Acalabrutinib in combination with rituximab and lenalidomide in patients with relapsed or refractory follicular lymphoma: Results of the phase 1b open‐label study ( ACE ‐ LY ‐003)

Summary Patients with relapsed/refractory (R/R) follicular lymphoma (FL) have limited effective treatment options. Bruton tyrosine kinase inhibitors (BTKis) increase the anti‐tumoural phenotype of tumour‐associated macrophages, providing rationale to combine them with rituximab and lenalidomide (R 2 ). Acalabrutinib, a second‐generation BTKi, has potential to improve R 2 efficacy without increasing T‐cell–mediated toxicity due to its lack of interleukin‐2–inducible T‐cell kinase inhibition. Here, we report safety and efficacy from a phase 1b dose‐finding study (NCT02180711) evaluating acalabrutinib plus R 2 in patients with R/R FL. Overall, 29 patients received acalabrutinib plus R 2 (lenalidomide 15 mg, n = 8; lenalidomide 20 mg, n = 21). At a median acalabrutinib exposure of 21 months, the most common grade ≥3 treatment‐emergent adverse event (TEAE) was neutropenia (37.9%). The incidence of grade ≥3 serious TEAEs was 37.5% and 52.4% in the lenalidomide 15‐mg and 20‐mg cohorts, respectively; overall, the most common were COVID‐19 pneumonia, COVID‐19 infection and pneumonia. Earlier treatment withholdings/reductions were observed in the 20‐mg cohort. With a median follow‐up of 34.1 months, the overall response rate was 75.9%. The complete response rate was 25.0% and 42.9% in the lenalidomide 15‐ and 20‐mg cohorts, respectively. Due to acceptable toxicity and preliminary efficacy, the lenalidomide 20‐mg dose was selected for further investigation.