Waveline-001: Updated Results from a Phase 1 Dose Escalation and Cohort Expansion Study of Zilovertamab Vedotin (MK-2140) in Non-Hodgkin Lymphoma

Background: Zilovertamab vedotin (ZV) is a receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeting antibody-drug conjugate comprising zilovertamab, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E. ROR1 is a transmembrane protein absent in mature tissues but highly expressed in certain hematologic malignancies, making it an attractive therapeutic target. Safety and efficacy of ZV are being investigated in the phase 1 WAVELINE-001 study (NCT03833180), which is a dose escalation and cohort expansion analysis in patients (pts) with relapsed and/or refractory (R/R) hematologic malignancies. Initial results showed ZV had a tolerable safety profile and promising antitumor activity in R/R non-Hodgkin lymphoma (NHL; Wang M, et al. NEJM Evid. 2021;1[1]). Updated results, including PFS and OS for mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Richter transformation (RT), are presented.

Methods: Eligible pts aged ≥18 years of age, with a histological diagnosis of MCL, DLBCL, or RT; had ECOG PS 0-2; and progression during or relapsed after prior systemic therapy, were included. WAVELINE-001 included 3 dosing schedules. Data from Schedule 1 are presented; Schedules 2 and 3 are ongoing. In Schedule 1, pts received ZV IV at a starting dose of 0.5 mg/kg on day 1 Q3W, increasing to 2.5 mg/kg using an accelerated plus 3 + 3 dose escalation design. Primary end point was determination of the maximum tolerated dose and/or recommended dosing regimen (RDR). Secondary end points included safety, ORR, DOR, PFS, and OS.

Results: A total of 54 pts were enrolled in Schedule 1, of which 30 pts were treated at the established RDR of 2.5 mg/kg. At data cutoff (May 18, 2022), median follow-up was 15.3 months (range, 0.5-37.8). Median age was 70.0 yrs, 57% of pts were male, 48% had an ECOG PS of 0, 65% had received ≥3 prior therapies, 80% had NHL (FL, n=3; DLBCL, n=15; MCL, n=17; MZL, n=1; RT, n=7), and 20% had other disease (AML, n=3; CLL/SLL, n=7; mixed histology, n=1). MCL pts had received a median (range) of 4 (1-9) prior lines of therapy. All MCL pts received prior BTKi therapy, and none had prior CAR-T or CAR-NK therapy. 59% of MCL pts were Ann Arbor stage IV. DLBCL pts received a median (range) of 4 (1-7) prior lines of therapy, 67% of pts had received prior CAR-T or CAR-NK therapy; 47% of pts were GCB, and 33% were ABC subtype. Five pts (71%) with RT had the DLBCL subtype. No pts with RT received autologous stem cell transplant and received a median (range) of 3 (1-10) prior therapies.

Any-cause adverse events (AEs) occurred in 52 (96%) pts. Any-grade treatment-related AEs (TRAEs) occurred in 40 pts (74%); most common (≥20%) were peripheral neuropathy (46%), neutrophil count decreased (35%), fatigue (35%), nausea (28%), and diarrhea (20%). Decreases in hemoglobin and platelet count occurred in 13% and 11% of pts, respectively. Grade 3-4 TRAEs occurred in 28 pts (52%), most commonly neutrophil count decreased (33%), platelet count decreased (11%), and peripheral neuropathy (7%). AEs of special interest regardless of causality occurred in 76% of pts; most common were hematopoietic cytopenia (56%) and peripheral neuropathy (48%). For pts experiencing peripheral neuropathy, most cases were grade 1/2 (41%); 7% were grade 3. Median (range) time to onset of first peripheral neuropathy was 49 (1-162) days. No incidences of tumor lysis syndrome or infusion reactions occurred and no grade 5 TRAEs occurred. AEs led to ZV discontinuation in 12 pts (22%) and interruption or reduction in 24 (44%).

ORR was 33% (5/15; 95% CI, 12-62; 3 CR/2 PR) in DLBCL, 53% (9/17; 95% CI, 28-77; 2 CR/7 PR) in MCL, and 57% (4/7; 95% CI, 18-90; 1 CR/3 PR) in RT. No responses were seen among the other indications treated. Median DOR (range) was 4.6 months (2.9-21.5) for DLBCL, 10.0 (0-20.3) for MCL, and 2.8 (0-2.8) for RT. Median PFS (95% CI) was 3.9 months (0.5-7.0) for DLBCL, 11.4 (4.0-NE) for MCL, and 4.7 (0.7-NE) for RT. Median OS (95% CI) was 9.1 months (1.0-NE) for DLBCL, 18.0 (7.1-NE) for MCL, and 24.0 (2.7-NE) for RT. Among 12 pts with NHL (10 DLBCL and 2 RT) who had undergone prior CAR-T/CAR-NK therapy, ORR was 33% (4/12; 95% CI, 10-65).

Conclusions: Updated results from WAVELINE-001 support prior analyses showing ZV had a tolerable safety profile and promising response rates, and favorable PFS and OS among heavily pre-treated pts with DLBCL, MCL, and RT, including pts who had received prior CAR-T/CAR-NK therapy.

Spurgeon:Acerta Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Gilead Sciences, Ionis, Janssen, and Velos Bio, Merck, Incyte: Research Funding; Data Safety Monitoring Board for the Fred Hutchinson Cancer Research Center.: Other: Data Safety Monitoring Board for the Fred Hutchinson Cancer Research Center.; Velos Bio, Karyopharm, Genentech, Janssen, and Pharmacyclics;: Consultancy. Mei:Novartis: Consultancy; Celgene: Research Funding; Morphosys: Research Funding, Speakers Bureau; CTI: Honoraria; Incyte: Research Funding; Beigene: Research Funding; EUSA: Honoraria. Barr:Merck, abbive, gilead, Beigene, Genentech, Astrazeneca, Janssen, TG therapeutics, Celgene, BMS, Morphosys, Adaptive: Consultancy. Barrientos:Merck, Oncternal, Pharmacyclics/Abbvie: Research Funding; Beigene, AstraZeneca, Pharmacyclics/Abbvie: Consultancy. de Vos:BeiGene: Other: Participation on a Data Safety Advisory Board. Furman:AbbVie, AstraZeneca, Beigene, BMS, Genentech, Janssen, Loxo, MEI Pharma, Pharmacyclics, Sanofi, TG Therapeutics, X4 Pharmaceuticals: Consultancy. Patel:Celgene: Consultancy, Research Funding, Speakers Bureau; CRISPR Therapeutics: Research Funding; Curis, Inc: Research Funding; Epizyme: Consultancy, Research Funding; Caribou Biosciences: Consultancy; Trillium Therapuetics/Pfizer: Consultancy, Research Funding; Velos Bio: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Nurix: Research Funding; Morphosys: Consultancy; MEI Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; Abbvie: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Fate Therapeutics: Research Funding; Genetech/Roche: Consultancy, Research Funding, Speakers Bureau; Kite pharma: Consultancy, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Xencor: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; ADC Therapeutics: Consultancy; Aptevo Therapeutics: Research Funding. Thompson:AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding. Choi:Abbvie, TG Therapeutics, Geron, Merck, Oncternal, Pharmacyclics: Research Funding. Wang:Merck & Co., Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ogbu:Merck & Co., Inc.: Current Employment, Current equity holder in publicly-traded company. Nahar:Merck & Co., Inc.: Current Employment. Wang:Pepromene Bio: Consultancy; Genmab: Research Funding; Celgene: Research Funding; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Milken Institute: Consultancy; Oncternal: Consultancy, Research Funding; Merck: Honoraria; Juno Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Medscape: Honoraria; LLC TS Oncology: Honoraria; IDEOlogy Health: Honoraria; Eastern Virginia Medical School: Honoraria; Dava Oncology: Honoraria; Vinverx: Research Funding; Molecular Templates: Research Funding; Loxo Oncology: Research Funding; Lilly: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria; Meeting Minds Experts: Honoraria; MJH Life Sciences: Honoraria; Moffit Cancer Center: Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria; Practice Point Communications (PPC): Honoraria; Studio ER Congressi: Honoraria; Oncology Specialty Group: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy; InnoCare: Consultancy, Research Funding; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; AbbVie: Consultancy.