Pirtobrutinib Data and Sequencing After Covalent BTK Inhibitor Progression

Dr. Shadman introduces pirtobrutinib, the non-covalent BTKi currently approved as second-line therapy after covalent BTKi exposure. At ASH, two head-to-head trials were presented: pirtobrutinib versus bendamustine-rituximab in treatment-naïve patients, and pirtobrutinib versus ibrutinib in a mixed population including approximately one-third treatment-naïve patients.

A pooled analysis combining treatment-naïve patients from both studies generated frontline data for pirtobrutinib. With 24-month follow-up, 93.2% of patients were free from progression or death, impressive-looking frontline data, though Dr. Lipsky cautions this represents very early follow-up where results are expected to look favorable.

The critical academic concern is the long-term resistance mutation profile emerging when patients eventually progress on frontline non-covalent BTKi therapy, and whether subsequent options including venetoclax would remain available. Laboratory-informed concerns exist that covalent BTKi after non-covalent BTKis would lack clinical efficacy, though definitive proof awaits accumulating post-progression experience. A complementary pooled analysis from BRUIN and BRUIN-CLL321 showed pirtobrutinib achieves median PFS of approximately 19.5 months (time to next treatment approximately 32 months) when used second-line after covalent BTKi. Dr. Lipsky notes this is somewhat below earlier phase 1 to 2 expectations, suggesting that combination approaches with pirtobrutinib in second-line may be worth exploring to improve outcomes.

Both panelists agree on an important sequencing principle: covalent BTKi followed by non-covalent BTKi is a reasonable strategy with supporting evidence, whereas the reverse order (non-covalent first, then covalent) lacks evidence and should not be used in clinical practice.