From the Guidelines
Pirtobrutinib is preferred over ibrutinib for patients who have developed resistance to ibrutinib or have specific BTK mutations, due to its non-covalent binding mechanism and potentially fewer cardiovascular side effects, as suggested by recent studies 1.
Comparison of Pirtobrutinib and Ibrutinib
Pirtobrutinib and ibrutinib are both Bruton's tyrosine kinase (BTK) inhibitors used to treat certain blood cancers. The key differences between them lie in their mechanism of action, side effect profiles, and efficacy in specific patient populations.
- Pirtobrutinib is a newer, non-covalent BTK inhibitor that can work in patients who have developed resistance to ibrutinib, making it a valuable option for those with specific BTK mutations 1.
- Ibrutinib, the first-generation BTK inhibitor, binds covalently to BTK and has been used longer in clinical practice for conditions like chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström's macroglobulinemia.
Dosage and Administration
- The typical dose for ibrutinib is 420-560 mg once daily, while pirtobrutinib is typically dosed at 200 mg once daily.
Side Effect Profiles
- Pirtobrutinib generally has fewer cardiovascular side effects compared to ibrutinib, which can cause atrial fibrillation and hypertension, as reported in studies such as 1.
- Both medications require regular monitoring for side effects, with ibrutinib requiring particular attention to bleeding risk, as it affects platelet function.
Choice Between Medications
- The choice between pirtobrutinib and ibrutinib depends on the specific cancer being treated, prior treatments, presence of resistance mutations, and the patient's cardiovascular risk profile, as outlined in guidelines such as 1.
- For patients with relapsed or refractory disease, especially those with a history of resistance to ibrutinib, pirtobrutinib may offer a better therapeutic option due to its ability to overcome resistance mechanisms, as suggested by recent clinical practice guidelines 1.
From the Research
Comparison of Pirtobrutinib and Ibrutinib
- Pirtobrutinib is a non-covalent Bruton's tyrosine kinase (BTK) inhibitor, whereas ibrutinib is a covalent BTK inhibitor 2, 3, 4, 5, 6.
- Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent BTK inhibitors such as ibrutinib 2, 4.
- The overall response rate for pirtobrutinib in patients with Richter transformation was 50·0% (95% CI 38·7-61·3), with 11 (13%) of 82 patients achieving a complete response and 30 (37%) of 82 patients achieving a partial response 2.
- Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors, including ibrutinib, with similar overall response rates in BTK-pretreated and naïve patients 4.
- The PI3K/AKT pathway plays a crucial role in both intrinsic and acquired resistance to pirtobrutinib in chronic lymphocytic leukemia (CLL), and therapeutically targeting this pathway may offer a promising strategy to overcome pirtobrutinib resistance 3.
- Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib compared to ibrutinib 4.
- Pirtobrutinib is more selective for BTK and binds noncovalently to the receptor, whereas ibrutinib is a covalent inhibitor 4, 6.
- The development of BTK resistance mutations in CLL patients appears to depend on the specific BTK inhibitor administered, with different inhibitors showing distinct allosteric changes that alter the conformational equilibrium of full-length BTK 6.