Breakthroughs in biomedical technology are offering new hope for cancer patients, particularly with innovative therapies targeting ROR1 (receptor tyrosine kinase-like orphan receptor 1). Recent clinical trial data presented at the 66th American Society of Hematology (ASH) Annual Meeting, especially regarding zilovertamab vedotin and CS5001, has attracted considerable attention.

Zilovertamab vedotin (MK-2140, VLS-101)

Zilovertamab vedotin is an antibody–drug conjugate (ADC) comprising a monoclonal antibody recognizing extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin monomethyl auristatin E (MMAE).

Figure 1. Structure of Zilovertamab vedotin

At the ASH meeting on December 8th, Merck presented initial findings from the Phase 2 waveLINE-007 trial. This trial investigated the effectiveness of zilovertamab vedotin in combination with cyclophosphamide, doxorubicin and prednisone plus rituximab (R-CHP) for the treatment of patients with previously untreated diffuse large B-cell lymphoma (DLBCL). At a pre-planned analysis, zilovertamab vedotin in combination with R-CHP achieved a 100% (n=15) complete response (CR) rate in patients treated with zilovertamab vedotin at 1.75 mg/kg. 

As of data cut-off, 36 patients were enrolled in the study to receive zilovertamab vedotin plus R-CHP intravenously on day 1 of each 21-day cycle (Q3W) for up to eight cycles. After a median follow-up of 17.6 months, patients receiving the 1.75 mg/kg, 2.0 mg/kg, and 2.25 mg/kg doses achieved objective response rates (ORR) of 100%, 93.3%, and 100%, respectively. While the median duration of response (DOR) hasn't been reached for all participants yet, and the total 12-month DOR was 93.5%. Based on this data, the recommended zilovertamab vedotin dose was determined to be 1.75 mg/kg.

In terms of safety, serious treatment-related adverse events (TRAEs) occurred in 11% (n=4) of patients (1.75 mg/kg [n=1], 2.0 mg/kg [n=1], 2.25 mg/kg [n=2]). Grade 3-4 TRAEs were observed in 58% (n=21) of patients. The most frequent of these side effects were neutropenia, nausea, anemia, and diarrhea.

Merck has registered a Phase 3 clinical trial on ClinicalTrials.gov to further assess zilovertamab vedotin plus R-CHP as a first-line treatment for DLBCL. This larger trial, expected to begin in December 2024, will enroll 1,046 participants.

CS5001 (LCB71)

CS5001 is an ADC composed of a human anti–ROR1 IgG1 monoclonal antibody which is site-specifically conjugated to a pyrrolobenzodiazepine dimer prodrug through a proprietary lysosomal cleavable β-glucuronide linker. CS5001 is currently the second most advanced ROR1-targeting ADC in global development, trailing only Merck’s zilovertamab vedotin.

Figure 2. Structure of CS5001 (Note: From the structural formula of CS5001, it can be seen that its linker utilizes a PEG linker. You can learn more about this topic through the article "Application of PEG Derivatives in ADC Linkers.")

Recently, at the ASH meeting, CStone Pharmaceuticals presented updated clinical data on CS5001 as a single-agent therapy for advanced lymphomas. Notably, CS5001 is the first ROR1 ADC to demonstrate clinical activity in both solid tumors and lymphomas, suggesting potential best-in-class status.

CS5001 has shown promising anti-tumor activity in B-cell lymphomas. Across all dose levels, the overall ORR was 48.4%. Notably, at the DL8 (125 μg/kg), the ORR reached 76.9% in 13 evaluable patients.

• ◆ Hodgkin Lymphoma (HL): Objective responses were observed at doses of  DL5 (50 μg/kg) and higher, including 3 complete responses (CRs) and 3 partial responses (PRs) among 10 evaluable patients at DLs 5-9 (ORR: 60.0%). Specifically, at the DL8 (125 μg/kg), 2 CRs and 1 PR were observed in 3 evaluable patients.

• ◆ Non-Hodgkin Lymphoma (NHL): Objective responses were observed at doses of DL7 (100 μg/kg) and higher, including 3 CRs (2 DLBCL and 1 MCL) and 6 PRs (3 DLBCL, 1 MZL, 1 HGBC and 1 FL) among 16 evaluable patients at DLs 7-9 (ORR: 56.3%). The DL8 (125 μg/kg) again showed a higher ORR of 70% in 10 evaluable patients.

Global multi-center Phase 1 trials of CS5001 are ongoing in the United States, Australia, and China. Dose escalation has been completed, and enrollment is continuing to further evaluate the DL8 (125 μg/kg) or DL9 (156μg/kg). A Phase 1b dose-expansion study, with the potential to support regulatory approval across multiple tumor types, is expected to initiate soon.

About ROR1

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a type I transmembrane protein that belongs to the receptor tyrosine kinase-like orphan receptor (ROR) family. It consists of an extracellular region (containing immunoglobulin-like, cysteine-rich, and kringle domains), a transmembrane region, and an intracellular region (with tyrosine kinase, serine/threonine-rich, and proline-rich domains).

Figure 1. Structure of ROR1

ROR1 plays a critical role in tumor growth and metastasis by mediating non-canonical Wnt signaling. This signaling pathway regulates various biological processes such as cell proliferation, migration, and adhesion. When Wnt5a, a ligand of ROR1, binds to ROR1, it activates the NF-κB pathway in tumor cells, promoting cell migration, invasion, and the epithelial-mesenchymal transition (EMT), which is associated with cancer metastasis.

While ROR1 expression is very low in normal adult tissues, it is significantly overexpressed in a wide range of malignant tumors, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), childhood acute lymphoblastic leukemia (ALL), lung adenocarcinoma, ovarian cancer, breast cancer, colon cancer, and melanoma. This overexpression makes ROR1 a promising tumor-specific biomarker. For example, ROR1 expression has been correlated with advanced clinical stages and lymph node metastasis in colorectal cancer, serving as an independent prognostic factor. Similarly, in ovarian cancer, high ROR1 expression is linked to higher tumor grades and lymph node metastasis. In pancreatic cancer, ROR1 is a key factor in the invasive phenotype of circulating tumor cells.

Figure 4.ROR1 expression in 28 different cancers, data from https://www. Proteinatlas.org

Beyond ADCs, other therapeutic modalities targeting ROR1 are also under development, including monoclonal antibodies, bispecific antibodies, and CAR-T cell therapy.

Table 1. Therapies targeting ROR1 under clinical trials

Conclusion

The expanding field of ROR1-targeted therapies gives us confidence that these innovative treatments will translate into more precise and effective options for cancer patients. These therapies offer broad potential across a range of cancers and pave the way for new research avenues and promising clinical applications in the fight against cancer.

The expanding field of ROR1-targeted therapies gives us confidence that these innovative treatments will translate into more precise and effective options for cancer patients. These therapies offer broad potential across a range of cancers and pave the way for new research avenues and promising clinical applications in the fight against cancer.

Huateng Pharma is dedicated to being your most reliable partner to provide high-quality PEG linkers to promote the progress of your ADC R&D. PEG Linker is one of the most widely used linkers  in ADCs, which can increase the water solubility, improve the DAR value and increase the cycle half-life of ADCs.

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