Therapies that target B-cell receptor signaling kinases have made great strides in chronic lymphocytic lymphoma (CLL) and other B-cell malignancies. According to results from a phase 2 trial recently published in Blood, entospletinib, a selective spleen tyrosine kinase (Syk) inhibitor, shows promise in the treatment of relapsed or refractory CLL and non-Hodgkin lymphoma (NHL).
“Novel agents treating the BCR [B-cell receptor] signaling cascade are transforming the management of patients with CLL,” noted lead investigator Jeff Sharman, MD, of the Willamette Valley Cancer Institute in Springfield, Oregon. “Inhibition of key signaling enzymes within the pathway is becoming an important therapeutic strategy.”
As part of a larger multicenter study of lymphoid malignancy treatment, the compound, entospletinib, an adenosine triphosphate competitive inhibitor of Syk, was evaluated for safety and efficacy in 41 CLL patients with progressive disease.
Prior treatment for CLL comprised either a regimen of a therapeutic antibody administered for two or more doses of treatment, or a regimen of at least one cytotoxic agent administered for two or more cycles of treatment. In addition, patients were required to have a Kamofsky performance status of at least 60 percent and a life expectancy of at least 3 months.
Patients received 800 mg of entospletinib, twice daily, for a 28-day cycle. The primary endpoint was progression-free survival (PFS) at 24 weeks; secondary endpoints included tolerability, objective response rate (ORR), duration of response (DOR), time to response, and lymph node response rate.
Tumor response was assessed every eight weeks during the first 24 weeks and every 12 weeks thereafter. Blood samples were collected on the first day of each treatment cycle, as well as multiple times during the first and second treatment cycles.
At a median follow-up time of 7.7 months, PFS was 70.1 percent (95% CI 51.3 – 82.7) and median PFS was 13.8 months.
The ORR was 61 percent (95% CI 44.5 – 75.8%), with 25 patients achieving a partial response and three achieving a nodal response. However, no patients achieved a complete response. Thirteen patients had stable disease, and one had progressive disease.
“Therapeutic targeting of BCR signaling kinases has proven to be an effective strategy in CLL and select B-cell malignancies,” Dr. Sharman told ASH Clinical News. “Our research shows that inhibition of Syk kinase with entospletinib results in significant clinical activity approximately comparable to idelalisib.”
In the CLL cohort, 15 patients (36.6%) experienced adverse events, 14 (34.1%) with disease progression, and one death (2.4%) due to septic pneumonia that was unrelated to entospletnib therapy. For the entire 186-patient cohort treated with entospletinib, nearly all (96.8%) experienced at least one treatment-emergent adverse event; for 54 patients (29%), those events were deemed “serious” and included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia.
“Entospletinib was considerably better tolerated than fostamatinib, the first Syk kinase inhibitor studied, although significant liver function test abnormalities were noted in some patients,” Dr. Sharman observed.
“Development of entospletinib is currently focused on optimizing the formulation and dose,” he added. “Pivotal phase 3 studies are currently being considered but have not yet started accrual.”
As to whether enstospletinib could have a role as first-line therapy for CLL, or as an alternative to other agents to which these patients are intolerant, Dr. Sharman offered cautious encouragement.
“If entospletinib were studied prior to either ibrutinib or idelalisib – other key BCR signal inhibitors – it would be considered a remarkable breakthrough,” he said. “With the emergence of several new effective therapies that have already obtained FDA approval, the route to regulatory approval for entospletinib will require demonstration of efficacy in unique patient populations. This could include CLL and other B-cell malignancies.”
Sharman J, Hawkins M, Kolibaba K, et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective Syk inhibitor, in chronic lymphocytic leukemia. Blood. 2015 February 18. [Epub ahead of print.]