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

Background: Patients with diffuse large B cell lymphoma (DLBCL) have a poor prognostic outcome despite recent progress with combination regimens that include cyclophosphamide, doxorubicin, and prednisone plus rituximab (R-CHP). Lymphoid cancers express near-ubiquitously ROR-1 and are responsive to antibody-drug conjugates (ADC) that deliver monomethyl auristatin E (MMAE). Zilovertamab vedotin (ZV) is a ROR1-targeting ADC with a MMAE payload that has shown promising efficacy in patients with DLBCL (Wang et al., 2021). In the WAVELINE-007 (NCT05406401) we evaluated the safety and efficacy of ZV in combination with R-CHP in patients with untreated DLBCL. Methods: This nonrandomized, open-label phase 2 trial enrolled eligible patients aged ≥18 years with DLBCL confirmed by positron emission tomography by BICR per Lugano criteria, no prior treatment for DLBCL, and ECOG performance score 0-1 to receive ZV (1.75, 2.0, 2.25 mg/kg) plus R-CHP Q3W 6 or 8 cycles. The primary endpoint was safety (number of patients with dose limiting toxicity [DLT], adverse events [AE], and discontinuation due to AE) to establish the ZV recommended Phase 2 dose (RP2D), and complete response rate per Lugano 2014 response criteria by investigator. Secondary endpoints were objective response rate (ORR) and duration of response (DOR) per Lugano criteria by investigator. The data cut-off date was 18 Dec 2023. Results: At data cut-off, 36 patients were enrolled to receive R-CHP plus ZV 1.75 mg/kg (n=15), 2.0 mg/kg (n=15), or 2.25 mg/kg (n=6). The median (range) age was 64 years (21-79) for all patients, 21 (58%) had ECOG PS 1, 17 (47%) had Ann Arbor stage IV disease, and 3 (8%) had a NCCN International Prognostic Index of high risk. The median (range) follow-up was 10.0 months (mo) (6.7 -17.0) for all patients, with median follow-up of 9.2 mo, 9.9 mo and 12.4 mo, respectively, for patients receiving ZV 1.75 mg/kg, 2.0 mg/kg, or 2.25 mg/kg. At data cut-off, 2 (6%) patients had discontinued due to physician decision (1 receiving ZV 2.0 mg/kg and 1 receiving ZV 2.25 mg/kg). A total of 4 DLTs (diarrhea and pneumonia [grade 3] in 2 patients receiving ZV 2.0 mg/kg, and febrile neutropenia [grade 4] and hypokalemia [grade 3] in 2 patients receiving ZV 2.25 mg/kg) were reported. All cause AEs occurred in 36 (100%) patients, and 1 (3%) patient discontinued one of the components of R-CHP due to an all-cause AE. Grade 3-4 drug-related AEs were reported in 22 (61%) patients (6 receiving ZV 1.75 mg/kg, 11 ZV 2.0 mg/kg, and 5 ZV 2.25 mg/kg), most commonly neutropenia (13 [36%]). No discontinuations due to ZV and no grade 5 drug-related AEs were reported. Complete response at end-of-treatment (EOT) was achieved in all 15 (100%) patients receiving ZV 1.75 mg/kg, 14 (93%) patients receiving ZV 2.0 mg/kg (1 patient discontinued due to physician decision), and 5 (83%) patients receiving ZV 2.25 mg/kg, for an overall CR rate at end of treatment of 94.4% (95% CI, 81-99). One patient receiving ZV 2.25 mg/kg had partial response at end of treatment, but its best response was CR. One patient receiving ZV 2.0 mg/kg was not evaluable for efficacy since they discontinued treatment due to physician decision. The ORR was 100%, 93%, and 100%, respectively, with median DOR not reached (NR) for all patients. The 12-mo DOR was 90% for ZV 1.75 mg/kg and ZV 2.0 mg/kg, and NR for ZV 2.25 mg/kg. One patient receiving ZV 1.75 mg/kg had progressive disease after 12 weeks follow up, and one patient in ZV 2.0 mg/kg died around 24 weeks after EOT of unknown reason. Following the totality of the data from the three dose levels (1.75mg/kg, 2mg/kg, 2.25mg/kg) RP2D was determined to be 1.75mg/kg. Upon determination of RP2D, the waveLINE-007 trial is designed to further evaluate a lower dose level (RP2D-1 of 1.5 mg/kg) in combination with R-CHP for which it is currently enrolling patients. Conclusions: The study evaluating zilovertamab vedotin in combination with R-CHP as front-line treatment for patients with DLBCL has demonstrated highly promising efficacy and a manageable safety profile. The recommended Phase 2 dose (RP2D) of ZV was established at 1.75 mg/kg and the combination therapy at this dose level achieved objective response rate and complete response rate at end of treatment of 100%. The combination provided a robust response in patients with DLBCL and warrants further evaluation in a larger population.