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 garnered significant attention.
Zilovertamab Vedotin Demonstrates High Response Rate in DLBCL
Merck presented initial findings from the Phase 2 waveLINE-007 trial at the ASH meeting. 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). The data showed that 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 the 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. The total 12-month duration of response (DOR) was 93.5%. Based on this data, the recommended zilovertamab vedotin dose was determined to be 1.75 mg/kg.
Regarding safety, serious treatment-related adverse events (TRAEs) occurred in 11% (n=4) of patients. Grade 3-4 TRAEs were observed in 58% (n=21) of patients, the most frequent being neutropenia, nausea, anemia, and diarrhea.
Merck has registered a Phase 3 clinical trial to further assess zilovertamab vedotin plus R-CHP as a first-line treatment for DLBCL, expected to begin in December 2024 with 1,046 participants.
CS5001 Shows Promising Activity in Advanced Lymphomas
CStone Pharmaceuticals presented updated clinical data on CS5001 as a single-agent therapy for advanced lymphomas at the ASH meeting. CS5001 is the first ROR1 ADC to demonstrate clinical activity in both solid tumors and lymphomas.
CS5001 has shown promising anti-tumor activity in B-cell lymphomas. Across all dose levels, the overall ORR was 48.4%. At the DL8 (125 μg/kg) dose, the ORR reached 76.9% in 13 evaluable patients.
In 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.
In 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 is expected to initiate soon.
ROR1 as a Therapeutic Target
ROR1 plays a critical role in tumor growth and metastasis by mediating non-canonical Wnt signaling, regulating cell proliferation, migration, and adhesion. 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, making it a promising tumor-specific biomarker.
Beyond ADCs, other therapeutic modalities targeting ROR1 are also under development, including monoclonal antibodies, bispecific antibodies, and CAR-T cell therapy.
The expanding field of ROR1-targeted therapies gives 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.
