Effect of Dose Modifications on Response to Duvelisib in Patients with Relapsed/Refractory (R/R) CLL/SLL in the DUO Trial

Ian Flinn; Marco Montillo; Árpád Illés; Gabriel Etienne; Julio Delgado; Bryone Kuss; Constantine Tam; Fritz Offner; Francesc Bosch; Matthew Davids; Ulrich Jager; Paolo Ghia; Florence Cymbalista; David Weaver; Stephanie Lustgarten; Hagop Youssoufian; Stephan Stilgenbauer; Nicole Lamanna

doi:10.1016/j.clml.2019.07.204

Abstract

Context
Duvelisib, a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment of R/R CLL/SLL after ≥2 prior therapies. In the phase 3 DUO trial, duvelisib 25 mg BID significantly improved efficacy vs ofatumumab in patients with R/R CLL/SLL. Treatment-emergent AEs (TEAEs) of special interest (AESIs) were moderate and manageable with early intervention and dose modification.
Objective
To examine dose modification patterns and their impact on response to duvelisib in the DUO trial.
Design
Dose interruptions (DIs) or reductions (DRs) were permitted per study protocol to manage TEAEs. Responses were assessed by IRC.
Results
Among 158 duvelisib-treated patients, median duration of exposure was 11.6 months. DIs occurred more frequently than DRs (80% vs 27%). The most common AESIs leading to DI were diarrhea/colitis (28%), infections (27%), cutaneous reactions (13%), and neutropenia (12%). Among 118 responders, median time to first response was 1.9 months and median duration of response was 11.1 months. Median time to first DI was 3.9 months and median duration was 15 days. Response to duvelisib was improved or maintained in most patients evaluated for response who had ≥1 DI for >1 week (84%) or >2 weeks (82%) followed by ≥3 weeks on duvelisib. In a landmark analysis, median PFS was similar in patients with and 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 CR/PR was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across AESIs ranged from 2.2 to 4.3 months and median duration across AESIs was up to 4 weeks. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of duvelisib (≤10%).
Conclusions
DIs/DRs can contribute to the effective management of TEAEs with duvelisib. These findings suggest that DIs of >1 week do not negatively impact response to duvelisib or PFS.

Original language	English
Article number	CLL-029
Pages (from-to)	S273-S274
Number of pages	2
Journal	Clinical Lymphoma, Myeloma & Leukemia
Volume	19
Issue number	S1
DOIs	https://doi.org/10.1016/j.clml.2019.07.204
Publication status	Published - 1 Sept 2019
Externally published	Yes

Keywords

Dose Modifications
Duvelisib
chronic lymphocytic leukemia
PI3K
CLL

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.clml.2019.07.204Licence: In Copyright

Cite this

Flinn, I., Montillo, M., Illés, Á., Etienne, G., Delgado, J., Kuss, B., Tam, C., Offner, F., Bosch, F., Davids, M., Jager, U., Ghia, P., Cymbalista, F., Weaver, D., Lustgarten, S., Youssoufian, H., Stilgenbauer, S., & Lamanna, N. (2019). Effect of Dose Modifications on Response to Duvelisib in Patients with Relapsed/Refractory (R/R) CLL/SLL in the DUO Trial. Clinical Lymphoma, Myeloma & Leukemia, 19(S1), S273-S274. Article CLL-029. https://doi.org/10.1016/j.clml.2019.07.204

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title = "Effect of Dose Modifications on Response to Duvelisib in Patients with Relapsed/Refractory (R/R) CLL/SLL in the DUO Trial",

abstract = "ContextDuvelisib, a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment of R/R CLL/SLL after ≥2 prior therapies. In the phase 3 DUO trial, duvelisib 25 mg BID significantly improved efficacy vs ofatumumab in patients with R/R CLL/SLL. Treatment-emergent AEs (TEAEs) of special interest (AESIs) were moderate and manageable with early intervention and dose modification.ObjectiveTo examine dose modification patterns and their impact on response to duvelisib in the DUO trial.DesignDose interruptions (DIs) or reductions (DRs) were permitted per study protocol to manage TEAEs. Responses were assessed by IRC.ResultsAmong 158 duvelisib-treated patients, median duration of exposure was 11.6 months. DIs occurred more frequently than DRs (80% vs 27%). The most common AESIs leading to DI were diarrhea/colitis (28%), infections (27%), cutaneous reactions (13%), and neutropenia (12%). Among 118 responders, median time to first response was 1.9 months and median duration of response was 11.1 months. Median time to first DI was 3.9 months and median duration was 15 days. Response to duvelisib was improved or maintained in most patients evaluated for response who had ≥1 DI for >1 week (84%) or >2 weeks (82%) followed by ≥3 weeks on duvelisib. In a landmark analysis, median PFS was similar in patients with and 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 CR/PR was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across AESIs ranged from 2.2 to 4.3 months and median duration across AESIs was up to 4 weeks. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of duvelisib (≤10%).ConclusionsDIs/DRs can contribute to the effective management of TEAEs with duvelisib. These findings suggest that DIs of >1 week do not negatively impact response to duvelisib or PFS.",

keywords = "Dose Modifications, Duvelisib, chronic lymphocytic leukemia, PI3K, CLL",

author = "Ian Flinn and Marco Montillo and {\'A}rp{\'a}d Ill{\'e}s and Gabriel Etienne and Julio Delgado and Bryone Kuss and Constantine Tam and Fritz Offner and Francesc Bosch and Matthew Davids and Ulrich Jager and Paolo Ghia and Florence Cymbalista and David Weaver and Stephanie Lustgarten and Hagop Youssoufian and Stephan Stilgenbauer and Nicole Lamanna",

year = "2019",

month = sep,

day = "1",

doi = "10.1016/j.clml.2019.07.204",

language = "English",

volume = "19",

pages = "S273--S274",

journal = "Clinical Lymphoma, Myeloma & Leukemia",

issn = "2152-2650",

publisher = "Cancer Media Group",

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}

Flinn, I, Montillo, M, Illés, Á, Etienne, G, Delgado, J, Kuss, B, Tam, C, Offner, F, Bosch, F, Davids, M, Jager, U, Ghia, P, Cymbalista, F, Weaver, D, Lustgarten, S, Youssoufian, H, Stilgenbauer, S & Lamanna, N 2019, 'Effect of Dose Modifications on Response to Duvelisib in Patients with Relapsed/Refractory (R/R) CLL/SLL in the DUO Trial', Clinical Lymphoma, Myeloma & Leukemia, vol. 19, no. S1, CLL-029, pp. S273-S274. https://doi.org/10.1016/j.clml.2019.07.204

TY - JOUR

T1 - Effect of Dose Modifications on Response to Duvelisib in Patients with Relapsed/Refractory (R/R) CLL/SLL in the DUO Trial

AU - Flinn, Ian

AU - Montillo, Marco

AU - Illés, Árpád

AU - Etienne, Gabriel

AU - Delgado, Julio

AU - Kuss, Bryone

AU - Tam, Constantine

AU - Offner, Fritz

AU - Bosch, Francesc

AU - Davids, Matthew

AU - Jager, Ulrich

AU - Ghia, Paolo

AU - Cymbalista, Florence

AU - Weaver, David

AU - Lustgarten, Stephanie

AU - Youssoufian, Hagop

AU - Stilgenbauer, Stephan

AU - Lamanna, Nicole

PY - 2019/9/1

Y1 - 2019/9/1

N2 - ContextDuvelisib, a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment of R/R CLL/SLL after ≥2 prior therapies. In the phase 3 DUO trial, duvelisib 25 mg BID significantly improved efficacy vs ofatumumab in patients with R/R CLL/SLL. Treatment-emergent AEs (TEAEs) of special interest (AESIs) were moderate and manageable with early intervention and dose modification.ObjectiveTo examine dose modification patterns and their impact on response to duvelisib in the DUO trial.DesignDose interruptions (DIs) or reductions (DRs) were permitted per study protocol to manage TEAEs. Responses were assessed by IRC.ResultsAmong 158 duvelisib-treated patients, median duration of exposure was 11.6 months. DIs occurred more frequently than DRs (80% vs 27%). The most common AESIs leading to DI were diarrhea/colitis (28%), infections (27%), cutaneous reactions (13%), and neutropenia (12%). Among 118 responders, median time to first response was 1.9 months and median duration of response was 11.1 months. Median time to first DI was 3.9 months and median duration was 15 days. Response to duvelisib was improved or maintained in most patients evaluated for response who had ≥1 DI for >1 week (84%) or >2 weeks (82%) followed by ≥3 weeks on duvelisib. In a landmark analysis, median PFS was similar in patients with and 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 CR/PR was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across AESIs ranged from 2.2 to 4.3 months and median duration across AESIs was up to 4 weeks. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of duvelisib (≤10%).ConclusionsDIs/DRs can contribute to the effective management of TEAEs with duvelisib. These findings suggest that DIs of >1 week do not negatively impact response to duvelisib or PFS.

AB - ContextDuvelisib, a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment of R/R CLL/SLL after ≥2 prior therapies. In the phase 3 DUO trial, duvelisib 25 mg BID significantly improved efficacy vs ofatumumab in patients with R/R CLL/SLL. Treatment-emergent AEs (TEAEs) of special interest (AESIs) were moderate and manageable with early intervention and dose modification.ObjectiveTo examine dose modification patterns and their impact on response to duvelisib in the DUO trial.DesignDose interruptions (DIs) or reductions (DRs) were permitted per study protocol to manage TEAEs. Responses were assessed by IRC.ResultsAmong 158 duvelisib-treated patients, median duration of exposure was 11.6 months. DIs occurred more frequently than DRs (80% vs 27%). The most common AESIs leading to DI were diarrhea/colitis (28%), infections (27%), cutaneous reactions (13%), and neutropenia (12%). Among 118 responders, median time to first response was 1.9 months and median duration of response was 11.1 months. Median time to first DI was 3.9 months and median duration was 15 days. Response to duvelisib was improved or maintained in most patients evaluated for response who had ≥1 DI for >1 week (84%) or >2 weeks (82%) followed by ≥3 weeks on duvelisib. In a landmark analysis, median PFS was similar in patients with and 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 CR/PR was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across AESIs ranged from 2.2 to 4.3 months and median duration across AESIs was up to 4 weeks. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of duvelisib (≤10%).ConclusionsDIs/DRs can contribute to the effective management of TEAEs with duvelisib. These findings suggest that DIs of >1 week do not negatively impact response to duvelisib or PFS.

KW - Dose Modifications

KW - Duvelisib

KW - chronic lymphocytic leukemia

KW - PI3K

KW - CLL

U2 - 10.1016/j.clml.2019.07.204

DO - 10.1016/j.clml.2019.07.204

M3 - Meeting Abstract

SN - 2152-2650

VL - 19

SP - S273-S274

JO - Clinical Lymphoma, Myeloma & Leukemia

JF - Clinical Lymphoma, Myeloma & Leukemia

IS - S1

M1 - CLL-029