Pitobrutinib/Pitobrutinib VS Zanubrutinib: A big competition between the two drugs!

Pirtobrutinib and zanubrutinib (Zanubrutinib) are both BTK (Bruton tyrosine kinase) inhibitors and are used to treat B-cell malignancies, especially pan>Mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other diseases, but there are significant differences between them in terms of mechanism of action, selectivity, drug resistance response ability and clinical positioning.

Pittobrutinib is a non-covalent, reversibly bindingBTK inhibitor, while zanubrutinib is a second-generation covalent, irreversible BTK inhibitor. This difference in binding method determines that pitobrutinib can still maintain its inhibitory activity on BTK in the face of BTK gene mutations, especially the C481S mutation, thus providing a new option for patients who have developed resistance to covalent BTK inhibitors such as Ibrutinib, Acalabrutinib or zanubrutinib.

The clinical positioning of zanubrutinib is mainly for patients with newly treated or relapsed B-cell lymphoma. Because it has higher BTK selectivity and fewer off-target effects, it has relatively minor side effects, lower risks of arrhythmia and bleeding, and is suitable for long-term maintenance treatment. Pitobrutinib, on the other hand, focuses more on solving the drug resistance problem after failure of early BTK treatment, and especially shows good results in CLL patients with positive C481 mutations, which makes it often used as a "back-line treatment" in clinical practice.

Overseas data shows that pitobrutinib can still achieve a remission rate of up to 73% after BTK inhibitor failure. Its efficacy and safety have been fully verified in the LOXO-305 (BRUIN) study. It is for this reason that it was awarded "breakthrough therapy" designation by the FDA and will be approved in 2023 for the treatment of relapsed/refractory mantle cell lymphoma that has been previously treated with BTK inhibitors.

In addition, in terms of metabolic pathways, zanubrutinib is mainly metabolized byCYP3A4 and should be used with caution in patients with weak liver function. Although pitobrutinib is also metabolized by CYP3A enzymes, its half-life is shorter, its pharmacokinetics are more stable, and its dose adjustment is more flexible, which has practical advantages for tumor patients who take many concomitant medications and have impaired organ function. There are also slight differences in adverse reactions between the two. Common side effects of zanubrutinib include neutropenia, bleeding tendency, mild diarrhea, etc., while pitobrutinib may cause fatigue, muscle pain, mild to moderate infection and elevated liver enzymes, and is generally well tolerated.

Generally speaking, zanubrutinib has established a solid position in the treatment of newly diagnosed and relapsed and refractory B-cell lymphomas. It is especially suitable for patients who are intolerant to ibrutinib or require long-term medication. Pitobrutinib has filled the gap of "no drug available" after BTK inhibitor treatment resistance and has become an emerging weapon for precision treatment. In the future, the sequencing and combination strategies of the two in the treatment process (such as combination with the BCL2 inhibitor Venetoclax) will still be the focus of clinical research, which is of great significance for improving the long-term response rate of B-cell malignant tumors.

Reference materials:https://go.drugbank.com/drugs/DB17472