Zandelisib/Zanubrutinib Elicit High Response Rate in Mantle Cell Lymphoma and Follicular Lymphoma


In a population of patients with patients with mantle cell lymphoma and follicular lymphoma, zandelisib plus zanubrutinib did not increase the rate or severity of class-related adverse effects.

Zandelisib (ME-401)/zanubrutinib (Brukinsa) combination therapy demonstrated safety and tolerability as well as robust, long-lasting responses in a small population of patients with mantle cell lymphoma (MCL) and relapsed/refractory follicular lymphoma, according to a presentation on results from a phase 1b trial (NCT02914938) during 2022 American Society of Hematology (ASH) Annual Meeting.

In patients with MCL, the overall response rate (ORR) was 72.2% (n = 13/18), of whom 27.8% (n = 5/18) had a complete response (CR) and 44.4% (n = 8/18) had a partial response (PR). Additionally, tumor reduction was observed in 94% (n = 17/18) of patients who underwent post-baseline disease assessment.

The estimated median DOR and PFS, respectively, were not evaluable (NE; 95% CI, 2.3-NE) with a median follow-up of 9.4 months (95% CI, 3.7-14.5) and 10.1 months (95% CI, 3.3-NE) with a median follow-up of 11.1 months (95% CI, 2.4-14.9).

Among patients with follicular lymphoma, zandelisib plus zanubrutinib yielded an ORR of 86.7% (n = 26/30), with 23.3% (n = 7/30) of patients achieving a CR and 63.3% (n = 19/30) having a PR. In a post-baseline disease assessment, tumor reduction was observed in 97% (n = 29/30) of patients with follicular lymphoma.

The median DOR and PFS for patients with follicular lymphoma, respectively, were 20.6 months (95% CI, 9.6-NE) with a median follow-up of 9.2 months (95% CI, 4.0-15.0) and 22.4 months (95% CI, 11.4-NE) with a median follow-up of 11.1 months (95% CI, 10.9-16.6).

Investigators of the open-label, multi-arm phase 1b study evaluated zandelisib in combination with zanubrutinib in patients with relapsed or refractory follicular lymphoma or MCL in disease-specific extension cohorts. Patients received 60 mg of zandelisib once a day on days 1 to 7 of a 28-day cycle in addition to 80 mg of zanubrutinib twice a day. Trial investigators conducted disease assessments after cycles 2 and 6 of treatment, then every 6 cycles thereafter.

The primary end point of the study was safety and tolerability. Key efficacy end points included overall response rate (ORR) based on Lugano criteria, duration of response (DOR), and progression-free survival (PFS).

Patients 18 years and older with grade 1 to 3A follicular lymphoma or MCL were eligible to enroll on this study. Additional inclusion criteria included having received at least 1 prior line of therapy, adequate organ function, no cytopenias unless related to disease, and no prior treatment with PI3K or Bruton tyrosine kinase inhibitors.

Of 50 patients who were included in the study, 31 had follicular lymphoma and 19 had MCL. Among those with follicular lymphoma and MCL, respectively, the median ages were 69 years (range, 40-83) and 65 years (range, 52-78). Most patients in either arm were male (54.8% and 73.7%) and the median lines of previous therapy were 2 (range, 1-5) and 1.5 (range, 1-3), respectively. Additionally, 58.1% (n = 18/31) and 47.4% (n = 9/19) of patients in each respective arm received at least 2 prior lines of therapy.

A total of 19.4% (n = 6/31) and 47.4% (n = 9/19) of patients in the follicular lymphoma and MCL, respectively were refractory to their last therapy; specifically, 29.0% (n = 9/31) and 47.4% (n = 9/19), respectively, were refractory to rituximab (Rituxan). Moreover, 3.2% (n = 1/31) and 10.5% (n = 2/19) of patients in each group, respectively, previously received an autologous stem cell transplant. Additionally, 71.0% (n = 22/31) and 47.4% (n = 9/19) of patients, respectively, had disease progression within 2 years of frontline chemoimmunotherapy.

With a median follow-up time of 13.5 months (range, 1.8-32.4) for patients with follicular lymphoma and 7.4 months (range, 1.9-20.9) for those with MCL, the most common grade 3 treatment-emergent adverse effects (TEAEs) included neutrophil count decrease (8%), alanine transaminase increases (8%), anemia (6%), and aspartate aminotransferase increases (6%). Grade 4 TEAEs included neutrophil count decrease (12%) and platelet count decrease (2%).

Trial investigators reported that 2 patients (4%) discontinued treatment due to treatment-related AEs, which included 1 event of decreased neutrophil count and 1 event of drug reaction with eosinophilia and systemic symptoms syndrome. Additionally, there was 1 fatal grade 5 TEAE related to COVID-19 complications observed in an unvaccinated patient with MCL who received 1 prior line of therapy.


Soumerai J, Diefenbach C, Kenkre V, et al. Safety and efficacy of the PI3Kδ inhibitor zandelisib in combination with the BTK inhibitor zanubrutinib in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or mantle cell lymphoma (MCL). Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 78.

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