First-line treatment with zilovertamab vedotin plus cyclophosphamide, doxorubicin, prednisone, and rituximab (R-CHP) has yielded high response rates in patients with diffuse large B cell lymphoma (DLBCL), according to findings from the phase 2 WAVELINE-007 trial presented at the 2024 ASH Annual Meeting. The study (NCT05406401) evaluated various dose levels of zilovertamab vedotin in combination with R-CHP.
The objective response rate (ORR) across all dose levels (n = 36) was 97.2% (95% CI, 85.5%-99.9%), consisting entirely of complete responses (CRs). At the recommended phase 2 dose (RP2D) of 1.75 mg/kg every 3 weeks (n = 15), the ORR was 100% (95% CI, 78.2%-100.0%), also entirely comprised of CRs. The median duration of response was not yet reached in any group, with a 12-month duration of response of 93.5% observed across all doses and 91.7% for the RP2D arm.
Efficacy Across Dose Levels
In the 2.0 mg/kg arm (n = 15), the ORR was 93.3% (95% CI, 68.1%-99.8%), with all responses being CRs. The 12-month duration of response in this group was 92.3%. The 2.25 mg/kg group also achieved a 100% ORR, entirely CRs, with a 100% 12-month duration of response. Across all doses, every patient experienced more than a 60% reduction in the target lesion size from baseline, with over a quarter experiencing a 100% reduction.
"Zilovertamab vedotin plus R-CHP demonstrated efficacy and robust responses as front-line treatment for DLBCL with a manageable safety profile," said lead investigator Muhit Ozcan, MD, Hematology Department, Ankara University School of Medicine, Cankaya-Ankara, Turkey. "These results warrant further evaluation of this combination in a larger population."
About Zilovertamab Vedotin
Zilovertamab vedotin is an antibody-drug conjugate consisting of a ROR1-targeting antibody with an MMAE cytotoxic payload. ROR1 is generally expressed across lymphoid malignancies, and studies have not shown a correlation between expression levels and efficacy with the agent. Therefore, ROR1 testing was not required for the study.
Trial Design and Patient Population
Intravenous doses of zilovertamab vedotin were escalated in 0.25 mg/kg increments between 1.75 mg/kg and 2.25 mg/kg every 3 weeks for up to 8 cycles. Most patients received the standard 6 cycles, common with R-CHOP. Of the 36 patients enrolled, 15 completed treatment at the 1.75 mg/kg dose, 14 of 15 completed treatment at the 2.0 mg/kg dose, and 5 of 6 completed treatment at the 2.25 mg/kg dose. Two patients discontinued before treatment completion due to physician decision. All patients also received R-CHP, with vincristine omitted from the traditional R-CHOP regimen due to potential overlapping adverse events with the investigational agent.
The median age was 64.0 years across all 36 enrolled patients. The ECOG performance status was 0 (42%) and 1 (58%). Bone marrow involvement was noted for 11% of patients, and half had Ann Arbor stage IV disease (50%). By NCCN-IPI criteria, 58% of patients were low-intermediate risk, with the remainder being high-intermediate risk (33%) and high risk (8%). The DLBCL cell of origin was germinal center B-cell-like for 28% and activated b-cell for 11%, with the remainder unknown.
Safety Profile
At the RP2D, there was no dose-limiting toxicity (DLT) with the zilovertamab vedotin combination. At the 2.0 mg/kg dose, there were 2 events: diarrhea and pneumonia. Two patients experienced DLT events at the 2.25 mg/kg dose level, both experiencing febrile neutropenia, with hypokalemia in one patient.
Treatment-related adverse events (TRAEs) were experienced by all patients. In the RP2D arm, 1 event (7%) was deemed serious. Five patients (33%) experienced a grade 3 or 4 TRAE at the RP2D. This increased to nearly all patients in the 2.00 and 2.25 mg/kg arms (73% and 83%, respectively). One patient discontinued treatment in the 2.0 mg/kg arm due to an AE. There were no other discontinuations of zilovertamab vedotin.
Future Directions
A phase 3 study, waveLINE-010, is being planned to compare the zilovertamab vedotin/R-CHP regimen with traditional R-CHOP in previously untreated DLBCL. Further research in the waveLINE-007 study is planned to explore a 1.5 mg/kg dose of zilovertamab vedotin.
