Zandelisib/Zanubrutinib Combination in R/R CLL and B-Cell Malignancies Shows Clinical Benefit

Phase 1 data presented at 2021 EHA indicate that a high rate of response was associated with zandelisib plus zanubrutinib therapy in patients with relapsed/refractory B-cell malignancies and chronic lymphocytic leukemia.

Rates of response showed promise for future clinical utility of zandelisib (ME-401) plus zanubrutinib (Brukinsa) in patients with relapsed/refractory B-cell malignancies and chronic lymphocytic leukemia (CLL), according to results of a phase 1b study (NCT02914938) presented virtually at the 2021 European Hematology Association Annual Congress.

Results from the trial indicate that after a median follow-up of 6.6 months for all patients (range, 0.6-21.3; Group A, median follow-up = 3.6 months; Group B, median follow-up = 6.6 months), those with follicular lymphoma (n = 8), CLL and small lymphocytic lymphoma (SLL; n = 5), marginal zone lymphoma (MZL; n = 2), and mantle cell lymphoma (MCL; n = 1) had a complete response (CR) rate of 100%. Additionally, CRs and CRs with incomplete hematologic recovery occurred in 25% of those with follicular lymphoma, and 40% of those with CLL. Notably, there were no responders within the diffuse large B-cell lymphoma (DLBCL)/ high-grade B-cell lymphomas (HGBCL) subgroup (n = 2).

“Responses were observed in all patients with indolent B-cell non-Hodgkin lymphoma histologies and CLL,” according to Jacob Soumerai, MD, a clinical investigator in lymphoma, Medicine, at Massachusetts General Hospital, and an assistant professor of medicine at Harvard Medical School. “Among 13 patients treated in group B, 8 remain on treatment [with] an ongoing treatment response, 4 came off [treatment] due to progression, and 1 came off to do grade 3 alanine aminotransferase [ALT] elevation.”

Dual inhibition of PI3Kδ and BTK pathways has demonstrated synergistic activity that is notable, even at suboptimal concentrations. The strategy could work to even overcome resistance to monotherapies, both acquired and existing. This formed the rationale for leveraging an innovative dosing schedule with the PI3Kδ inhibitor zandelisib in combination with the oral BTK inhibitor zanubrutinib, with the intent to improve the tolerability of a dual targeted approach, as well as offer improved responses.

The phase 1b, multi-cohort study enrolled patients with an ECOG performance status of 0-2 who had progressed on 1 or more prior therapies for a B-cell malignancy. Patients were required to have measurable disease and have received no prior PI3K or BTK inhibitor therapies.

A 6 + 6 trial design was implemented, with 2 treatment dose schedules utilized over the course of the study. All patients were treated with a pneumocystis jiroveci pneumonia prophylaxis. Additionally, patients were treated until they experienced disease progression, drug intolerance, or withdrawal of consent.

Group A, which included 7 patients, was given 60 mg of oral zandelisib daily for 8 weeks, followed by days 1 to 7 of each subsequent 28-day cycle, plus 160 mg of oral zanubrutinib twice daily. Over the 28-day dose-limiting toxicity (DLT) period, 1 patient with DLBCL was not evaluable for DLT due to a grade 3 adverse effect (AE) on day 1 because of treatment with a prior therapy. No other DLTs were observed in this cohort.

At cycle 2, 1 patient who developed grade 3 elevated aspartate aminotransferase (AST)/ ALT and grade 3 rash discontinued treatment due to the rash AE. Additionally, 1 other patient experienced grade 3 AST/ALT and discontinued to undergo transplant. With these findings in mind, investigators increased the DLT observation period to 56 days.

In group B (n = 13), patients received 60 mg of oral zandelisib daily on days 1 through 7 of each 28-day cycle starting at cycle 1, as well as a twice daily dose of zanubrutinib of 80 mg. During the DLT period of 56 days, 1 patient with HGBCL was not evaluable due to disease progression on day 14, and 2 patients developed grade 3 elevated AST/ALT in cycle 2. Although 1 patient is receiving ongoing treatment on the study, another patient discontinued due to recurrence of grade 3 ALT increase. Based on these findings, investigators opened disease-specific expansion cohorts using the Group B dosing schedule.

Among the patients enrolled on the study, the median age was 70 years old (range, 44-85), with an even split between male and female patients. Additionally, patients had received a median of 2 prior therapies (range, 1-8), with 55% of patients having undergone 2 or more therapies prior to enrolling on the study. Thirty percent of patients were refractory to rituximab (Rituxan), and 30% had tumor bulk that was greater than 55 mm.

Imaging scans were given on months 3, 7, 13, and then every 6 months until progression, with reported responses based on Lugano criteria and International Workshop on CLL guidelines. Two patients with DLBCL and HGBCL did not receive on therapy scans, as 1 developed clinically progressive disease and the other needed to discontinue early due to an AE from a prior therapy.

In terms of safety, the most common grade 3 or higher treatment-emergent AEs (TEAEs) in group A included neutropenia (43%), ALT increase (29%), AST increase (29%), and thrombocytopenia (29%). Common all grade TEAEs included neutropenia (57%), thrombocytopenia (57%), and diarrhea (43%). In group B, the most common grade 3 or higher TEAEs included neutropenia (23%), ALT increase (15%), and AST increase (15%), with any grade TEAEs including neutropenia (46%), AST increase (23%), thrombocytopenia (23%), and diarrhea (23%).

“We are currently enrolling expansion cohorts for follicular lymphoma and MCL [utilizing the group B regimen],” Soumerai concluded.


Soumerai JD, Jagadeesh D, Salman HS, et al. Tolerability and efficacy of the combination of PI3KΔ inhibitor zandelisib (ME-401) and BTK inhibitor zanubrutinib in patients with relapsed or refractory (R/R) B-cell malignancies: initial results. Presented at 2021 European Hematology Association Annual Congress; June 9-17, 2021; Virtual. Abstract S214.

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