A novel ROR1-targeted antibody-drug conjugate (ADC), zilovertamab vedotin, also known as  MK-2140 or VLS-101, has demonstrated encouraging clinical efficacy, consistent pharmacokinetics, and a favorable safety profile in patients with heavily pretreated mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). This is the conclusion of a study presented at the 62nd Annual Meeting and Exposition of the American Society of Hematology (ASH), held virtually December 5-8, 2020.[1]

Zilovertamab vedotin is a novel ADC that includes the humanized monoclonal antibody (IgG1k) zilovertamab (previously UC-961 or cirmtuzumab), a highly specific for tumor tissue and a proteolytically cleavable maleimidocaproyl-valine-citrulline-para-aminobenzoate linker linking the anti-microtubule cytotoxin monomethyl auristatin E (MMAE) to the antibody. The mean MMAE-to-antibody ratio (DAR) is 4

Zilovertamab vedotin binding to tumor cell ROR1 results in rapid internalization, trafficking to lysosomes, antibody-drug conjugate cleavage, and the release of MMAE.

An attractive target
Receptor tyrosine kinase-like orphan receptor 1 or ROR1 is a cell-surface protein that mediates signaling from its ligand, Wnt5a, and drives physiologic embryonic stem cell proliferation. It is an oncofetal protein that plays a role in embryonic development. And while physiologic expression of ROR1 disappears before birth, the pathologic expression of the protein is known to reappear in aggressive cancers, where it is expressed on the tumor cell surface. ROR1-expressing hematologic and solid tumors are generally associated with poor outcomes. [2][3]

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The study presented at the 2021 annual meeting of the American Society of Hematology confirmed an objective response rate (ORR) among patients with mantle cell lymphoma (n = 15) of 47%, including 5 partial responses (PRs) and 2 complete responses (CRs). The ORR in patients with diffuse large B-cell lymphoma (n = 5) was 80%, including 2 PRs and 2 CRs.

Furthermore, patients with MCL who had prior high-dose therapy or hematopoietic stem cell transplant (HSCT) and patients with DLBCL who had prior high-dose therapy, HSCT, or CAR T-cell therapy had confirmed Partial Response (PR) or Complete Response (CR).

Michael Wang, M.D., trained in a basic science research lab at the National Institutes of Health (NIH) for six years. His goal is to significantly contribute to curing mantle cell lymphoma and substantially impact B-cell lymphoma survival. Photo Courtesy: © 2022 The University of Texas MD Anderson Cancer Center. Used with permission.

“The zilovertamab vedotin efficacy results provide clinical proof of concept for targeting ROR1, demonstrating durable objective responses in patients with advanced MCL or large B-cell lymphoma, including those with prior BTK inhibitor therapy or cellular therapies,” said lead study author Michael L. Wang, MD, Puddin Clarke endowed professor in the Department of Lymphoma & Myeloma at the University of Texas MD Anderson Cancer Center.

Wang is also the U.S. Principal Investigator and Chairman of the steering committee for the new phase 3 superiority study ZILO-301, which investigates zilovertamab + plus Ibrutinib vs. Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) + placebo in patients with relapsed or refractory Mantle Cell Lymphoma (MCL)

The study randomizes patients with relapsed or refractory MCL who have experienced stable disease or partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo, and all patients will continue receiving oral ibrutinib.

Dosing regimen
The phase 1 trial explored an every-3-week dosing regimen in a 3+3 design. Zilovertamab vedotin was administered in 30-minute intravenous infusions. The initial dose given was 0.5 mg/kg of zilovertamab vedotin (n = 1), followed by 1.0 mg/kg (n = 3), 1.5 mg/kg (n = 3), 2.25 mg/kg (n = 11), and 2.5 mg/kg (n = 14). As part of this study, intrapatient dose escalation was allowed, and interpatient and intrapatient dose modulation was used to establish the starting dose.

In this study, adult patients eligible for enrollment included those with relapsed and/or refractory B-cell cancer who are most likely to express ROR1. To participate, patients had to have progressive cancer or had to be intolerant to standard therapies.  They had to have adequate organ function.

Overall, the trial enrolled patients with B-cell malignancies. These malignancies included MCL (n = 15; 46.9%), CLL (n = 7; 21.9%), DLBCL (n = 5; 15.6), follicular lymphoma (n = 3; 9.4%), marginal zone lymphoma (n = 1; 3.1%), and Richter transformation lymphoma (n = 1; 3.1%).

Evaluable patients participating in the study (n = 32) had a median age of 70 (range, 54-84) and more than half (n = 19 / 59.4%) were male. Patients had ECOG performance statuses of 0 (n = 18; 56.3%) 1 (n = 10; 31.3%), or 2 (n = 4; 12.5%).

Prior treatment
Participating patients had a median of 4 prior lines of systemic therapy (range, 1-24).  Therapies included anti-CD20 antibodies (n = 31; 97%), alkylators (n = 28; 88%), BTK inhibitors (n = 22; 69%), corticosteroids (n = 20; 63%), anthracyclines (n = 18; 57%), vinca alkaloids (n = 18; 56%), antimetabolites (n = 16; 50%), cereblon inhibitors (n = 8; 25%), proteasome inhibitors (n = 8; 25%), topoisomerase 2 inhibitors (n = 8; 25%), BCL-2 inhibitors (n = 7; 21%), as well as PI3K inhibitors (n = 4; 12%). In addition, 16% (n = 5) of patients had prior autologous transplant and 19% (n = 6) had prior CAR T- or NK-cell therapy.

Adverse events
The pharmacokinetics of zilovertamab vedotin were consistent with expected profiles of MMAE-containing antibody-drug conjugates. Also, the safety profile of zilovertamab vedotin is similar to expected MMAE-related adverse effects (AEs).

The primary acute toxicity, grade 3 and 4 neutropenia was observed in 25% and 28% of patients, respectively. Prophylactic or reactive granulocyte colony-stimulating factor therapies (G-CSF), a blood growth factor that stimulates the bone marrow to produce more infection-fighting white blood cells called neutrophils, such as pegfilgrastim (Neulasta; Amgen) and filgrastim (Neupogen; Amgen), were effective in preventing or treating neutropenia.

Grade 2 and 3 neuropathy was observed in 22% and 13% of patients, respectively, and was the primary cumulative toxicity observed. Neuropathy was manageable with dose interruptions or dose modifications.

Grade 3 diarrhea was observed in 9% of patients, but it is unclear whether the toxicity was due to zilovertamab vedotin. Moreover, diarrhea was managed with evaluation for alternate causes, antidiarrheals, and dose modifications.

Grade 1 and grade 2 alopecia was observed in 3% and 6% of patients, respectively.

Not observed or negligible
Although expected, in this study, the investigators did not observe instances of infusion reaction, venous irritation, tumor lysis syndrome, ocular, skin, cardiac, pulmonary, renal, hepatic, or metabolic toxicities, drug- or exposure-related cardiac QT interval prolongation, or clinically consequential immunogenicity. Despite not giving routine antiemetic prophylaxis to participating patients, cases of emetogenic potential, including nausea and vomiting, were negligible.

Ongoing studies
Based on the findings of the study, the investigators established a phase 2 starting dose of zilovertamab vedotin of 2.5 mg/kg administered every 3 weeks.

Clinical trials
A Study of Zilovertamab Vedotin (MK-2140 / VLS-101) in Participants With Hematologic Malignancies (MK-2140-001) – NCT03833180

Highlights of prescribing information
Pegfilgrastim (Neulasta; Amgen)(Prescribing Information)
Filgrastim (Neupogen; Amgen)(Prescribing Information)
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech)(Prescribing Information)

[1] Wang ML, Barrientos JC, Furman RR, et al. 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. Presented at: 2020 ASH Annual Meeting held December 5-8, 2020; virtual. Abstract 121.
[2] Zhang S, Zhang H, Ghia EM, Huang J, Wu L, Zhang J, Lam S, Lei Y, He J, Cui B, Widhopf GF 2nd, Yu J, Schwab R, Messer K, Jiang W, Parker BA, Carson DA, Kipps TJ. Inhibition of chemotherapy-resistant breast cancer stem cells by a ROR1 specific antibody. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1370-1377. doi: 10.1073/pnas.1816262116. Epub 2019 Jan 8. PMID: 30622177; PMCID: PMC6347692.
[3] Balakrishnan A, Goodpaster T, Randolph-Habecker J, Hoffstrom BG, Jalikis FG, Koch LK, Berger C, Kosasih PL, Rajan A, Sommermeyer D, Porter PL, Riddell SR. Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res. 2017 Jun 15;23(12):3061-3071. doi: 10.1158/1078-0432.CCR-16-2083. Epub 2016 Nov 16. PMID: 27852699; PMCID: PMC5440207.

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