LONG TERM INTEGRATED SAFETY ANALYSIS OF UMBRALISIB (TGR-1202), A PI3K-DELTA/CK1-EPSILON INHIBITOR WITH A DIFFERENTIATED SAFETY PROFILE, IN PATIENTS WITH RELAPSED/REFRACTORY LYMPHOID MALIGNANCIES
Author(s): ,
Matthew S. Davids, MD, MMSC
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Ian W. Flinn, MD, PhD
Affiliations:
Sarah Cannon Research Institute,Nashville,United States;Tennessee Oncology,Nashville,United States
,
Anthony R. Mato, MD
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Owen A. O'Connor, MD, PhD
Affiliations:
Center for Lymphoid Malignancies, Columbia University Medical Center,New York,United States
,
Daniel M. Brander, MD
Affiliations:
Duke University Medical Center,Durham,United States
,
Matthew A. Lunning, DO
Affiliations:
University of Nebraska Medical Center,Omaha,United States
,
Julie M. Vose, MD, MBA
Affiliations:
University of Nebraska Medical Center,Omaha,United States
,
Loretta Nastoupil, MD
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Nathan Fowler, MD
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Christopher R. Flowers, MD, MS
Affiliations:
Winship Cancer Institute, Emory University,Atlanta,United States
,
Jennifer R. Brown, MD, PhD
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Marshall T. Schreeder, MD
Affiliations:
Clearview Cancer Institute,Huntsville,United States
,
Nilanjan Ghosh, MD, PhD
Affiliations:
Levine Cancer Institute,Charlotte,United States
,
Frederick Lansigan, MD
Affiliations:
Dartmouth-Hitchcock Medical Center,Lebanon,United States
,
Bruce D. Cheson, MD
Affiliations:
Georgetown University Medical Center,Washington DC,United States
,
Paul M. Barr, MD
Affiliations:
Wilmot Cancer Institute, University of Rochester,Rochester,United States
,
John M. Pagel, MD, PhD
Affiliations:
Swedish Cancer Institute,Seattle,United States
,
Alexey Danilov, MD, PhD
Affiliations:
Oregon Health & Science University,Portland,United States
,
Javier Pinilla-Ibarz, MD, PhD
Affiliations:
H. Lee Moffitt Cancer Center & Research Institute,Tampa,United States
,
Changchun Deng, MD, PhD
Affiliations:
Center for Lymphoid Malignancies, Columbia University Medical Center,New York,United States
,
John M. Burke, MD
Affiliations:
Rocky Mountain Cancer Centers,Aurora,United States;US Oncology,Woodlands,United States
,
Tanya Siddiqi, MD
Affiliations:
City of Hope National Medical Center,Duarte,United States
,
Manish R. Patel, MD
Affiliations:
Florida Cancer Specialists,Sarasota,United States;Sarah Cannon Research Institute,Nashville,United States
,
Charles M. Farber, MD, PhD
Affiliations:
Summit Medical Group/MD Anderson Cancer Center,Summit,United States
,
Parameswaran Venugopal, MD
Affiliations:
Rush University Medical Center,Chicago,United States
,
John G. Gribben, MD DSc FMedSci
Affiliations:
Barts Hospital Cancer Institute, Queen Mary University of London,London,United Kingdom
,
Pier Luigi Zinzani, MD, PhD
Affiliations:
Institute of Hematology "L. e A. Seràgnoli", University of Bologna,Bologna,Italy
,
Hari P. Miskin, MS
Affiliations:
TG Therapeutics, Inc.,New York,United States
,
Peter Sportelli
Affiliations:
TG Therapeutics, Inc.,New York,United States
,
Michael S. Weiss
Affiliations:
TG Therapeutics, Inc.,New York,United States
Susan M. O'Brien, MD
Affiliations:
University of California Irvine, Chao Family Comprehensive Cancer Center,Orange,United States
(Abstract release date: 05/17/18) EHA Library. S. Davids, MD, MMSC M. 06/15/18; 214906; PF444
Matthew S. Davids, MD, MMSC
Matthew S. Davids, MD, MMSC
Contributions
Abstract

Abstract: PF444

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
First generation PI3Kδ inhibitors such as idelalisib and duvelisib are active in patients (pts) with lymphoid malignancies, but are often associated with significant immune-mediated adverse events (AEs), including transaminitis, diarrhea/colitis, and pneumonitis.  These toxicities can be severe, and frequently lead to treatment discontinuation; moreover, these toxicities may arise only after pts have been on drug for several months.  Umbralisib (TGR-1202) is a next generation, once-daily, oral PI3Kδ/CK1ε inhibitor, that is active in pts with relapsed/refractory (R/R) lymphoid malignancies (Burris et al, 2018).  We previously have presented data suggesting that umbralisib has a favorable safety profile, though follow-up in the prior analysis was short, and the crucial information about the rate of late immune-mediated AEs with umbralisib was not available due to short follow-up.

Aims
We performed an integrated safety analysis focusing on key immune-mediated AEs with long term follow-up of pts on umbralisib.

Methods
Safety data were pooled from 5 completed or ongoing Phase 1 or 2 studies with umbralisib alone or in combination with other agents. All studies shared similar key eligibility criteria: pts had R/R lymphoid malignancies w/out limit to # of prior therapies. Umbralisib was dosed daily until PD or toxicity, while dosing of combination agents varied.

Results
A total of 347 pts were included in the analysis.  Patients received the following regimens:  umbralisib as monotherapy (146 pts) or umbralisib in combination with: the glycoengineered anti-CD20 mAb ublituximab (“U2”, 98 pts), ibrutinib (32 pts), ublituximab + ibrutinib (38 pts), or ublituximab + bendamustine (33 pts).  Among the 347 pts, 34% had CLL/SLL, 33% DLBCL, 21% indolent NHL, and 12% other lymphomas.  Pts had a median 3 prior therapies. Median duration of exposure to umbralisib was 6.5 months, with the longest patient on daily umbralisib for 4+ years.  The most common all-grade non-hematologic toxicities were: diarrhea (44% All – 29% GR1, 11% GR2, 4% GR3), nausea (39% All – 25% GR1, 13% GR2, 1% GR3), and fatigue (35% All – 19% GR1, 14% GR2, 2% GR3).  The median time to onset for diarrhea events was early (32 days) and resolved in a median of 7 days.  All-grade hematologic toxicities included neutropenia (22%), anemia (20%), and thrombocytopenia (18%).  Grade 3/4 adverse events are described in Table 1. Key adverse events prevalent in prior generation PI3Kδ inhibitors were infrequent: transaminitis (8.6% All; G3/4 2.3%), colitis (1.4% All; G3/4 0.9%), and pneumonitis (1.4% All; G3/4 0.3%).  Discontinuations due to treatment related adverse events were rare at under 10% for all studies. A total of 167 pts treated with umbralisib for a minimum duration of 6 months were included in a sub-analysis of long term safety.  The median duration of exposure amongst these pts was 15.6 months (range 6.4 – 60.6 months).  A summary of AEs occurring after 6 months on therapy is presented in Table 2.

Conclusion
In this integrated analysis with long term follow-up, once-daily umbralisib exhibited a differentiated safety profile compared to prior generation PI3Kδ inhibitors.  In particular, late onset diarrhea or colitis commonly associated with first-generation PI3Kδ inhibitors was infrequent.  Umbralisib can be safely combined with a diverse array of other agents active in lymphoid malignancies, and is currently being studied in the global registration directed UNITY-CLL Phase 3 randomized trial (NCT02612311) and UNITY-NHL Phase 2b randomized trial (NCT02793583).

Session topic: 20. Indolent Non-Hodgkin lymphoma – Clinical

Keyword(s): Chronic Lymphocytic Leukemia, Non-Hodgkin's lymphoma, PI3 kinase, PI3K

Abstract: PF444

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
First generation PI3Kδ inhibitors such as idelalisib and duvelisib are active in patients (pts) with lymphoid malignancies, but are often associated with significant immune-mediated adverse events (AEs), including transaminitis, diarrhea/colitis, and pneumonitis.  These toxicities can be severe, and frequently lead to treatment discontinuation; moreover, these toxicities may arise only after pts have been on drug for several months.  Umbralisib (TGR-1202) is a next generation, once-daily, oral PI3Kδ/CK1ε inhibitor, that is active in pts with relapsed/refractory (R/R) lymphoid malignancies (Burris et al, 2018).  We previously have presented data suggesting that umbralisib has a favorable safety profile, though follow-up in the prior analysis was short, and the crucial information about the rate of late immune-mediated AEs with umbralisib was not available due to short follow-up.

Aims
We performed an integrated safety analysis focusing on key immune-mediated AEs with long term follow-up of pts on umbralisib.

Methods
Safety data were pooled from 5 completed or ongoing Phase 1 or 2 studies with umbralisib alone or in combination with other agents. All studies shared similar key eligibility criteria: pts had R/R lymphoid malignancies w/out limit to # of prior therapies. Umbralisib was dosed daily until PD or toxicity, while dosing of combination agents varied.

Results
A total of 347 pts were included in the analysis.  Patients received the following regimens:  umbralisib as monotherapy (146 pts) or umbralisib in combination with: the glycoengineered anti-CD20 mAb ublituximab (“U2”, 98 pts), ibrutinib (32 pts), ublituximab + ibrutinib (38 pts), or ublituximab + bendamustine (33 pts).  Among the 347 pts, 34% had CLL/SLL, 33% DLBCL, 21% indolent NHL, and 12% other lymphomas.  Pts had a median 3 prior therapies. Median duration of exposure to umbralisib was 6.5 months, with the longest patient on daily umbralisib for 4+ years.  The most common all-grade non-hematologic toxicities were: diarrhea (44% All – 29% GR1, 11% GR2, 4% GR3), nausea (39% All – 25% GR1, 13% GR2, 1% GR3), and fatigue (35% All – 19% GR1, 14% GR2, 2% GR3).  The median time to onset for diarrhea events was early (32 days) and resolved in a median of 7 days.  All-grade hematologic toxicities included neutropenia (22%), anemia (20%), and thrombocytopenia (18%).  Grade 3/4 adverse events are described in Table 1. Key adverse events prevalent in prior generation PI3Kδ inhibitors were infrequent: transaminitis (8.6% All; G3/4 2.3%), colitis (1.4% All; G3/4 0.9%), and pneumonitis (1.4% All; G3/4 0.3%).  Discontinuations due to treatment related adverse events were rare at under 10% for all studies. A total of 167 pts treated with umbralisib for a minimum duration of 6 months were included in a sub-analysis of long term safety.  The median duration of exposure amongst these pts was 15.6 months (range 6.4 – 60.6 months).  A summary of AEs occurring after 6 months on therapy is presented in Table 2.

Conclusion
In this integrated analysis with long term follow-up, once-daily umbralisib exhibited a differentiated safety profile compared to prior generation PI3Kδ inhibitors.  In particular, late onset diarrhea or colitis commonly associated with first-generation PI3Kδ inhibitors was infrequent.  Umbralisib can be safely combined with a diverse array of other agents active in lymphoid malignancies, and is currently being studied in the global registration directed UNITY-CLL Phase 3 randomized trial (NCT02612311) and UNITY-NHL Phase 2b randomized trial (NCT02793583).

Session topic: 20. Indolent Non-Hodgkin lymphoma – Clinical

Keyword(s): Chronic Lymphocytic Leukemia, Non-Hodgkin's lymphoma, PI3 kinase, PI3K

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