Reference: January 2026 | Issue 1 | Vol 12 | Page 42
Also presented at the ASH Annual Meeting were the results from the first randomised phase 3 study comparing a non-covalent and covalent BTK inhibitor as frontline therapy for chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL).
The study included patients who had not received any previous treatment, which is a first for any phase 3 study directly comparing BTK inhibitors, and patients with relapsed or refractory (R/R) disease after receiving treatments other than a covalent BTK inhibitor.
The study enrolled 662 adult patients with CLL or SLL. Of these, 225 had not received any prior treatments, and 437 were R/R to prior treatments and had not received any BTK inhibitors. Participants were randomly assigned to receive either pirtobrutinib or ibrutinib and remain on their assigned therapy in the event of disease progression or unacceptable side effects.
The study’s primary endpoint, non-inferiority of pirtobrutinib for overall response rate (ORR), was achieved in the full study population. Of 662 participants, the ORR was 87.0 per cent among those receiving pirtobrutinib and 78.6 per cent among those receiving ibrutinib.
The results consistently favoured pirtobrutinib across the majority of subgroups, including those who were treatment-naive, R/R to prior treatments, and those with various high-risk disease characteristics.
“Pirtobrutinib was clearly non-inferior to ibrutinib, and the response rate actually favours pirtobrutinib in the total cohort,” said lead study author, Prof Jennifer Woyach, Ohio State University College of Medicine, US. “This shows that pirtobrutinib is a reasonable choice in both the treatment-naive and relapsed/refractory settings.”
Preliminary findings show 18-month PFS rates of 86.9 per cent in the pirtobrutinib arm and 82.3 per cent in the ibrutinib arm.
“The PFS is still a little bit immature at this point, but trends toward favouring pirtobrutinib in all of the groups – in the total cohort, in the R/R group, and, importantly, in the treatment-naive cohort,” said Dr Woyach.
“That’s really important, because given the safety of pirtobrutinib, it suggests that this might be a good option in the future for some patients with frontline CLL/SLL.”
The rates of treatment-emergent adverse events (AEs) and treatment discontinuation due to AEs were similar between arms, however, those receiving pirtobrutinib experienced lower rates of AE-related dose reductions, treatment discontinuation due to progressive disease, and cardiovascular AEs including hypertension and atrial fibrillation.
These results may indicate pirtobrutinib is especially suitable for use in older or more frail patients. “While the efficacy and safety of pirtobrutinib have been very clearly established when given after a covalent BTK inhibitor, there are likely going to be subgroups of patients where pirtobrutinib is a more attractive option instead of the covalent BTK inhibitors,” said Dr Woyach.
Dr Woyach said future clinical trials could help refine the use of pirtobrutinib alone or in combination with other therapies as a frontline treatment.
