Phase 2 Trial of Entospletinib (GS-9973), a Selective SYK Inhibitor, in Follicular Lymphoma (FL)

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 (Kd 7.6 nM, no other kinase < 100 nM).

Methods: This Phase 2 trial is evaluating Entospletinib 800 mg BID in a 41 subject cohort with previously treated FL in a study of 165 subjects with lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria.

Results: For the subjects with FL included in this analysis, median age was 67 years (range 41 – 89), 49% were male. The median number of prior Rx regimens was 2 (range 1-8). Prior treatments (Rxs) included anti-CD20 antibodies (rituximab 100%, ofatumumab 5%), alkylating agents (95%; bendamustine 51%) and anthracyclines (51%). Baseline risk factors: Ann Arbor Stg III-IV (66%), Gr 3a FL (27%), FLIPI ≥3 (34%). At the time of this analysis, 41 subjects with follicular lymphoma were enrolled and 38 subjects have been treated through first response assessment (1 subject ongoing prior to first response assessment, 1subject discontinued due to AE and 1 subject withdrew consent). Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (46%/12%), nausea (42%/2%), diarrhea(27%/0%), decreased appetite (22%/0%), vomiting (22%/0%) and common laboratory abnormalities were increased AST (37%/17%), increased ALT (34%/20%), increased total bilirubin (27%/5%), anemia (34%/10%) and neutropenia (22%/10%). Reversible Grade 3 or 4 ALT/AST elevations occurred in 8 (19.5%) FL subjects. 3 subjects died while on study: 2 from progressive disease and 1 from acute renal failure investigator reported as unrelated to study drug. Investigator response assessments are available for 29 subjects, 16/29 (55%) subjects experienced reduced tumor bulk measured by SPD; 3 (10%) achieved a decrease of ≥ 50%. CR has not been observed at this early evaluation. 14/41 subjects continue on Rx. Median duration of Rx for all patients was 15 weeks. Among all patients who experienced reduction in tumor volume, median duration of Rx was 25 weeks (range 4-51).

Conclusions: Entospletinib monotherapy given with this dose and schedule was generally well tolerated and demonstrated moderate activity in subjects with advanced relapsed FL, including those with poor prognostic features. Updated data with longer follow-up duration will be presented at the meeting.