Study of the drug zilovertamab vedotin (MK-2140) as monotherapy and in combination with nemtabrutinib in patients with previously treated B-cell non-Hodgkin lymphoma

Lymphomas are malignant diseases of the lymphatic system, which plays a central role in the immune system. They arise from abnormal lymphocytes—a type of white blood cell—and are classified as Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Non-Hodgkin lymphomas are further classified as T-cell or B-cell lymphomas, depending on the cell type, with the latter being significantly more common. Typical symptoms of lymphoma include painless swollen lymph nodes, persistent fatigue, unexplained weight loss, fever, and night sweats. The choice of treatment depends on the specific type of lymphoma and the stage of the disease and typically includes chemotherapy, immunotherapy, or targeted therapies.

This study focuses on specific subtypes of B-cell lymphomas, which can vary greatly in their course, aggressiveness, and response to treatment. Mantle cell lymphoma (MCL) is usually aggressive, whereas follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) typically have a slow (indolent) course but can relapse. Richter transformation (Richter syndrome; RS) is a rare but highly aggressive lymphoma that arises from CLL.

Standard treatment for these lymphomas often consists of chemotherapy, immunotherapy, and targeted therapies such as BTK inhibitors. These inhibit the protein Bruton’s tyrosine kinase (BTK), which is important for survival and signal transduction in B cells. In the event of a relapse or lack of response (recurrent or refractory = r/r) to such therapies, there are currently insufficient treatment options available.

Zilovertamab vedotin is a novel type of drug. It is an antibody-drug conjugate (ADC) that binds to the ROR1 protein on cancer cells. After binding, it is taken up by the cell, where it releases the conjugated active ingredient monomethylauristatin E (MMAE)—a chemotherapeutic agent designed to destroy the cancer cells. Nemtabrutinib is a new BTK inhibitor that has also not yet been approved.

The goal of the MK-2140-006 study is to investigate the efficacy and safety of zilovertamab vedotin alone and in combination with nemtabrutinib. This is an open-label Phase 1/2 study. Depending on the type of disease and prior treatments, patients will be assigned to one of the following cohorts (A–E):

Cohort A: r/r MCL following treatment with a BTK inhibitor and, if applicable, CAR-T therapy → monotherapy with zilovertamab vedotin

Cohort B: r/r Richter transformation after ≥1 prior therapy → Monotherapy

Cohort C: r/r MCL after ≥1 prior therapy, but without a BTK inhibitor → Combination of zilovertamab vedotin + nemtabrutinib

Cohort D: r/r FL and CLL after ≥2 prior therapies (including certain active substances), with no further treatment options → Monotherapy

Cohort E: r/r FL after ≥2 prior therapies (including certain active substances), with no further treatment options → monotherapy

All patients receive zilovertamab vedotin (alone or in combination) as an infusion every 3 weeks. Treatment will continue until the disease progresses or side effects make continued treatment unfeasible. The study is open-label, meaning all patients know which treatment group they have been assigned to. The study is randomized, meaning assignment is random. Follow-up will continue for up to 57 months. The primary study objectives are safety and the objective response rate (ORR).

Eligible participants are women and men aged 18 years or older with a confirmed diagnosis of r/r B-cell lymphoma who meet the specific prior therapy criteria for their respective cohort. There must be no active central nervous system (CNS) lymphoma.