A phase I/II study of CR011-vcMMAE, an antibody-drug conjugate (ADC) targeting glycoprotein NMB (GPNMB) in patients (pts) with advanced melanoma

Abstract

9032 Background: GPNMB is expressed on melanoma cells and represents a potential target for ADCs. CR011-vcMMAE is a fully-human monoclonal antibody to GPNMB conjugated to the tubulin inhibitor monomethylauristatin E (MMAE). Dose limiting toxicity in Phase I (n=32) was rash; tumor shrinkage including one partial response (PR) was observed. We now report Phase II data at the maximum tolerated dose of 1.88 mg/kg iv q3w. Methods: Eligible pts had unresectable stage III or stage IV melanoma and had received no more than 1 prior cytotoxic regimen but any number of other therapies. Pts received CR011-vcMMAE until disease progression (PD) or intolerable toxicity. The primary endpoint was overall response (ORR) by RECIST using a minimax two-stage design (p0=0.5; p1=0.2, α=β=0.1) with 18 patients in the first stage and a total of 32 pts. Secondary endpoints included progression free survival (PFS) and duration of response. Results: 36 pts (median age 67 years [range 37–79]; 94% stage IV; 68% M1c) were treated for a median of 2.4 months (m)(range 0.5–7.5m). 18 pts discontinued (14 PD, 2 consent, 1 adverse event [AE], 1 stable disease [SD]) and 18 pts were ongoing. The study met the criteria for advancement to the second stage; 4 PRs (1 unconfirmed) and 19 SD (range 1.7–7.5 mo) have been observed; final ORR is pending. The unconfirmed PR was in a pt with 96% tumor reduction and PD 6 weeks later. Median PFS was 4m. The most common AEs were rash (81%), fatigue (72%), alopecia (63%) and pruritus (56%). The most common grade 3/4 AEs were neutropenia (22%) and rash (19%). Grade 2 or higher rash was associated with longer PFS. Conclusions: CR011-vcMMAE is active and well-tolerated in heavily pretreated pts with advanced melanoma. Rash may be a useful biomarker for activity. More frequent dosing is being explored. [Table: see text]