Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.

P2/3, N=290, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2027 --> Sep 2027 | Trial primary completion date: Jun 2027 --> Sep 2027

The total mAb, acMMAE, and free MMAE model showed a good fit to the data. The pediatric population can match the acMMAE adult exposure at the same weight-based dose regimen without concerns that the toxic MMAE concentration will reach higher levels than found in adults.

P2, N=60, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Apr 2029 | Trial primary completion date: Jan 2026 --> Apr 2029

P1, N=111, Recruiting, Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd.

P2, N=102, Terminated, VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Completed --> Terminated; Business reasons

Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their in vivo half-life with fatty side chains for albumin binding. The antitumor candidate II-3 displayed exceptional affinity (KD = 1.72 × 10-9 M), internalization efficiency, anticancer potency (IC50 = 0.015 ± 0.002 μM), and pharmacokinetics (t1/2 = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.

P1/2, N=90, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P1/2, N=90, Not yet recruiting, Merck Sharp & Dohme LLC

P2/3, N=260, Recruiting, Merck Sharp & Dohme LLC | N=420 --> 260 | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2025 --> Jun 2027

P1, N=91, Completed, VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Active, not recruiting --> Completed | N=330 --> 91

P2, N=140, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P1, N=330, Active, not recruiting, VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial primary completion date: Sep 2023 --> Dec 2023

The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.

P1, N=156, Recruiting, CStone Pharmaceuticals | Trial completion date: Mar 2024 --> Jun 2025

In this updated analysis of waveLINE-004, zilovertamab vedotin continued to demonstrate clinically meaningful antitumor activity in pts with R/R DLBCL who had progressed after or were ineligible for ASCT and/or CAR T-cell therapy. The safety profile of zilovertamab vedotin was manageable, and consistent with the known profile of MMAE-containing agents.

Outlining the discovery and development of a novel ROR1 ADC using a newly designed β-Glu Exatecan linker payload; Providing an overview of the preclinical characterization of STRO-003 anti-tumor efficacy across xenograft and PDX tumor models; Highlighting the pharmacokinetics and attractive safety profile of STRO-003 in non-human primates

P2, N=102, Completed, VelosBio Inc. | Active, not recruiting --> Completed | N=210 --> 102

The results of this updated analysis support prior findings from waveLINE-001 showing ZV had a tolerable safetyprofile and promising antitumor activity in pts with heavily pretreated DLBCL, MCL, and RT, including those who had received prior CAR-T/CAR-NK therapy.

At the data cutoff (Nov 16, 2022), 40 pts had been enrolled and had received ≥1 dose of zilovertamab vedotin; 23 (58%) pts had discontinued treatmentand 17 (43%) were ongoing.The median age was 68.0 years, 29 pts (73%) were male, 37 pts (93%) had an ECOG PS of 0 or 1,and 24 pts (60%) had received ≥3 prior lines of therapy. Theseearly results from waveLINE-004 show that zilovertamab vedotin had clinically meaningful antitumor activity and a manageablesafety profilethat was consistent with other monomethyl auristatin E–containing agents in pts with R/R DLBCL who had progressed after or wereineligiblefor ASCTand CAR-Tcell therapy.

P2, N=210, Active, not recruiting, VelosBio Inc. | Recruiting --> Active, not recruiting | Trial completion date: Nov 2024 --> Aug 2023 | Trial primary completion date: May 2024 --> Jul 2023

Follow-up vaccination studies were performed to further explore the significance of STRO-003-induced ICD and protective immunity in vivo. These results demonstrate that tumor cells pre-treated with STRO-003 or SC3386 undergo potent immunogenic cell damage which can, in turn, mount protective immunity in vivo.

P2, N=210, Recruiting, VelosBio Inc. | Trial completion date: Mar 2024 --> Nov 2024 | Trial primary completion date: Sep 2023 --> May 2024

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.

Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients...In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT, the standardof-care has generally been R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by rituximab, maintenance. In recent years, bendamustinebased therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients...In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib...Acalabrutinib, originally referred to as ACP-196, is a novel, irreversible BTK inhibitor that was designed to be more kinase-selective than ibrutinib. Orelabrutinib is an orally administered, potent, irreversible and highly selective BTK-inhibitor being developed the treatment of B cell malignancies and autoimmune diseases. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. Zanubrutinib received accelerated approval in the USA on 14 November 2019 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, based on overall response rate (ORR) seen in phase II and I/II clinical trials. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. Zilovertamab vedotin is an antibodydrug conjugate, which binds specifically to receptor tyrosine kinase-like orphan receptor-1 (ROR-1), an oncoprotein that is pathologically expressed in mantle cell lymphoma and other malignancies. The development of anti-CD19 CAR T-cell therapy represents a major advance in the treatment of patients with chemorefractory B-cell malignancies.

In the part 1 dose confirmation phase, 30 patients from cohort A will receive ZV at increasing doses of 1.75, 2.0, 2.25, and 2.5 mg/kg; starting at 1.75 mg/kg plus gemcitabine-oxaliplatin + rituximab (R-GemOx) to establish the recommended phase 2 dose using the mTPI design...The safety run-in phase of part 2 will include 30 patients from cohort B who will receive ZV + bendamustine and rituximab (BR)...Key secondary end points in the dose expansion phase of part 2 for both cohorts include objective response rate (complete response and partial response) and duration of response, both by BICR per Lugano 2014 criteria, and overall survival. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

PFS, disease control rate by BICR, overall survival, ORR per investigator review, pharmacokinetic profile, biomarker analysis (including correlation of outcomes and ROR1 expression on tumor cells), and health-related quality of life are exploratory end points. ORR with 95% CI will be estimated by the Clopper-Pearson method.

P2, N=60, Ongoing, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc

Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics-such as covalent Bruton tyrosine kinase inhibitors, lenalidomide, and venetoclax-are being incorporated into "chemotherapy-free" regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve mantle cell lymphoma. After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib. These new therapies show promising efficacy, even among high-risk patients, and will likely translate to improvements in survival outcomes for patients with progressive mantle cell lymphoma following treatment with a Bruton tyrosine kinase inhibitor.

For pts who received prior CAR-T/CAR-NK, the ORR was 40.0% (95% CI, 16.3%-67.6%); 2 pts had a CR and 4 had a PR. Conclusion Targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in pts with relapsed/refractory NHL.

P2, N=210, Recruiting, VelosBio Inc. | N=90 --> 210

Since all the components of ADCs, including the antibody, linker and payload, as well as the conjugation method, play critical roles in ADC's efficacy and performance, their choice and combination will determine how far they can be advanced. This review summarizes the design and development of current anti-ROR1 ADCs and highlights an emerging trend to target ROR1 for cancer therapy.

These data suggest that targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in patients with relapsed/refractory NHL.

Brexucabtagene autoleucel, the first and only FDA approved chimeric antigen receptor (CAR) T product in MCL, demonstrated unprecedented efficacy in overcoming resistance to Bruton's tyrosine kinase inhibitors...Importantly, VLS-101 safely induced tumor regression in PDX models resistant to CAR T-cell therapy, ibrutinib and/or venetoclax...These data also provide strong evidence for future enrollment of post-CD19 CAR T-cell relapsed MCL patients in a first in-human phase 1b VLS-101 trial. The upcoming testing in a clinical setting will provide important insights on this new therapeutic development aiming to overcome the CAR T resistance via targeting ROR1, which is a rising unmet clinical need in MCL.

In combination with other clinically relevant targeting drugs as venetoclax a synergistic apoptotic effect was seen. Two other small molecules (ARI-1 and strictinin) bound also to ROR1 and inhibited tumor growth. Development of small molecule ROR1 inhibitors is warranted to include this novel therapeutic approach for cancer therapy.

Options in this setting may depend of treatment availability, patient and physician preference, and patient age and comorbidity status. We discuss the rapid recent development of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in this space as well as the utility of allogenic stem cell transplantation and novel therapies such as non-covalent, reversible BTK inhibitors, ROR1 antibody drug conjugates and bispecific antibodies.

The activity of NM32-2668 has the potential to provide significant benefit to patients with ROR1+ malignancies on a convenient dosing schedule. We intend to rapidly progress NM32-2668 to clinical development.

No abstract available