of infection.^4,8 Similarly, patients should be advised to report unexpected signs and symptoms of bleeding or bruising but should also take caution to avoid bruises, cuts, or burns. Patients should be advised to use a soft toothbrush and maintain good oral hygiene, to use an electric razor rather than razor blades, to use files instead of nail clippers, and to blow their nose gently.⁸

Monitoring of blood counts during treatment will occur on a regular basis. Pirtobrutinib may need to be stopped prior to major surgeries or other medical and dental procedures.^4,8 Because of reported arrhythmias, patients should be advised to report signs and symptoms such as palpitations, dizziness, chest discomfort, and shortness of breath.4 Some patients may develop secondary solid tumors or skin cancers. Patients should not become pregnant, nor should they breastfeed while taking pirtobrutinib and for 1 week after the last dose.

Advice for Nurses Who Administer This Agent:

Pirtobrutinib is a strong CYP3A substrate. Therefore, concomitant use with strong CYP3A inhibitors will increase the systemic exposure of the drug, which may increase potential adverse reactions.4 Conversely, concomitant use with a strong or moderate CYP3A inducer will decrease the systemic exposure of the drug and lead to potential reduced efficacy. Medication reconciliation, to include over-the counter medications, vitamins, and herbal products, should occur regularly to optimize treatment effectiveness and minimize risks of drug-to-drug interactions. Grapefruit or grapefruit juice may interact with pirtobrutinib, and patients should avoid eating or drinking these during treatment.⁸

Nurses should assist patients with drug procurement through retail or specialty pharmacies and support patients’ oral adherence to therapy.By doing so, nurses must consider treatment goals and relevant patient barriers (which may be of a physical, social, or emotional nature) as well as access to care.⁹

How to Safely Handle This Drug

Pirtobrutinib is to be stored at room temperature, in a dry location away from light and away from children and pets.⁸ Patients should self-administer the drug whenever possible, using good handwashing before and after administration. If it is necessary for a caregiver to assist with administration, gloves should be worn to avoid touching the drug while the caregiver transfers the dose to a disposable cup. Both gloves and disposable medicine cups should be discarded after one-time use.

References

1. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. FDA. News release. January 27, 2023. Accessed July 10, 2023. https://bit.ly/45HtxEm
2. Muñoz J, Sarosiek S, Castillo JJ. Managing Ibrutinib-intolerant patients with B-cell malignancies. Oncologist. 2023;28(4):309-318. doi:10.1093/oncolo/oyac260
3. NCCN. Clinical Practice Guidelines in Oncology. Mantle cell lymphoma, version 5.2023. Updated July 7, 2023. Accessed July 26, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
4. Jaypirca. Prescribing information. Eli Lilly and Company; 2023. Accessed July 10, 2023. https://bit.ly/3YE3CK7
5. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021; 397(10277): 892-901. doi:10.1016/S0140-6736(21)00224-5
6. Naeem A, Utro F, Wang Q, et al. Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance. Blood Adv. 2023;7(9):1929-1943. doi:10.1182/bloodadvances.2022008447
7. Jensen JL, Mato AR, Pena C, Roeker LE, Coombs CC. The potential of pirtobrutinib in multiple B-cell malignancies. Ther Adv Hematol. 2022;13:20406207221101697. doi:10.1177/20406207221101697
8. Oral Chemotherapy Education. Pirtobrutinib. Accessed August 9, 2023. https://bit.ly/3Zb9xY4
9. Oncology Nursing Society. Oral adherence toolkit. Updated 2016. Accessed August 1, 2023. https://bit.ly/4613kjN