Dr Awan on Treatment Considerations With Pirtobrutinib in Hematologic Malignancies

“For now, noncovalent BTK inhibitors should be used only after [progression on] covalent BTK inhibitors and a BCL-2 inhibitor.”

Farrukh Awan, MD, professor, Department of Internal Medicine, member, Division of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, discusses treatment considerations with the use of pirtobrutinib (Jaypirca) in previously treated patients with hematologic malignancies.

The emergence of pirtobrutinib, along with other noncovalent BTK inhibitors, represents a promising advancement, particularly for patients refractory to prior BTK inhibitor therapies, Awan begins. These agents have demonstrated encouraging efficacy, especially in patients intolerant to covalent BTK inhibitors, as these patients tend to respond better than those with true BTK inhibitorresistance, he explains. Similarly, outcomes are generally favorable if the patient has been exposed to, but not rendered refractory by, BTK and BCL-2 inhibitors, according to Awan. However, for patients who are refractory to both BTK and BCL-2 inhibitors, the responses to noncovalent BTK inhibitors, although decent, tend to be less durable, Awan emphasizes. This is an important consideration; pirtobrutinib and similar agents are valuable treatment options but they may not consistently deliver long-lasting remissions, he says.

Another key point is the relatively limited understanding of resistance mechanisms associated with these newer therapies. he continues. Early data from small studies indicate evolving resistance patterns, but more extensive research is needed, he notes. What is currently known is that patients exposed to noncovalent BTK inhibitors may develop resistance mutations that render covalent BTK inhibitors ineffective, he states, noting that this highlights the importance of sequencing therapies carefully to optimize patient outcomes.

Based on current evidence, noncovalent BTK inhibitors should be reserved for patients who have already progressed on covalent BTK inhibitors and BCL-2 inhibitors, he reiterates. Using noncovalent BTK inhibitors earlier in the treatment sequence may limit future options due to cross-resistance, he explains. As more data become available, these recommendations may evolve, but for now, careful treatment sequencing remains critical, Awan concludes.