Pirtobrutinib, known by the brand name Jaypirca, is a targeted therapy medication used for certain types of blood cancer. It represents a different approach within its class of drugs, offering a new option for patients with specific B-cell leukemias and lymphomas. The development of this drug addresses some of the challenges encountered with previous treatments. This treatment is administered as a once-daily oral tablet.
How Pirtobrutinib Works
Pirtobrutinib functions by targeting a specific protein called Bruton’s tyrosine kinase (BTK). BTK is a signaling protein that plays a part in the survival and multiplication of certain cancer cells. In some B-cell cancers, this signaling pathway is overactive, promoting the growth and spread of malignant cells. By inhibiting BTK, pirtobrutinib effectively blocks these growth signals, which can lead to the death of the cancer cells.
The distinct characteristic of pirtobrutinib lies in its method of binding to the BTK protein. It is a non-covalent, or reversible, inhibitor. This means it binds to the BTK protein temporarily, functioning much like a key that can enter a lock, turn it off, and then be removed to work again. This mechanism allows it to repeatedly inhibit the BTK protein as it is produced by the cell.
This reversible binding contrasts with older, covalent BTK inhibitors. Covalent inhibitors form a permanent bond with the BTK protein at a specific site known as C481. These drugs are like a key that breaks off in the lock, permanently disabling that single protein molecule. Pirtobrutinib’s ability to bind without forming a permanent bond allows it to maintain its inhibitory activity even when changes occur in the cancer cell.
Approved Cancer Treatments
Regulatory agencies have authorized pirtobrutinib for specific patient populations based on evidence from clinical trials. The U.S. FDA has approved its use for adults with relapsed or refractory mantle cell lymphoma (MCL). This approval specifies that patients must have already received at least two prior lines of systemic therapy, one of which must have been a different type of BTK inhibitor. The approval for MCL was granted under an accelerated pathway based on the response rate observed in studies.
The medication is also approved for adults diagnosed with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). For these conditions, the approval is for patients who have been treated with at least two previous lines of therapy. These prior treatments must include both a BTK inhibitor and another class of drug known as a BCL-2 inhibitor.
The standard dose is a 200 mg tablet taken orally once a day, and treatment continues until the disease progresses or the patient experiences unacceptable toxicity. Continued approval for these uses may depend on the results of further confirmatory trials to verify the clinical benefit.
Effectiveness After Other Therapies
Because pirtobrutinib does not rely on a permanent bond at the C481 site, it can still effectively bind to and inhibit the BTK protein even when a resistance mutation is present. This non-covalent mechanism allows it to re-establish BTK inhibition in patients whose disease has progressed while on a covalent BTK inhibitor. This provides a way to extend the benefits of targeting the BTK pathway after resistance to other drugs in the same class has developed.
Clinical studies have shown that pirtobrutinib is effective in patients who have previously been treated with covalent BTK inhibitors like ibrutinib, acalabrutinib, and zanubrutinib. In the BRUIN study for MCL, all patients had received a prior BTK inhibitor, with the majority having discontinued it because their disease was no longer responding. The results showed that pirtobrutinib could still produce meaningful responses in this heavily pretreated population.
Potential Side Effects
Treatment with pirtobrutinib is associated with a range of side effects. Common adverse effects include:
- Fatigue
- Increased tendency for bruising
- Musculoskeletal pain
- Diarrhea
- Swelling
There are also less frequent but more serious risks that require prompt medical attention. These can include:
- Severe or fatal infections
- Bleeding events
- Low blood cell counts (cytopenias)
- Heart rhythm problems, such as atrial fibrillation and atrial flutter
- The emergence of second primary cancers
It is important for individuals taking pirtobrutinib to communicate with their healthcare provider about any new or worsening symptoms.