First-in-human phase 1 study of ABBV-085, an antibody-drug conjugate (ADC) targeting LRRC15, in sarcomas and other advanced solid tumors.

Abstract

3004 Background: ABBV-085 is an ADC (conjugated to monomethyl auristatin E, drug:antibody ratio of 2:1) directed against leucine-rich repeat containing 15 (LRRC15), a type 1 transmembrane protein highly expressed on the surface of sarcomas and cancer-associated fibroblasts in stroma of many other cancers. ABBV-085 induced antitumor activity in both in vitro and xenograft models of sarcoma. This phase 1, first-in-human, 2-part study assessed the safety/tolerability of ABBV-085 in patients (pts) with advanced solid tumors (NCT02565758). Methods: Eligible pts (≥18 yr; advanced solid tumors) received ABBV-085 intravenously in a 3+3 dose-escalation (DE) design; 0.3- to 4.8-mg/kg doses every 2 wk (8 cohorts). Pharmacokinetics (PK) were assessed in cycle 1 and cycle 3. Results: As of Dec 2018, 78 pts were enrolled in monotherapy DE and dose-expansion (EXP) cohorts (≤2.7 mg/kg, n = 21; 3.6 mg/kg, n = 45; 4.2 mg/kg, n = 6; 4.8 mg/kg, n = 6); median age: 58 yr (range 21–84); median treatment (Tx) duration: 6.2 wk (range 0.3–54.4). Overall, 77 (98.7%) pts reported ≥1 Tx-emergent adverse events (TEAEs). Fatigue (48.7%) was most common; 19 (24.4%) pts reported grade 1/2 blurred vision (reversible on study discontinuation). Grade ≥3 TEAEs were reported in 56 (71.8%) pts; anemia (14.1%) was the most common. Dose-limiting toxicities occurred at 3.6 mg/kg (n = 1; anemia), 4.2 mg/kg (n = 1; hypertriglyceridemia), and 4.8 mg/kg (n = 2; ileus and nausea); 3.6 mg/kg was chosen as the recommended phase 1b dose (RP1bD). PK exhibited dose-proportional increase in the area under the curve after single-dose administration; half-life was 2.84 days at the RP1bD. Of the 27 sarcoma pts (DE [n = 8]/EXP [n = 19] cohorts; undifferentiated pleomorphic sarcoma [n = 10], osteosarcoma [n = 10], and other sarcomas [n = 7]) treated at the RP1bD, 4 (14.8%) had confirmed partial response (PR; 2 [7.4%] unconfirmed), 8 (29.6%) had stable disease, 11 (40.7%) had progressive disease; 2 (7.4%) were not evaluable. The median duration of response (confirmed responders) was 7.6 mo (95% CI: 5.6–9.2). Updated safety and efficacy data will be reported. Conclusions: ABBV-085 was well tolerated with durable PR observed in pts with advanced sarcomas. Clinical trial information: NCT02565758.