Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk.

Methods: This Phase 2 trial is evaluating entospletinib 800 mg BID in a study of 204 patients with previously treated lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria.

Results: A cohort of 69 patients with iNHL (41 follicular lymphoma [FL], 11 lymphoplasmacytoid lymphoma [LPL], 17 marginal zone lymphoma [MZL]) are included in this analysis. Median age was 66 years (range 41 - 89). 58% were male. The median number of prior treatments (Rxs) regimens was 3 (range 1- 14). Prior Rxs included anti-CD20 antibodies (rituximab 99%, ofatumumab 4%), alkylating agents (90%; bendamustine 51%) and anthracyclines (35%). Baseline risk factors: Ann Arbor Stg III-IV (70%), Gr 3a FL (29%), FLIPI ≥3 (34%). Median duration of Rx was 16 weeks with 10 patients continuing on Rx. Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (54%/13%), nausea (49%/4%), diarrhea(36%/0%), vomiting (26%/0%), headache (23%/1%), pyrexia (23%/3%), decreased appetite (22%/0%), constipation (22%/1%) and common laboratory abnormalities were increased AST (33%/15%), increased ALT (41%/19%), increased total bilirubin (32%/16%), anemia (36%/13%) and neutropenia (38%/13%). 4 patients died while on study from progressive disease. At the time of this analysis, 66 of 69 patients have been treated through first response assessment (1 patient ongoing not reaching first response assessment, 1 patient discontinued due to AE and 1 patient withdrew consent prior to it). 38 out of 61 (62%) patients evaluable for SPD experienced reduced tumor burden, with median duration of Rx 28 weeks (range 4-92). 9/61 (15%) achieved a decrease of ≥ 50% in SPD. The ORR was 13.0% (95% CI: 6.1%, 23.3%), with 7 patients achieving a PR, one LPL patient achieving MR and one patient achieving a CR. Forty-one patients (59.4%) had stable disease. The primary end point of 24 weeks PFS was 48.9% (95% CI: 34.6%, 61.7%). Median PFS was 5.5 months (95% CI: 4.4 months, 8.2 months). There were 39 patients (56.5%) with events of disease progression.

Conclusions: Entospletinib monotherapy given with this dose and schedule was well tolerated and demonstrated activity in patients with advanced relapsed iNHL, including those with poor prognostic features. Further development of entospletinib in iNHL will focus on the development of combination approaches with chemotherapy and targeted agents.


Sharman:Calistoga: Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Off Label Use: Management of CLL/SLL and follicular lymphoma. Kolibaba:Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; GSK: Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. Eng:Gilead: Employment. He:Gilead Sciences: Employment. Hu:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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