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First-line zilovertamab vedotin plus cyclophosphamide, doxorubicin, prednisone, and rituximab (Rituxan; R-CHP) yielded high response rates in patients with diffuse large B cell lymphoma (DLBCL) who received zilovertamab vedotin at various dose levels, according to findings from the phase 2 WAVELINE-007 trial (NCT05406401).
Data from the dose-escalation study presented at the 2024 ASH Annual Meeting showed that the objective response rate (ORR) across all dose levels (n = 36) was 97.2% (95% CI, 85.5%-99.9%), which consisted entirely of complete responses (CRs). At the zilovertamab vedotin 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%), which also was entirely comprised of CR. 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.
Additionally, the ORR in the 2.0 mg/kg arm (n = 15) was 93.3% (95% CI, 68.1%-99.8%), which was comprised entirely of CRs. The 12-month duration of response in this group was 92.3%. In the 2.25 mg/kg group, the ORR, also entirely CRs, was 100%, and the 12-month duration of response was 100%. Across all doses, every patient experienced more than a 60% reduction in the target lesion size from baseline, with more than 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," lead investigator Muhit Ozcan, MD, Hematology Department, Ankara University School of Medicine, Cankaya-Ankara, Turkey, said during a presentation of the results. "These results warrant further evaluation of this combination in a larger population."
Zilovertamab vedotin is an antibody-drug conjugate consisting of a ROR1-targeting antibody with an MMAE cytotoxic payload. In general, Ozcan noted, ROR1 is expressed across all lymphoid malignancies and in studies a correlation was not seen between expression levels and efficacy with the agent. As a result, testing for ROR1 was not a prerequisite for the study.
For the study, 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 no more than 8 cycles. Even though 8 cycles were allowed, most used the more standard 6 cycles, which is common with R-CHOP, Ozcan noted.
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. There were 2 patient discontinuations before treatment completion. Both were listed as physician decision. All patients also received R-CHP. The vincristine was omitted from the traditional R-CHOP regimen due to potentially overlapping adverse events (AEs) with the investigational agent, Ozcan said.
The median age was 64.0 years across all 36 enrolled patients. The ECOG performance status across all patients was 0 (42%) and 1 (58%). Bone marrow involvement was noted for 11% of patients and half of patients 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.
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, 1 being diarrhea and the other pneumonia. Two patients experienced DLT events at the 2.25 mg/kg dose level, both experienced febrile neutropenia along with hypokalemia in 1.
Treatment-related adverse events (TRAE) were experienced by all patients enrolled in the study. In the RP2D arm, 1 of these events (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.
A phase 3 study to further examine zilovertamab vedotin is currently being planned under the name waveLINE-010. In this study, the zilovertamab vedotin/R-CHP regimen will be compared with traditional R-CHOP in previously untreated DLBCL. Additionally, further research in the waveLINE-007 study is planned to explore a 1.5 mg/kg dose of zilovertamab vedotin, Ozcan noted.
Reference
Ozcan M, Barca EG, Kim TM, et al. Waveline-007: dose escalation and confirmation, and efficacy expansion trial of zilovertamab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone plus rituximab in patients with diffuse large b cell lymphoma. Blood. 2024;144(suppl 1):578. doi:10.1182/blood-2024-200271