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Abstract Introduction: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein that is overexpressed in multiple cancers, including hematological malignancies. Zilovertamab vedotin (MK-2140) is an antibody -drug conjugate comprising a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the antimicrotubule cytotoxic agent monomethyl auristatin E (MMAE). Preclinical evidence demonstrated the cytotoxicity of zilovertamab vedotin in hematologic cell lines. This first human phase 1 dose escalation study (NCT03833180) evaluated the safety and efficacy of zilovertamab vedotin at various doses in patients with relapsed/refractory hematologic malignancies. Methods: Eligible patients aged ≥18 years with an Eastern Cooperative Oncology Group Performance Status of 0-2 and histological diagnosis of chronic lymphocytic leukemia/small lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, acute lymphoid leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma (NHL; mantle cell lymphoma MCL, follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma DLBCL, Richter transformation, Burkitt lymphoma, and T-cell-NHL) were enrolled. Participants received zilovertamab vedotin intravenously at starting doses of 0.50 mg/kg (up to 2.5 mg/kg) on day 1 every 3 weeks (Q3W) (Schedule 1), 1.0 mg/kg (planned up to 2.25 mg/kg) on day 1 and 8 Q3W (Schedule 2), or 1.0 mg/kg (planned up to 2.25 mg/kg) on days 1, 8, and 15 Q4W (Schedule 3) using an accelerated plus 3+3 dose escalation design. The primary end point was determination of the maximum tolerated dose (MTD). Secondary end points included safety, objective response rate (ORR), and duration of response (DOR). We present data for participants with NHL enrolled in Schedule 1. Results: A total of 51 patients were enrolled in Schedule 1 (starting dose 0.5 n=1, 1.00 n=3, 1.50 n=3, 2.00 n=3, 2.25 n=11, or 2.50 n=30 mg/kg) as of the data cutoff of May 18, 2021. Median (range) age of patients was 70 (44-91) years, 54.9% of patients were male, 49.0% had an ECOG PS of 0, and 41/51 (80%) were diagnosed with NHL; 13/51 (25.5%) were diagnosed with DLBCL and 17/51 (33.3%) were diagnosed with MCL. Enrollment in Schedules 2 and 3 is currently ongoing. The MTD for Schedule 1 was determined to be 2.5 mg/kg. Any-cause adverse events (AEs) occurred in 48 patients (94.1%), most commonly (≥30%) nausea (45.1%), fatigue (45.1%), peripheral neuropathy (41.2%), diarrhea (37.3%), dizziness (35.3%), and neutrophil count decrease (33.3%). Grade ≥3 AEs occurred in 33 (64.7%) patients, most commonly (≥5%) neutrophil count decrease (29.4%), hemoglobin decrease (15.7%), febrile neutropenia (7.8%), peripheral neuropathy (7.8%), platelet count decrease (7.8%), diarrhea (5.9%), lipase increase (5.9%), and pneumonia (5.9%). One patient died due to acute respiratory failure; however, it was not considered treatment-related by the investigator. A total of 7 (13.7%) patients permanently discontinued due to an AE and 18 (35.3%) had treatment interrupted or reduced due to an AE. Treatment-related AEs occurred in 36 patients (70.6%), most commonly (≥20%) peripheral neuropathy (41.2%), fatigue (37.3%), neutrophil count decrease (29.4%), nausea (27.5%), and diarrhea (21.6%); 24 patients (47.1%) experienced a grade ≥3 treatment-related AE. For Schedule 1, ORR was 36.6% (15/41 95% CI: 22.1%-53.1%) among all participants with NHL, with 5 having a complete response (CR) and 10 having a partial response (PR). ORR was 38.5% (95% CI: 13.9%-68.4%) for the 13 patients in the NHL group who had DLBCL; 3 patients had a CR and 2 patients had a PR. ORR was 52.9% (95% CI: 27.8%-77.0%) for the 17 patients in the NHL group who had MCL; 2 patients had a CR and 7 patients had a PR. Median (range) DOR was 7.8 months (2.1-17.6+ months) among all participants in Schedule 1 with NHL who achieved a response. Conclusion: These data suggest that targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in patients with relapsed/refractory NHL. Disclosures Wang: Anticancer Association: Honoraria; Dava Oncology: Honoraria; BioInvent: Research Funding; Bayer Healthcare: Consultancy; Hebei Cancer Prevention Federation: Honoraria; Lilly: Research Funding; Scripps: Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Research Funding; CAHON: Honoraria; InnoCare: Consultancy, Research Funding; Molecular Templates: Research Funding; Pharmacyclics: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Genentech: Consultancy; Newbridge Pharmaceuticals: Honoraria; VelosBio: Consultancy, Research Funding; Celgene: Research Funding; Physicians Education Resources (PER): Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; OMI: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Chinese Medical Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Mumbai Hematology Group: Honoraria; Moffit Cancer Center: Honoraria; BGICS: Honoraria; CStone: Consultancy; Imedex: Honoraria; Epizyme: Consultancy, Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Mei: Janssen: Honoraria; EUSA: Honoraria; Sanofi-Genzyme: Honoraria; Morphosys: Honoraria; TG Therapeutics: Other: Institution: Research Grant/Funding; Epizyme: Other: Institution: Research Grant/Funding; BMS: Other: Institution: Research Grant/Funding; Beigene: Other: Institution: Research Grant/Funding; Incyte: Other: Institution: Research Grant/Funding. Barr: Beigene: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Abbvie/Pharmacyclics: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy. Furman: Acerta/AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Beigene: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Loxo Oncology: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; AstraZeneca: Honoraria; Sunesis: Consultancy; Oncotracker: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Morphosys: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy. Patel: TG Therapeutics: Consultancy, Speakers Bureau; Abbvie: Consultancy; Sunesis Pharmaceuticals: Research Funding; Juno Pharmaceuticals: Consultancy; MEI Pharma: Consultancy, Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Millenium/Takeda: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Trillium Therapeutics: Research Funding; BeiGene: Consultancy; Aptevo Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Xencor: Research Funding; Velos Bio: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Curis, Inc: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Zhu: Merck Gilead Sciences: Other: Institution: Research Grant/Funding; Bristol Myers Squibb: Other: Institution: Research Grant/Funding; BeiGene: Other: Institution: Research Grant/Funding; AstraZeneca: Other: Institution: Research Grant/Funding; Acerta Pharma: Other: Institution: Research Grant/Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Other: Institution: Research Grant/Funding; Genentech: Consultancy, Other: Institution: Research Grant/Funding; Karyopharm: Consultancy; Velos Bio: Consultancy, Other: Institution: Research Grant/Funding; Merck Fred Hutchinson Cancer Research Center: Other: Data Safety Monitoring Board.
Wang et al. (Fri,) studied this question.