Safety and Efficacy in Patients with Advanced Lymphomas from a Global Phase 1a/1b, First-in-Human Study of CS5001, a Novel Anti-ROR1 ADC

Background Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an embryonic tyrosine kinase-like molecule which is overexpressed at high frequency in B cell malignancies and in a broad spectrum of solid tumors. CS5001 is an antibody drug conjugate (ADC) composed of a human anti-ROR1 IgG1 monoclonal antibody with tumor-specific efficacy and low systematic toxicity which is site-specifically conjugated to a pyrrolobenzodiazepine dimer prodrug through a proprietary lysosomal cleavable β-glucuronide linker. Preclinical studies have shown potent anti-tumor activity in various lymphomas and solid tumor models. Here, we report clinical safety and efficacy data in patients with advanced lymphomas from the first-in-human study of CS5001 (NCT05279300). Method This is an ongoing, global, first-in-human, phase 1a (dose escalation)/1b (dose expansion) study evaluating the safety, pharmacokinetics (PK), and anti-tumor activity of CS5001 in patients with advanced lymphomas and solid tumors. CS5001 was administered intravenously every 3 weeks. Phase 1a is dose escalation using a Bayesian optimal interval design, with an accelerated titration at the first dose level (7 μg/kg), followed by 15, 22.5, 33.5, 50, 75, 100, 125, 156, and 195 μg/kg. Dose-limiting toxicity (DLT) for each cohort was evaluated during the first 2 cycles of study treatment. Patients with lymphomas were eligible irrespective of baseline ROR1 expression status and they must be eastern cooperative oncology group (ECOG) performance status 0-1, have histologically diagnosed Hodgkin lymphoma (HL) or B-cell non-Hodgkin lymphoma (NHLs) including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), etc. and have failed ≥ 2 prior therapies (a prior brentuximab vedotin and at least one checkpoint inhibitor [if eligible] treatment was necessary for relapse or refractory classical HL). In parallel with dose escalation, additional patients were backfilled to selected dose levels deemed safe to further evaluate the safety and efficacy of CS5001. The primary objectives of phase 1a are to evaluate the safety/tolerability and establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). The secondary objectives are to evaluate the PK, immunogenicity, and preliminary anti-tumor activity of CS5001. Adverse events were evaluated per NCI CTCAE 5.0. Objective responses in lymphomas were assessed by investigators according to the 2014 Lugano response criteria. Results As of 2 July 2024, 23 patients with advanced lymphomas (11 HL and 12 B-cell NHLs [10 DLBCL, 1 FL, 1 MCL]) were treated at 33.5 μg/kg (n= 2), 50 μg/kg (n= 2), 75 μg/kg (n= 5), 100 μg/kg (n= 8), 125 μg/kg (n= 5), 156 μg/kg (n= 1); 18 (78.3%) patients had discontinued the treatment and 5 (21.7%) were ongoing. The median age was 50 years (range, 30-81); 12 (52.2%) patients were male; 19 (82.6%) patients were Asian; 18 (78.3%) patients had an ECOG PS of 1 and most patients (19, 82.6%) had ≥3 lines of prior anti-tumor treatments. No DLT was observed and MTD was not reached. For the lymphomas, treatment related adverse events (TRAEs) occurred in 20 (87.0%) patients; the most commonly reported TRAEs were anaemia (n= 9, 39.1 %), white blood cell count decreased (n= 6, 26.1 %), decreased appetite (n= 6, 26.1%), aspartate aminotransferase increased (n= 5, 21.7 %). Grade ≥3 TRAEs occurred in 11 (47.8%) patients; the most common events were fatigue, gamma-glutamyltransferase increased and pneumonia (n=3 [13.0%] each). Encouraging anti-tumor activity was observed in advanced HL and B-cell NHLs, with objective response rate (ORR) of 43.5% across all the dose levels. For HL, objective responses were observed from dose level 5 (50 μg/kg) and above, including 2 complete responses (CRs) and 4 partial responses (PRs) among 10 evaluable patients at dose levels 5-10 [ORR: 60.0%]. For B-cell NHLs, objective responses were observed from dose level 7 (100 μg/kg) and above, including 2 CR (1 DLBCL and 1 MCL) and 2 PRs (2 DLBCL) among 8 evaluable patients at dose levels 7-10 (ORR: 50.0%). Dose escalation and backfilling enrollment are still ongoing; updated data from more patients with lymphomas will be presented at the conference. Conclusion CS5001 was well tolerated and showed promising efficacy in patients with advanced lymphomas. Current data support continued evaluations for the RP2D and subsequent phase 1b dose expansion.