VLS-101, a ROR1-Targeting Antibody-Drug Conjugate, Demonstrates a Predictable Safety Profile and Clinical Efficacy in Patients with Heavily Pretreated Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma

Introduction: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is physiologically expressed during embryogenesis, largely disappears by birth, but can be reexpressed pathologically in transformed tissues of many hematological and solid cancers. VLS-101 is an antibody-drug conjugate (ADC) comprising a rapidly internalizing, humanized monoclonal antibody (UC-961) that recognizes extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin, monomethyl auristatin E (MMAE). Methods: This first-in-human, Phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and efficacy of VLS-101 in patients unselected for tumor ROR1 expression who had previously treated chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Richter transformation lymphoma (RTL). VLS-101 was infused over 30 min every 3 wk until cancer progression or intolerable toxicity. After accrual of 1 patient at the first dose level, cohorts were enrolled by 3+3 dose escalation with additional patients accrued and intrapatient dose escalation permitted to refine estimates of maximum tolerated dose and recommended dosing regimen (RDR). Results: 32 patients were enrolled, including 19 males and 13 females with median (range) ages of 70 (54-84) ys; ECOG performance status (n) of 0 (18), 1 (10), or 2 (4); and tumor types (n) of MCL (15), CLL (7), DLBCL (5), FL (3), MZL (1), and RTL (1). Patients had received a median (range) of 4 (1-24) prior systemic therapies including hematopoietic stem cell transplantation (5) and/or chimeric antigen receptor (CAR)-T or -natural killer (NK) cells (6). Among patients with MCL, 15/15 (100%) had received a Bruton tyrosine kinase inhibitor (BTKi), 13/15 (87%) discontinued the BTKi due to progressive disease, and 2/15 (13%) discontinued for atrial fibrillation after 15.6 or 68.5 months of BTKi therapy. Patients (n) by VLS-101 starting dose were 0.5 (1), 1.0 (3), 1.5 (3), 2.25 (11), and 2.5 (14) mg/kg. With intrapatient dose escalation, many patients (n) received a maximum of 2.25 mg/kg (12) or 2.5 mg/kg (17) during VLS-101 therapy (range: 1 to 13 cycles). Cycle 1 DLTs (n/N) by mg/kg dose level were 0.5 (0/1), 1.0 (0/3), 1.5 (0/3), 2.25 (1/11 [9%] Gr 4 neutropenia), and 2.5 (2/14 [14%]; one Gr 4 neutropenia; one Gr 3 diarrhea of uncertain cause). Gr 4 neutropenia occurred in 9/32 (28%) patients; 1/32 (3%) had neutropenic fever. Granulocyte colony-stimulating factor successfully ameliorated neutropenia. Baseline Gr 1 neuropathy was present in 10/32 (31%) patients. On-study reversible Gr 3 neuropathy occurred in 3/32 (9%) patients; no Gr 4 neuropathy occurred. Except for Gr ≤2 alopecia in 3/32 (9%) patients, other adverse events were not obviously drug-related. Considering all 175 infusions administered, drug-related infusion reactions, vomiting, tumor lysis syndrome, rash, hepatic or renal abnormalities, or QT prolongation were not observed. PK showed changes in ADC and MMAE exposures proportional with VLS-101 dose and a mean ADC half-life of ~2.5 d. PD indicated exposure-dependent ROR1 occupancy on circulating CLL cells. No neutralizing anti-drug antibodies were detected. Objective tumor responses were not seen in patients with other tumor types but were observed in 7/15 (47%) of patients with MCL (4 partial; 3 complete) and in 4/5 (80%) of patients with DLBCL (2 partial; 2 complete). From start of therapy, 6/7 patients with responding MCL have responses ongoing at 35, 38, 45, 47, 50, and 58 wk and 2/4 patients with responding DLBCL have responses ongoing at 23 and 47 wk of follow-up. Conclusions: In heavily pretreated patients, VLS-101 infusions were well tolerated and demonstrated a predictable safety profile consistent with an MMAE-containing ADC. Tumor selectivity was confirmed, with no evidence of ROR1-mediated toxicities or non-MMAE toxicities that would suggest normal tissue binding. Considering all data, the VLS-101 RDR was 2.5 mg/kg every 3 wk. Efficacy results provide clinical proof of concept for targeting ROR1 with VLS-101 and demonstrate durable objective responses in patients with advanced MCL or DLBCL, including those with prior BTKi or cellular therapies. Phase 1-2 studies of VLS-101 monotherapy and combination therapy in patients with hematological cancers and solid tumors are planned. Figure Disclosures Wang: Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Oncternal: Consultancy, Research Funding; MoreHealth: Consultancy; Juno: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; OncLive: Honoraria; Guidepoint Global: Consultancy; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria. Barrientos:Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Oncternal Therapeutics: Research Funding; Sandoz: Consultancy; Janssen: Honoraria; AstraZeneca: Consultancy. Furman:Verastem: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genentech: Consultancy. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barr:AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Morphosys: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Choi:Genentech: Consultancy; Pharmacyclics/Abbvie: Research Funding. de Vos:Bayer: Consultancy; Verastem: Consultancy. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Rule:Janssen: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy. Flanders:VelosBio: Current Employment, Current equity holder in private company. Jessen:VelosBio: Current Employment, Current equity holder in private company; eFFECTOR: Current equity holder in private company. Riebling:VelosBio: Current Employment, Current equity holder in private company. Graham:Ce3: Current Employment. King:Ce3: Current Employment; VelosBio: Consultancy; AI Therapeutics: Consultancy. Schmidt:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Lannutti:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Johnson:Zentalis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Current equity holder in publicly-traded company; Neoleukin: Current equity holder in publicly-traded company; Oncternal: Divested equity in a private or publicly-traded company in the past 24 months; Appelis: Divested equity in a private or publicly-traded company in the past 24 months; Acerta: Patents & Royalties; VelosBio: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Miller:Cleveland BioLabs: Consultancy, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company; Cancer Genetics: Current equity holder in publicly-traded company; Incuron: Consultancy; Zentalis: Consultancy, Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; EpiThany: Current equity holder in private company; AstraZeneca: Current equity holder in publicly-traded company; VelosBio: Consultancy, Current Employment, Current equity holder in private company; AI Therapeutics: Consultancy, Current equity holder in private company; Catalys Pacific: Consultancy. Spurgeon:Cardinal Health: Honoraria; VelosBio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; Beigene: Research Funding; Verastem: Research Funding.