Zandelisib/Zanubrutinib Produces Promising Safety, Efficacy in Relapsed/Refractory B-Cell Malignancies

Partner | Cancer Centers | <b>City of Hope</b>

Alexey V. Danilov, MD, discusses the safety and efficacy achieved with the novel combination comprised of zandelisib and zanubrutinib in patients with relapsed/refractory B-cell malignancies.

The novel PI3Kδ inhibitor zandelisib (ME-401) plus the BTK inhibitor zanubrutinib (Brukinsa) demonstrated encouraging clinical activity and tolerability when used in patients with relapsed or refractory B-cell malignancies, according to Alexey V. Danilov, MD, who added that the utilization of an intermittent dosing scheduling could be key to avoiding known toxicities.

Initial results from an ongoing phase 1b trial (NCT02914938), which were presented during the 2021 ASCO Annual Meeting, indicated that when zandelisib was delivered on an intermittent schedule of a daily dose of 60 mg on days 1 to 7 of each 28-day cycle, plus zanubrutinib at a twice-daily dose of 80 mg, the regimen was well tolerated in this patient population. Notably, the doublet did not result in additive toxicity vs each agent alone.1

Notably, the regimen elicited an overall response rate (ORR) of 100% in patients with relapsed or refractory indolent B-cell malignancies and chronic lymphocytic leukemia, although no patients with high-grade B-cell lymphomas or diffuse large B-cell lymphoma responded.

“More data are necessary to fully understand the activity of this [regimen], whether 2 [drugs are] better than 1 in this case, and whether the intermittent dosing schedule will help to fully overcome the potential adverse effects of PI3K inhibition in patients with [B-cell malignancies, including] CLL,” Danilov said. “These early data are encouraging. Kudos to the study investigators for being audacious and inventive [by examining] this regimen.”

In an interview with OncLive®, Danilov, associate director of the Toni Stephenson Lymphoma Center, and professor in the Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, at City of Hope, discusses the safety and efficacy achieved with the novel combination comprised of zandelisib and zanubrutinib in patients with relapsed/refractory B-cell malignancies.

OncLive®: Initial data from a phase 1b trial examining zandelisib in combination with zanubrutinib were presented during the 2021 ASCO Annual Meeting. Could you provide an overview of this research?

Danilov: Zandelisib is a novel PI3Kδ inhibitor, which is now being developed [for use] in multiple B-cell malignancies, including CLL. The phase 1b study [presented during the meeting] enrolled patients with follicular lymphoma, CLL, and other B-cell malignancies. Twenty patients were treated [with the agent], one-quarter of whom had CLL, and 8 patients with follicular lymphoma. [Moreover,] in this study, zandelisib was combined with zanubrutinib, which is a BTK inhibitor.

The drug was administered on an intermittent dosing schedule. What is the rationale for this?

One big feature of this study is that zandelisib, the PI3Kδ inhibitor, was used on an intermittent [dosing] schedule. [The agent] was given for 2 cycles continuously and daily, and then it was given on days 1 through 7 of each subsequent cycle. The reason why the investigators decided to do that is because known toxicities exist with this class of PI3Kδ inhibitors. For example, idelalisib [Zydelig], which was the first of these agents [to be FDA approved], has a Black box warning for liver function test abnormalities, pneumonitis, and diarrhea colitis. [These are] some of the immune-mediated toxicities that we often struggle with [in practice]. The median time to onset of some of these toxicities, specifically pneumonitis and diarrhea colitis, is approximately between 3 and 4 months. Therefore, undergoing induction with daily dosing, followed by maintenance, may potentially circumvent some of this toxicity.

We believe this may provide some additional time for regulatory T cells to recover, since they initially get suppressed by PI3Kδ inhibition. Also, regulatory T cells often suppress autoimmunity. As such, by dosing PI3Kδ inhibitors intermittently, we potentially allow [for the] recovery of regulatory T cells, and therefore, introduce the necessary immunosuppression to avoid autoimmunity.

What were the findings of the trial?

In this study, the ORR was 100% [with this approach]; that means all patients responded to this combination, which is very encouraging. The [safety profile was] favorable. However, some cases of neutropenia [were observed], as well as grade 3 elevated aspartate aminotransferase and alanine aminotransferase. However, overall, it seemed that this regimen was tolerated quite well.


  1. Soumerai JD, Jagadeesh D, Salman HS, et al. Initial results of the combination of PI3Kδ inhibitor zandelisib (ME-401) and the BTK inhibitor zanubrutinib in patients (pts) with relapsed or refractory (R/R) B-cell malignancies. J Clin Oncol. 2021;39(suppl 15):7553. doi:10.1200/JCO.2021.39.15_suppl.7553