Phase 2 nemtabrutinib non-covalent BTK inhibitor plus rituximab anti-CD20 mAb in MZL

City of Hope is running this Phase 2, open-label combination study testing nemtabrutinib + rituximab in patients with marginal zone lymphoma (MZL) who have radiographically measurable nodal or extranodal disease. Nemtabrutinib (also known as MK-1026/ARQ 531) is a reversible (non-covalent) Bruton’s tyrosine kinase (BTK) inhibitor designed to block B-cell receptor signaling, including in settings where covalent BTK inhibitors can fail due to resistance mutations; it is being developed by Merck (after ArQule). Rituximab (Genentech/Roche and Biogen) is a CD20-directed monoclonal antibody that depletes CD20+ B cells through immune effector mechanisms. Patients take daily oral nemtabrutinib in 28-day cycles with a staged rituximab schedule across multiple cycles, with serial imaging and blood-based correlative work; some patients can continue nemtabrutinib beyond 12 cycles if responding. For MZL needing systemic therapy, current care commonly starts with anti-CD20–based therapy (rituximab alone or with chemo such as bendamustine) and, in later lines, BTK inhibitors (e.g., ibrutinib/zanubrutinib) or other targeted options—so this trial asks whether pairing CD20 depletion with a next-generation BTK strategy can deepen and prolong responses without immediate chemo.