Entospletinib Shows Modest Activity in Mantle Cell Lymphoma

Kathryn Kolibaba, MD

Entospletinib (GS-9973) was well tolerated and demonstrated modest activity in patients with relapsed or refractory mantle cell lymphoma (MCL), according to the results of a phase II trial, which were presented at the 2016 ASH Annual Meeting.

The objective response rate in this patient cohort was 15% (90% CI, 6.9%-28.1%), with 6 patients (15%) achieving a partial response and 23 patients (59%) maintaining stable disease control. The progression-free survival (PFS) rate at week 16 was 66% (95% CI, 46%-79%), and the median PFS was 5.6 months (95% CI, 3.6-8.9).

These findings come from a larger study that broadly assessed the safety and activity of entospletinib in patients with relapsed and refractory hematologic malignancies. Other malignancies included chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma, follicular lymphoma (FL), non-FL indolent non-Hodgkin lymphomas, and marginal zone lymphoma.

Entospletinib is a selective inhibitor of spleen tyrosine kinase (Syk). Syk mediates B cell receptor signaling in normal and transformed B cells. This particular pathway has been the central focus in several types of B cell related hematologic malignancies, including MCL.

“We’ve known that the Syk tyrosine kinase is active in hematologic malignancies for a very long time,” said Kathryn Kolibaba, MD, an investigator affiliated with the study. “The first targeted therapy that was studied was fostamatinib, but it was not very specific. It had a lot of toxicity, but also a lot of activity on other targets, other kinases. So we were very excited that a specific inhibitor of the Syk tyrosine kinase was developed in the hope that there might be both efficacy and decreased toxicity.”

Tumor response in this study was assessed per Cheson 2007 criteria with imaging scheduled at weeks 8, 16, 24, and then every 12 weeks thereafter. The primary endpoint was PFS at week 16, and an independent review committee evaluated all efficacy data.

The median age of the MCL patient cohort was 72 years (range, 49-92). The median number of prior regimens was 2. Prior treatments included anti-CD20 antibodies (95%), alkylating agents (95%), and anthracyclines (77%). Three patients (8%) had received ibrutinib (Imbruvica) as either an investigational drug (n = 1) or as an approved drug (n = 2). One patient (3%) received idelalisib (Zydelig).

“So many of these patients have had a long list of prior therapies,” said Kolibaba. “All of them were required to have had at least 1 previous line of therapy in order to be eligible, but many of them had really been heavily pretreated.”

Patients stayed on the study treatment for a median duration of 21 weeks, with 1 patient still continuing the regimen. Thirty-five patients (90%) were evaluable for tumor response, while 4 patients (10%) discontinued treatment prior to the initial tumor assessment.

Four treatment-related adverse events led to treatment discontinuation (all n = 1), including cardiac arrest, pruritus, pyrexia, and maculopapular rash. A total of 6 deaths were reported in this cohort, but none were related to the study drug.

“It’s helpful when you have active drugs that can be combined to have a low toxicity like this one, and to be able to add it to other therapies to improve outcomes in resistant diseases,” said Kolibaba. “We’re encouraged that entospletinib may have a role as a combination partner in the treatment of mantle cell lymphoma.”

The larger study looking at entospletinib’s activity in various hematologic malignancies is still ongoing, according to Kolibaba.

“This study is ongoing to add patients in the CLL cohort, who have had previous treatment with PI3K inhibitors and Bruton tyrosine kinase inhibitors, because that definitely represents a population with unmet needs.”

Sharman JP, Kolibaba KS, Shustov AR, et al. Results of a phase 2 trial evaluating efficacy and safety of entospletinib (GS-9973) in patients with mantle cell lymphoma. Blood. 2016 128:2963.