Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial

Abstract

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase I/II BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with relapsed / refractory B-cell malignancies (clinicaltrials.gov 03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (N=40, 31.5%), specifically atrial fibrillation (N=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%) or death (5.5%). The most frequent treatment-emergent AE were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 chronic lymphocytic / small lymphocytic lymphoma (CLL/SLL) and 21 mantle cell lymphoma (MCL) patients intolerant to prior BTKi, overall response rate to pirtobrutinib was 76.9% and 81.0%, respectively. Median progression-free survival for CLL/SLL was 28.4 months but was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Figure 1.

Recurrence with pirtobrutinib treatment of treatment emergent adverse events that had previously led to discontinuation of prior Bruton tyrosine kinase inhibitor within the same patient. Common treatment emergent adverse event (TEAE) categories that had led to discontinuation of prior Bruton tyrosine kinase inhibitor (BTKi) are shown; an individual patient may be counted in more than one category. ^aCardiac disorders include atrial fibrillation. ^bPrior discontinuation infection types were not specified for most patients, so any infection recurrence was investigated. Among the 6 patients with a grade >3 infection recurrence, 11 grade ≥3 events were reported and included: diarrhea and salmonellosis in 1 patient; bacteremia, septic shock, and fungal pneumonia in 1 patient; pneumonia, COVID-19, and COVID-19 pneumonia in 1 patient; and pneumonia, viral pneumonia, and COVID-19 pneumonia each in 1 patient. ^cGastrointestinal disorders include diarrhea. ^dOne patient had recurrence of pain in the same site, 3 had new / different pain, and 2 had no pain; no patient discontinued pirtobrutinib for pain.

Figure 2.

Pirtobrutinib efficacy in patients intolerant to prior Bruton tyrosine kinase inhibitor. Waterfall plot of best change in tumor burden based on investigator assessments. Best change in tumor size was defined as the maximum % change in the sum of product diameters (SPD) at a post-baseline assessment relative to baseline. Pirtobrutinib exhibited promising efficacy across B-cell malignancies among patients who experienced intolerance to prior Bruton tyrosine kinase inhibitor (BTKi). Data for 12 patients are not shown due to 6 patients having no target lesions identified at baseline, and 6 patients with no / incomplete post-baseline lesion measurements. CLL: chronic lymphocytic lymphoma; SLL: small lymphocytic lymphoma.

Figure 3.

Progression-free survival in patients intolerant to prior Bruton tyrosine kinase inhibitor. Median progression-free survival (PFS) for patients with chronic lymphocytic lymphoma (CLL) / small lymphocytic lymphoma (SLL) was 28.4 months (95% Confidence Interval [CI]: 21.8-not estimable [NE]), while median PFS was not estimable for patients with mantle cell lymphoma (MCL). Median overall survival was not estimable for CLL/SLL or MCL.