First report of ROR2 directed therapy with a conditionally active antibody drug conjugate in advanced melanoma.

3077 Background: The receptor tyrosine-kinase like orphan receptors (ROR) are mediators of noncanonical WNT signaling and tissue patterning. ROR2 upregulation is observed in malignancy and has been implicated in metastasis. Development of ROR2 directed conditionally active antibodies with enhanced affinity in the tumor microenvironment is a promising treatment strategy. Here we report our institution’s experience treating 5 patients with advanced cutaneous or uveal melanoma treated with the anti-ROR2 antibody drug conjugate ozuriftamab vedotin (MMAE) on the first in human phase 1 trial. (NCT03504488). Methods: Adults with advanced solid tumors naïve to vinca binding site therapies who had failed all standard of care therapy were eligible. The charts of all 5 patients with advanced melanoma treated at our institution were reviewed. Patients were treated with ozuriftamab vedotin at concentrations of 1.8 mg/kg or 3.0 mg/kg IV Q2W. Safety and efficacy data were collected. Patient samples were evaluated for pharmacokinetics and clinical correlates. Results: 4 out of the 5 patients achieved an objective response in target lesions, per RECIST v1.1 (Table 1). Two of these patients have maintained disease control, including one patient in complete remission (CR) >5 years and the other responding >1 year after starting treatment. Adverse events requiring dose reduction or interruption included neuropathy and neutropenia, both of which recovered with reduced dosing and/or colony stimulating factor. No patients discontinued therapy for adverse drug reactions. Pharmacokinetics showed predictable plasma concentrations of both drug and free MMAE. Anti-drug antibodies were not identified. Biopsies were assessed by IHC for ROR2. The biopsy belonging to the patient who achieved CR was strongly positive for ROR2. All other biopsies showed low/negative ROR2 staining of malignant cells. Conclusions: Ozuriftamab vedotin showed early promising antitumor activity in this first report describing ROR2 directed treatment in refractory advanced cutaneous and uveal melanoma. Clinical trial information: NCT03504488 . Efficacy and safety of ozuriftamab vedotin. Case 1 Case 2 Case 3 Case 4 Case 5 Melanoma Subtype Uveal Uveal Cutaneous Cutaneous Cutaneous Initial Dose (mg/kg) 1.8 1.8 3.0 1.8 1.8 Final Dose (mg/kg) 1.5 1.5 1.8 1.8 1.8 Best Target Lesion Response 10% increase 31.9% decrease (PR) 89% decrease(CR, w/ lymph nodes < 5 mm) 38.2% decrease(PR) 43.7% decrease(PR) Time to Progressive Disease (days) 35 +475* +2079* 127 84 Major Adverse Events G3 Neutropenia G2 Neuropathy G2 Neuropathy, G4 Neutropenia None None Other Adverse Events G2 Transaminitis, G2 Myalgia, G2 Arthralgia None G1 Salivary Inflammation, G1 Alopecia G2 Neuropathy G2 Neuropathy *Patient has not developed progressive disease since starting treatment.