Merck’s Zilovertamab Vedotin in Combination With R-GemOx Shows Promising Efficacy in Relapsed/Refractory DLBCL Patients: Phase 2 Results from waveLINE-003 Trial Presented at ASCO 2025
Merck, known as MSD outside the United States and Canada, has unveiled encouraging new clinical data from the dose-confirmation portion of its Phase 2/3 waveLINE-003 trial evaluating the investigational antibody-drug conjugate (ADC) zilovertamab vedotin. The therapy is being tested in combination with standard-of-care rituximab, gemcitabine, and oxaliplatin (collectively known as R-GemOx) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)—a particularly aggressive and challenging type of non-Hodgkin lymphoma.
The results, shared during an oral presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #7005), signal strong antitumor activity at the 1.75 mg/kg dose of zilovertamab vedotin when combined with R-GemOx. This dosing regimen yielded an objective response rate (ORR) of 56.3%, with eight complete responses (CRs) and one partial response (PR) among 16 evaluable patients. These data offer early evidence supporting zilovertamab vedotin’s potential to fill a critical unmet need in the treatment landscape for patients who have exhausted initial therapeutic options.
A Novel ADC Targeting ROR1
Zilovertamab vedotin is a next-generation, investigational ADC that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1), a protein that is aberrantly expressed on the surface of various hematologic malignancies, including DLBCL, but largely absent in normal adult tissues. By binding to ROR1 and delivering a potent cytotoxic payload directly into the cancer cells, zilovertamab vedotin offers the promise of a more targeted and less toxic approach to destroying malignant cells.
“This investigational ROR1-targeted ADC represents a potential first-in-class treatment for patients with difficult-to-treat forms of lymphoma,” said Dr. Philippe Armand, principal investigator of the waveLINE-003 trial and Director of Clinical Research at Dana-Farber Cancer Institute. “The early findings from the Phase 2 portion of the study are promising, particularly in a relapsed or refractory patient population where therapeutic options are limited and outcomes are often poor.”
Trial Design: waveLINE-003
The waveLINE-003 study (ClinicalTrials.gov Identifier: NCT05139017) is a Phase 2/3 randomized, multicenter, open-label trial designed to evaluate the safety, efficacy, and optimal dose of zilovertamab vedotin in combination with R-GemOx in patients with relapsed or refractory DLBCL. The trial is structured in two distinct phases: a dose-confirmation phase (Part 1) and an efficacy-expansion phase (Part 2).
Participants were adults with histologically confirmed DLBCL that had returned or failed to respond following at least one prior line of therapy. Patients enrolled in the trial had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they were well enough to receive investigational treatment.
In Part 1 of the study, a total of 40 patients were enrolled across three dosing cohorts:
- 1.5 mg/kg of zilovertamab vedotin + R-GemOx (n=17)
- 1.75 mg/kg of zilovertamab vedotin + R-GemOx (n=16)
- 2.0 mg/kg of zilovertamab vedotin + R-GemOx (n=7)
Each cohort received treatment every three weeks (Q3W) for up to six cycles.
Efficacy and Safety Results by Dose Cohort
The 1.75 mg/kg dose stood out with the most promising efficacy profile. At a median follow-up of 9.9 months (range, 4.0 to 30.0 months), the ORR was 56.3%, comprised of eight complete responses (50%) and one partial response (6.3%). The median duration of response (DOR) in this group was 8.7 months, though some responses were ongoing at the time of data cutoff.
In contrast, the 1.5 mg/kg cohort (n=15) demonstrated a lower ORR of 26.7%, with a CR rate of 20% and a PR rate of 6.7%. The median DOR in this group was longer, at 14.4 months, though the small sample size limits definitive conclusions. Median follow-up was 18.1 months.
Meanwhile, the 2.0 mg/kg cohort (n=7) showed an ORR of 57.1%, with three CRs (42.9%) and one PR (14.3%). However, this cohort also raised safety concerns. The median DOR was not reached at the time of analysis, and the follow-up was relatively short at 9.3 months (range, 6.0 to 10.0 months).
Safety Profile and Dose-Limiting Toxicities
Treatment-related adverse events (TRAEs) were common across all cohorts, occurring in 98% of patients. Grade 3 or higher TRAEs were reported in 63% of participants. The most frequently observed adverse events included diarrhea, nausea, anemia, and thrombocytopenia (low platelet count). Grade ≥3 adverse events were dominated by neutropenia (low white blood cell count), neutrophil count decrease, thrombocytopenia, and anemia.
Seven dose-limiting toxicities (DLTs) were reported across the study population:
- At 1.5 mg/kg: one Grade 4 febrile neutropenia
- At 1.75 mg/kg: one case of Grade 3 elevated liver enzymes (alanine aminotransferase) and one intestinal obstruction
- At 2.0 mg/kg: multiple Grade 3–4 toxicities, including diarrhea, febrile neutropenia, neutropenia, and thrombocytopenia. One patient died from treatment-related sepsis after discontinuing therapy.
These safety data played a pivotal role in determining the recommended Phase 2 dose (RP2D) of 1.75 mg/kg, balancing both efficacy and tolerability when used in combination with R-GemOx.
Advancing the Clinical Development of Zilovertamab Vedotin
Merck is aggressively pursuing further development of zilovertamab vedotin across multiple studies and DLBCL treatment settings:
- waveLINE-010 (NCT06717347): A Phase 3 trial assessing zilovertamab vedotin in previously untreated DLBCL patients.
- waveLINE-007 (NCT05406401): A Phase 2 study exploring the ADC’s performance in other hematologic malignancies.
- waveLINE-011 (NCT06890884): A newly initiated Phase 2, randomized, open-label trial comparing zilovertamab vedotin + R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) to polatuzumab vedotin + R-CHP. The study plans to enroll 594 patients and aims to evaluate complete response rates at end of treatment, with secondary endpoints including progression-free survival (PFS), overall survival (OS), and duration of complete response.
Expert Perspectives and Future Directions
“The Phase 2 results provide compelling support for further clinical development of zilovertamab vedotin in combination with standard chemotherapy,” said Dr. Gregory Lubiniecki, vice president of oncology clinical research at Merck Research Laboratories. “We are encouraged by the balance of activity and tolerability seen at the 1.75 mg/kg dose level and are eager to build on this momentum through our Phase 3 program.”
Dr. Lubiniecki also emphasized Merck’s broader oncology commitment, with data spanning over 25 different tumor types presented at ASCO 2025 as part of the company’s robust pipeline of investigational therapies.
The preliminary findings from the Phase 2 portion of waveLINE-003 suggest that zilovertamab vedotin at 1.75 mg/kg, when used alongside R-GemOx, may provide an effective and manageable treatment option for patients with relapsed or refractory DLBCL. While safety concerns persist at higher doses, the 1.75 mg/kg regimen appears to offer a promising balance of efficacy and tolerability, warranting further investigation in the ongoing Phase 3 trial.
As Merck continues to invest in innovation and explore the therapeutic potential of ROR1-targeting ADCs, zilovertamab vedotin may soon become a key player in reshaping the treatment landscape for DLBCL and other difficult-to-treat hematologic malignancies.
