Effect of dose modifications on response to duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma in the DUO trial

Purpose of the Study: Duvelisib, a first-in-class oral dual PI3K-, inhibitor, was approved by the FDA for treatment of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) after 2 prior therapies. In the phase 3 DUO trial, duvelisib 25 mg twice daily (BID) significantly improved efficacy vs ofatumumab (median progression-free survival [PFS], 13.3 vs 9.9 months; HR, 0.52 [P < .0001]; overall response rate, 74% vs 45% [P < .0001]) in patients with R/R CLL/SLL.1 Treatment-emergent adverse events (TEAEs) of special interest (AESI), such as infections, diarrhea, colitis, neutropenia, cutaneous reactions, ALT/AST elevation, and pneumonitis, were moderate and manageable with early intervention and dose modification. Summarized Description of the Project: Dose-modification patterns and their impact on response to duvelisib in the DUO trial were examined retrospectively. Dose interruption (DI) or  reduction  (DR)  to  15, 10, or 5 mg BID was permitted per study protocol to manage TEAEs. Responses were assessed by an independent review commit- tee before and after dose modifications and were analyzed using descriptive statistics.

Results: Among 158 duvelisib-treated patients, median duration of duvelisib exposure was 11.6 months (vs 5.3 months with ofatumumab). DI and DR occurred in 80% (126/158) and 27% (43/158) of patients, respectively. The most common AESI leading to DI were diarrhea/colitis (28%), infections (27%), cutaneous reactions (13%), and neutropenia (12%). Among responders (n = 118), median time to first response with duvelisib was 1.9 months, and estimated median duration of response was 11.1 months. Median time to first DI was 3.9 months, and median duration of DI was 15 days (range, 1-133 days). Response to duvelisib was improved or maintained in most patients evaluated for response who had 1 DI for > 1 week (84% [42/50]) or > 2 weeks (82% [31/38]) followed by 3 weeks on duvelisib. In a landmark analysis, median PFS was similar in patients with DI and those without DI for > 1 week (17.8 vs 16.3 months) or > 2 weeks (17.8 vs 16.3 months) within the first 3 months. The median time to DR after complete response or partial response was 5.6 months (n = 25) and median duration was 3.4 months. Median time to onset across AESI after starting duvelisib ranged from 2.2 to 4.3 months; median duration across AESI was 4 weeks. Proportions of patients experiencing AESI were stable or decreased over time after 0 to 3 months, 64% (101/158); > 3 to 6 months, 63% (86/137); > 6 to 9 months, 47% (54/114); > 9 to 12 months, 52% (52/100) and seldom led to discontinuation of duvelisib ( 10%).

Conclusion: DI/DR can contribute to the effective management of TEAEs with duvelisib in patients with R/R CLL/SLL. These findings suggest that DI of > 1 week do not negatively impact response to duvelisib or PFS.

References

1. Flinn IW, et al. Blood. 2018;132(23):2446-2455.