Phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine (AR).

Abstract

2509 Background: AR (BAY 94-9343) comprises a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DMR. A phase I study was conducted in patients (pts) with advanced solid tumors. Methods: Eligible pts with solid tumors refractory to standard treatment, adequate organ function, and ECOG performance status (PS) ≤ 1 were enrolled. AR was administered IV on 2 schedules: every 21 days (q3w) in 45 pts (21 mesothelioma [Meso], 9 pancreatic, 5 breast, 4 ovarian cancer [OC], 6 other) at doses ranging from 0.15 to 7.5 mg/kg and in an expansion cohort at 6.5 mg/kg (12 Meso and 20 OC); and weekly (qw) in 71 pts (31 Meso and 40 OC) randomized to either 1.8 mg/kg or 2.2 mg/kg. Pts were assessed for AEs weekly C1-C3 and on D1 in subsequent cycles. Tumor response was assessed q6w C1-C8 and q12w thereafter. Mesothelin expression in archival tumor samples was assessed by IHC (SP74, Ventana). Results: A total of 147 pts were evaluable: 64% female, mean age 61 yrs (range 18-88), PS 0/1 29%/71%. The 7.5 mg/kg q3w dose was not tolerated. The maximally tolerated dose (MTD) was 6.5 mg/kg q3w; 15 of 32 (47%) pts in MTD expansion had dose reduction to 5.5 mg/kg q3w. Adverse events (AEs) were similar to the mesothelin-ADC inhibitor class, including reversible keratopathy, asymptomatic liver function test increases, and gastrointestinal disorders. Drug-related (DR) serious AEs were low (11 total; 5 at the q3w MTD) and highly similar to this class of inhibitors. No DR deaths were reported. One patient in each expansion cohort discontinued due to a reversible DRAE. Partial response (PR), stable disease (SD), and disease control rates (DCR) were 18%/47%/65% at the q3w MTD (n = 38), 6%/35%/41% at 1.8 mg/kg qw (n = 34), and 3%/50%/53% at 2.2 mg/kg qw (n = 36). At the q3w MTD, the PR/SD/DCR for OC pts (n = 22) was 9%/50%/59% and for Meso pts (n = 16) was 31%/44%/75%, respectively. Five of 16 (31%) Meso pts treated at the MTD had a durable PR ( > 600 days in 4); the response rate in 2ndline Meso pts was 50% (5/10). Durable responses were also observed in OC pts. Conclusions: Preliminary data with AR at 6.5 mg/kg q3w showed durable PRs in pts with advanced Meso. All DRAEs were reversible. A phase II trial in 2nd-line metastatic pleural Meso is ongoing (NCT02610140). Clinical trial information: NCT01439152.