Trials in progress - a Phase II study of pirtobrutinib in combination with rituximab in untreated marginal zone lymphoma (PIONEER-MZL) Free

Marginal zone lymphoma (MZL) is the third most common B-cell lymphoma and accounts for ~7% of all newly diagnosed non-Hodgkin lymphomas (NHL) (Teral LR, et al. CA Cancer J 2016). The disease course is heterogeneous and includes three subtypes: splenic (SMZL), nodal (NMZL), and extranodal of mucosa associated lymphoid tissue (EMZL) with many patients having disease in more than one category. The optimal frontline management of MZL is not well defined and current treatment recommendations are largely adapted from follicular lymphoma. In patients requiring treatment, options include single agent rituximab (R) or R-chemotherapy with the latter showing a higher complete response rate and event-free survival (Zucca E, et al. JCO 2017). Bendamustine is the most commonly utilized chemotherapy backbone in North America, however, it poses several challenges including risk of infections, risk for secondary malignancies and T-cell compromise affecting future cellular therapy options.

Covalent BTK inhibitors (BTKis) have demonstrated efficacy in treating relapsed/refractory MZL with overall response rates (ORR) ranging from 53 to 68%, but the long-term utility of covalent BTKis may be limited by toxicity and acquired BTK resistance. Pirtobrutinib (pirto) is a non-covalent BTKi that has demonstrated excellent activity in B-cell malignancies including MZL (Patel K, et al. ASH 2023) and those with prior covalent BTK failure. Here, we investigate whether the addition of pirto to R (chemo-free approach) can improve the outcomes in patients with untreated MZL compared to historical controls.

PIONEER-MZL is a multicenter, single arm, open-label, nonrandomized risk-adapted phase 2 study (NCT06390956). Eligible patients are 18 years of age or older with histologically documented MZL with no prior systemic therapy, excluding prior antibiotics and radiation for localized disease, prior antiviral therapy for Hepatitis C, and prior splenectomy or other local surgical treatments. Patients must have adequate end-organ function including ANC ≥750 cells/mm3 independent of G-CSF support, platelet count ≥ 50,000 cells/mm3 independent of transfusion support, and hemoglobin ≥ 8 g/dL independent of transfusion support. These thresholds are lower in the event of documented bone marrow involvement.

This is an adaptive treatment intervention where all subjects begin with oral pirto (200 mg daily) and IV (or FDA-approved SQ) R (375 mg/m2) and includes 3 stages of treatment. Stage I is C1-C6 with the first response assessment after C6. At C7D1 subjects with a complete response (CR) will discontinue R and continue pirto treatment for 6 additional cycles following which, these subjects will discontinue treatment and proceed to end of treatment (EOT) and Long-Term Follow-Up (LTFU) visits. Those subjects who have stable disease (SD) or partial response (PR) at C7D1 will continue with R+pirto for 6 additional cycles. Subjects who have progressive disease (PD) at C7D1 will discontinue study treatment and proceed to EOT and LTFU. Treatment received between C7 and C12 is Stage II of treatment. Subjects who achieve a CR at C13 will continue treatment with pirto for an additional 6 cycles. After completion of C18, these subjects will proceed to EOT and LTFU. Subjects who have PR or SD at C13 will continue with pirto monotherapy for a maximum of 24 additional cycles unless they achieve CR on subsequent disease assessment scans or have PD, whichever happens first. Subjects who have PD at C13 will discontinue study treatment and proceed to EOT and LTFU. Only subjects with PR or SD at C13 will receive Stage III treatment. Stage I treatment is our primary treatment of interest. The treatment and response assessments at the end of Stage II and Stage III will be exploratory.

The primary endpoint is ORR at C7, while key secondary endpoints include CR rate at C7, duration of response, progression-free survival, and overall survival. As of July 1, 2025, 6 patients have been enrolled with a maximum expected sample size of 23 patients using Simon's two-stage minimax design (H₀: ORR ≤55% and H_a: ORR ≥80% with 80% power and one-sided type I error rate of 5%). Diagnostic tissue, peripheral blood and bone marrow aspirate from different timepoints are being banked with planned exploratory analysis including minimal residual disease testing, targeted and whole exome sequencing, and transcriptomics.