Dr. Danilov on the Rationale to Combine Entospletinib With Obinutuzumab in CLL

Alexey V. Danilov, MD, PhD, associate director, Toni Stephenson Lymphoma Center, professor, Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discusses the rationale to combine entospletinib (GS-9937) with obinutuzumab (Gazyva) in relapsed/refractory chronic lymphocytic leukemia (CLL).

Entospletinib is an inhibitor of B-cell receptor signaling, which is a significant target in CLL. Inhibiting B-cell receptor signaling has led to advancements in the treatment of patients with CLL, particularly regarding the BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence), Danilov explains. Moreover, entospletinib targets spleen tyrosine kinase (SYK), a cornerstone kinase in the signaling pathway as B-cell receptor signaling cannot happen without SYK, Danilov explains.

 Ultimately, SYK not only transmits signals to the B-cell receptor, but it also cooperates with the B-cell activation factor, which transmits signals from the CLL tumor microenvironment, Danilov continues. Overall, SYK is responsible for survival of CLL cells in the microenvironment, Danilov adds. Therefore, there is strong rationale for targeting SYK with entospletinib, as well as to combine the drug with obinutuzumab, a CD20-targeted antibody that has performed well in CLL with minimal toxicity, Danilov concludes.