Merck's Investigational Zilovertamab Vedotin at 1.75 mg/kg Dose Plus Standard of Care Showed Promising Antitumor Activity, Including Complete Response Rate, in Patients With Relapsed/Refractory DLBCL in Phase 2 Portion of waveLINE-003 Trial

Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced results from the dose confirmation portion of the Phase 2/3 waveLINE-003 study evaluating zilovertamab vedotin in combination with standard of care rituximab and gemcitabine-oxaliplatin (R-GemOx) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Zilovertamab vedotin is an investigational, potential first-in-class antibody drug conjugate (ADC) that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1). At a pre-planned analysis, zilovertamab vedotin 1.75 mg/kg in combination with R-GemOx achieved a 56.3% objective response rate (ORR) in patients with relapsed or refractory DLBCL (n=16), with eight complete responses (CR) and one partial response (PR). These data are being presented for the first time today during an oral presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #7005).

"Patients with relapsed or refractory diffuse large B-cell lymphoma continue to experience poor outcomes and an unmet need remains to help provide these patients with additional options to treat their cancer," said Dr. Philippe Armand, the study's principal investigator, Dana-Farber Cancer Institute. "These data from the Phase 2 portion of the waveLINE-003 trial are encouraging for patients and support further research in the relapsed/refractory setting in a larger patient population."

"In the Phase 2 portion of the waveLINE-003 trial, the 1.75 mg/kg dose of zilovertamab vedotin with rituximab, gemcitabine and oxaliplatin demonstrated a promising response rate, complete response rate and manageable safety profile in combination with standard of care," said Dr. Gregory Lubiniecki, vice president, oncology clinical research, Merck Research Laboratories. "The Phase 3 portion of this trial is already enrolling, and as we continue to advance our research of this investigational ROR1-directed ADC, these promising results amplify our belief in the potential of zilovertamab vedotin to treat multiple hematologic malignancies."

Zilovertamab vedotin is currently being evaluated in patients with previously untreated DLBCL in the Phase 3 waveLINE-010 study (NCT06717347) and in the Phase 2 waveLINE-007 study (NCT05406401). Additionally, we recently initiated the Phase 2 waveLINE-011 study (NCT06890884), which is a randomized, open-label clinical trial evaluating zilovertamab vedotin plus rituximab and cyclophosphamide, doxorubicin and prednisone (R-CHP) versus polatuzumab vedotin with R-CHP for the treatment of patients with DLBCL. The trial is estimated to enroll 594 patients and the primary endpoint is CR rate at end of treatment, with secondary endpoints of progression-free survival (PFS), overall survival (OS), event-free survival, duration of CR and safety. Global recruitment of the waveLINE-011 study has begun, with patients now enrolling.

As announced, data spanning more than 25 types of cancer are being presented from Merck's broad oncology portfolio and investigational pipeline at the 2025 ASCO Annual Meeting.

Study design and additional data from waveLINE-003

WaveLINE-003 is a Phase 2/3 randomized, multicenter, open-label, dose confirmation and expansion clinical trial (ClinicalTrials.gov, NCT05139017) designed to assess the safety and efficacy of zilovertamab vedotin in combination with standard of care options for the treatment of relapsed or refractory DLBCL after one or more lines of therapy. This study is divided into two parts: dose confirmation (part 1) and efficacy expansion (part 2) and enrolled adult participants with confirmed relapsed or refractory DLBCL after one or more lines of therapy and an Eastern Cooperative Oncology Group performance status of 0-2. In Part 1, primary endpoints were safety and recommended Phase 2 dose (RP2D). Secondary endpoints were ORR, duration of response (DOR) per Lugano 2014 response criteria by blinded independent central review and OS. Part 1 of the trial enrolled 40 patients (as of the August 1, 2024 data cutoff) to receive either:

• Zilovertamab vedotin (1.5 mg/kg intravenously [IV]) plus rituximab (375 mg/m² IV), gemcitabine (1000 mg/m² IV) and oxaliplatin (100 mg/m² IV), given every three weeks (Q3W) up to six cycles (n=17), or
• Zilovertamab vedotin (1.75 mg/kg IV) plus R-GemOx Q3W up to six cycles (n=16), or
• Zilovertamab vedotin (2.0 mg/kg IV) plus R-GemOx Q3W up to six cycles (n=7).

Treatment-related adverse events (TRAEs) were reported in 98% of patients (n=40). Grade ≥3 TRAEs occurred in 63% of patients (n=25). At the 1.5 mg/kg dose of zilovertamab vedotin plus R-GemOx, four patients completed treatment, eight discontinued due to progression and one withdrew, with four patients receiving ongoing treatment at data cut-off. At the 1.75 mg/kg dose, eight patients completed treatment, seven discontinued due to progression and one patient discontinued due to physician decision. In the 2.0 mg/kg dose cohort, three patients completed treatment, three patients discontinued treatment due to adverse events (AEs) (treatment-related sepsis and respiratory failure), and one patient withdrew due to physician decision. One patient died after discontinuing treatment due to treatment-related sepsis. The most common AEs were diarrhea, nausea, anemia and platelet count decrease, while the most common Grade ≥3 AEs were neutropenia, neutrophil count decrease, platelet count decrease and anemia.

Seven dose-limiting toxicities occurred across all participants. At the 1.5 mg/kg dose of zilovertamab vedotin plus R-GemOx, one participant had Grade 4 febrile neutropenia. At the 1.75 mg/kg dose, one participant experienced Grade 3 alanine aminotransferase increased and one patient had intestinal obstruction. At the 2.0 mg/kg dose, participants had Grade 3 diarrhea, Grade 4 neutrophil count decrease and Grade 4 thrombocytopenia (one patient each), and one patient experienced both Grade 3 febrile neutropenia and Grade 4 neutrophil count decrease.

The median follow-up for all participants was 9.8 months. At a median follow-up of 18.1 months (range, 2.4 to 23.3 months) in patients receiving the 1.5 mg/kg dose of zilovertamab vedotin (n=15), ORR was 26.7% (3 CR [20.0%], 1 PR [6.7%]) and median DOR was 14.4 months (95% CI, not reached [NR]-NR). At a median follow-up of 9.9 months (range, 4.0 to 30.0 months) for patients receiving the 1.75 mg/kg dose (n=16), ORR was 56.3% (8 CR [50.0%], 1 PR [6.3%]) and median DOR was 8.7 months (95% CI, 2.3-NR). At a median follow-up of 9.3 months (range, 6.0 to 10.0 months) for patients receiving the 2.0 mg/kg dose (n=7), the ORR was 57.1% (3 CR [42.9%], 1 PR [14.3%]) and median DOR was not reached (95% CI, 4.1-NR). Based on these results and accompanying safety data, the recommended Phase 2 dose of zilovertamab vedotin was determined to be 1.75 mg/kg when used with R-GemOx.

About diffuse large B-cell lymphoma

Lymphoma is cancer beginning in the lymphatic system – the network of organs, vessels and tissues that protects the body from infection. There are many subtypes of lymphoma, which is often categorized into two main types – Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma, the most common form of NHL, is derived from white blood cells that grow rapidly and uncontrollably, enlarging the lymph nodes and often migrating to other parts of the body. DLBCL accounts for approximately 25-30% of all NHLs worldwide. In the U.S., it is estimated that approximately 25,000 patients are diagnosed with DLBCL each year. The five-year relative survival rate for DLBCL is 60-70%.

About zilovertamab vedotin (MK-2140)

Zilovertamab vedotin is an investigational, potential first-in-class ADC that targets ROR1. ROR1 is a transmembrane protein that is overexpressed in multiple hematologic malignancies. Merck is committed to research with zilovertamab vedotin across B-cell malignancies and has established a robust program of clinical trials under the name waveLINE. In addition to waveLINE-003, the waveLINE program includes a Phase 3 study in patients with previously untreated DLBCL (waveLINE-010, NCT06717347), a Phase 2 study in patients with select B-cell lymphomas (waveLINE-006, NCT05458297), a Phase 2 study in patients with germinal center B-cell-like DLBCL (waveLINE-011, NCT06890884) and a Phase 2 study in patients with previously untreated DLBCL (waveLINE-007, NCT05406401).

About Merck in hematology

Merck is committed to advancing innovation and care for people with hematologic neoplasms and malignancies. Building on its leadership in oncology, the company has a broad clinical development program that evaluates novel mechanisms of action to address longstanding unmet needs for patients with hematologic disorders. Among Merck's research efforts are studies evaluating multiple investigational medicines as monotherapy or in combination with other therapies across a range of hematologic neoplasms and malignancies.

Merck's focus on cancer

Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

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