Combination of Glofitamab with Pirtobrutinib in BTK Inhibitor (BTKi)-Naive or Btki-Intolerant Patients with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL): A Multicenter Phase 2 Study of the University of California Hematologic Malignancies Consortium
Authors: Seshadri Madhav R , Huang Chiung-Yu , Donner Hildy , Pearse William B. , Young Patricia A. , Mead Monica , Esteghamat Naseem S. , Thacker Christine , Nguyen Lauren , Ai Weiyun , Spinner Michael A , Kaplan Lawrence David , Andreadis Charalambos 
Published: December 2024

Background
MCL is an aggressive and incurable B-cell malignancy. Pirtobrutinib is a noncovalent BTKi with single-agent activity in patients with R/R MCL (Mato 2021). Bispecific antibodies, which recruit native T-cells to induce cancer-directed immune responses, represent an emerging treatment modality in this disease. Data from a phase 1/2 trial of glofitamab, a CD20xCD3 bispecific antibody with a novel 2:1 format, in patients with R/R MCL showed overall response rate 85% and complete response rate 78.3% (Phillips 2024).
MCL can have an immune evasive phenotype, which is associated with inferior prognosis and may contribute to resistance to immunotherapies. Importantly, there is evidence that BTK inhibition may reverse these phenotypes through lymphoma-intrinsic and -extrinsic mechanisms, such as modulating immune checkpoint ligand expression, cytokine expression profiles, and cell composition of the microenvironment (Li 2018, Papin 2019).
Based on (1) single-agent activity of both glofitamab and pirtobrutinib in R/R MCL, (2) preclinical data demonstrating that BTK inhibition has immunomodulatory effects which may potentiate anti-lymphoma immune responses, and (3) largely non-overlapping toxicities, this investigator-initiated trial (NCT06252675) was designed to test the hypothesis that the combination of pirtobrutinib with glofitamab will be highly effective with tolerable toxicity in BTKi-naive or BTKi-intolerant patients with R/R MCL.
Objectives
The primary objectives of this phase 2 study are (1) safety as measured by incidence and severity of adverse events in the safety lead-in cohort, and (2) preliminary efficacy as measured by complete response rate (CRR) in the entire study population. Secondary objectives include (1) other measures of efficacy including progression-free and overall survival, (2) safety as measured by adverse events among all participants, (3) measurable residual disease (MRD) kinetics as measured by ClonoSeq assay (Adaptive), and (4) treatment-free interval among patients who discontinue treatment after achieving CR with undetectable MRD. Exploratory objectives include quality of life using patient-reported outcomes and biomarker analyses including targeted NGS and immunophenotyping studies.
Study design
This is a multicenter phase 2 open-label study. Eligible participants must have a diagnosis of MCL, previously treated with an anti-CD20 antibody and alkylating agent, BTKi-naïve or BTKi-intolerant without progression of disease during BTKi therapy, without prior exposure to a bispecific antibody. Additional eligibility criteria include age &gt;=18 years, adequate hematologic and organ function, and absence of significant comorbidities. Patients will receive obinutuzumab 2000 mg IV on C1D1-2, followed by glofitamab step-up dosing of 2.5 mg IV on C1D8, 10 mg on C1D15, and 30 mg on day 1 of C2-12 (21-day cycles). For the first 6 patients enrolled, pirtobrutinib 200 mg PO daily will start on C2D8 (Cohort 1), and for subsequent patients pirtobrutinib 200 mg PO daily will start on C1D1 (Cohort 2). Cohort 1 will serve as a safety lead-in and will also allow for correlative studies. Patients will be followed for at least 2 years from the start of study treatment. PETCT will be performed every 4-6 cycles. MRD will be assessed by peripheral blood ClonoSeq assay starting on C13D1 and every 6 cycles thereafter. Patients who achieve a CR with undetectable MRD may discontinue pirtobrutinib; patients who discontinue pirtobrutinib and subsequently experience progression of disease may resume pirtobrutinib on study.
We expect to enroll 30 patients, which will yield 84% power to detect a complete response rate (CRR) of 85% against the null hypothesis of CRR =&lt; 67% using a one-sample binomial test at one-sided type I error rate of 0.09. Key endpoints will be summarized using descriptive statistics as appropriate.
Conclusion
Targeted therapies and immunotherapies are increasingly being used in earlier lines of treatment for MCL. In the current trial we evaluate a regimen which we anticipate will be tolerable and highly active in R/R MCL, with the potential for MRD-guided limited-duration therapy. The trial is currently open for enrollment at UCSF and is expected to open at multiple centers through the University of California Hematologic Malignancies Consortium.