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.