Merck initiates Phase 3 waveLINE-010 trial for zilovertamab vedotin in diffuse large B-cell lymphoma

Merck, known as MSD outside the United States and Canada, has launched its pivotal Phase 3 waveLINE-010 clinical trial, evaluating the investigational antibody-drug conjugate (ADC) zilovertamab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP). This combination will be compared against the current standard treatment of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

The initiation of the waveLINE-010 trial represents a key milestone in Merck’s commitment to advancing cancer research, particularly within the field of hematologic malignancies. Patient enrolment has commenced globally, with the trial aiming to recruit approximately 1,046 participants. According to Dr. Gregory Lubiniecki, vice president of oncology clinical research at Merck Research Laboratories, the trial seeks to build on the promising data from the earlier Phase 2 waveLINE-007 trial, which explored zilovertamab vedotin’s potential benefits in combination therapies for DLBCL. Dr. Lubiniecki highlighted Merck’s focus on addressing unmet needs in aggressive lymphomas, stating that the goal is to evaluate whether this novel regimen can provide improved clinical outcomes compared to the current standard of care.

What is diffuse large B-cell lymphoma and why is new research important?

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma (NHL), accounting for roughly 25% to 30% of all NHL cases worldwide. This aggressive cancer originates from B cells, a type of white blood cell responsible for producing antibodies. In DLBCL, these cells grow uncontrollably, leading to rapidly enlarging lymph nodes and often spreading to other organs, including the liver, spleen, and bone marrow. The disease can progress quickly, making early detection and prompt treatment crucial for improving patient outcomes.

In the United States alone, around 25,000 new cases of DLBCL are diagnosed annually. While existing treatments like R-CHOP have significantly improved survival rates, the five-year relative survival rate remains between 60% and 70%. This statistic highlights a substantial need for more effective therapies, especially for patients who either do not respond to initial treatment or experience relapses after therapy. The limitations of current regimens underscore the urgency of novel therapeutic approaches like zilovertamab vedotin, which could potentially offer better outcomes and fewer side effects for patients battling this aggressive form of lymphoma.

How does zilovertamab vedotin work in treating DLBCL?

Zilovertamab vedotin is an investigational antibody-drug conjugate designed to target receptor tyrosine kinase-like orphan receptor 1 (ROR1), a protein that is overexpressed in various hematologic malignancies, including DLBCL. ROR1 plays a role in cancer cell survival and proliferation, making it an attractive target for therapeutic intervention. Unlike traditional chemotherapy, which can affect both cancerous and healthy cells, zilovertamab vedotin delivers a cytotoxic agent directly to cancer cells by binding to ROR1. This targeted approach is intended to minimise damage to healthy tissues, potentially reducing side effects while enhancing treatment efficacy.

Merck’s waveLINE clinical development programme is dedicated to exploring zilovertamab vedotin’s potential across multiple B-cell malignancies. In addition to waveLINE-010, Merck is conducting other studies, such as waveLINE-003, which evaluates the drug in relapsed or refractory DLBCL, and waveLINE-007, investigating its use in combination with R-CHP for patients with previously untreated DLBCL. The programme reflects Merck’s strategic focus on developing precision medicines that improve patient outcomes through targeted therapies.

What are the goals of the waveLINE-010 trial?

The waveLINE-010 trial is a global, randomised, open-label Phase 3 study registered under ClinicalTrials.gov (NCT06717347). Its primary endpoint is progression-free survival (PFS), which measures the length of time during and after treatment that a patient lives without disease progression. This endpoint is critical in determining the treatment’s effectiveness in controlling the disease. Secondary endpoints include the complete response (CR) rate at the end of treatment, overall survival (OS), event-free survival (EFS), duration of complete response, and the safety and tolerability of the combination therapy. These outcomes will help determine whether zilovertamab vedotin, when used with R-CHP, offers significant advantages over the standard R-CHOP regimen in improving patient survival and quality of life.

By focusing on both efficacy and safety, Merck aims to provide comprehensive data that could potentially change the standard of care for DLBCL. The inclusion of diverse endpoints ensures that the trial evaluates not only how well the drug controls the disease but also its long-term benefits and potential risks, providing a holistic view of its therapeutic value.

What do experts say about the potential impact of this trial?

Experts in oncology are closely watching the progress of the zilovertamab vedotin trial, as ADCs represent a promising class of drugs in cancer therapy. Dr. Lubiniecki noted that antibody-drug conjugates have already demonstrated significant benefits in other cancers, and Merck hopes to replicate that success in DLBCL. The medical community is particularly interested in how zilovertamab vedotin compares to existing treatments in terms of both efficacy and safety.

Clinical researchers believe that if zilovertamab vedotin proves effective in this large Phase 3 trial, it could potentially shift the standard of care for DLBCL, especially for patients who are less responsive to traditional therapies. Early data from the waveLINE-007 trial, presented at the 66th American Society of Hematology Annual Meeting in December 2024, showed encouraging signs regarding the drug’s efficacy and safety profile, further fuelling optimism within the medical community. These results suggest that zilovertamab vedotin may offer a viable alternative for patients who currently have limited treatment options, potentially improving survival rates and quality of life.

What’s next for Merck’s waveLINE programme?

The launch of the waveLINE-010 trial underscores Merck’s broader ambitions in oncology, particularly its focus on developing innovative therapies for hematologic malignancies. The company’s strategic investment in the waveLINE programme reflects a commitment to addressing the complex challenges associated with B-cell cancers. As patient enrolment progresses, Merck will continue to share data from its ongoing trials, offering insights into zilovertamab vedotin’s potential as part of combination therapies.

The oncology landscape is rapidly evolving, and trials like waveLINE-010 could play a pivotal role in shaping the future of lymphoma treatment. Merck’s dedication to expanding its research portfolio highlights its commitment to finding new solutions for patients with aggressive cancers. With each new study, the company moves closer to potentially transforming the standard of care for DLBCL, providing hope for patients and their families around the world.