An Improved Benefit-Risk Profile of Duvelisib in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Received ≥2 Prior Therapies

Context
Despite effective frontline therapies, many patients with CLL or SLL eventually relapse and require additional therapies to control their disease. Duvelisib, a first-in-class oral dual PI3K-δ,γ inhibitor, was approved by the FDA for the treatment of relapsed or refractory CLL or SLL after ≥2 prior therapies.
Objective
To characterize the efficacy and safety of duvelisib in patients who had received ≥2 prior therapies in the phase 3 DUO trial.
Design
Patients were randomized 1:1 to oral duvelisib 25 mg BID or IV ofatumumab (OFA) 300 mg once, then 2000 mg for 12 doses total. The primary endpoint was progression-free survival (PFS) as assessed by a blinded IRC.
Results
Of the 319 total patients randomized, 191 had received ≥2 prior therapies (93 duvelisib; 98 ofatumumab). In this population, the median number of prior therapies was 3 (range, 2-10). Duvelisib was superior to OFA across all efficacy endpoints, including median PFS (duvelisib 16.4 mo, OFA 9.1 mo; HR, 0.4, P<0.0001), ORR (duvelisib 78.9%, OFA 38.6%; OR, 7.3, P<0.0001), and LNRR (duvelisib 88.4%, OFA 13.9%; P<0.0001). AEs occurring in >25% of patients who received duvelisib (all grade; grade ≥3) were diarrhea/colitis (58%; 24%), neutropenia (40%; 38%), pyrexia (33%; 2%), upper respiratory infection (30%; 0%), pneumonia (29%; 22%) and fatigue (26%; 3%). Many AEs were successfully managed through dose modifications, with dose reductions occurring in 28% and dose interruptions occurring in 74% of patients who received duvelisib; diarrhea/colitis (10%) and neutropenia (5%) were the most common AEs leading to dose reduction. 22 patients discontinued duvelisib due to a related AE; diarrhea/colitis (n=8), pneumonia (n=3) and pneumonitis (n=2) were the only treatment-related events leading to discontinuation in >1 patient. 11 patients (12%) treated with duvelisib experienced a fatal AE. The only fatal events to occur in >1 patient were hemorrhagic stroke (n=2) and staphylococcal pneumonia (n=2). AEs with OFA were similar to those previously reported.
Conclusions
Duvelisib monotherapy had a manageable safety profile and demonstrated significantly improved clinical outcomes over OFA in CLL/SLL patients who had received ≥2 prior therapies, a population in need of additional targeted therapies.