Samrotamab vedotin, also known as ABBV-085 is an antibody-drug conjugate or ADC being developed by AbbVie.
The investigational drug is a monoclonal antibody 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.
Mechanism of Action
Following intravenous administration, the monoclonal antibody moiety of ABBV-085 targets and binds to leucine-rich repeat containing 15 (LRRC15) expressed on tumor cells. Upon binding and internalization, the cytotoxic agent is released and kills the LRRC15-expressing cancer cells, through an as of yet unknown mechanism of action (MOA).
Samrotamab vedotin (ABBV-085) is investigated in a multicenter, phase I, open-label, dose-escalation study in subjects with advanced solid tumors (NCT02565758). The trial is an open-label dose escalation study designed to evaluate the safety and pharmacokinetics of ABBV-085 and determine the recommended Phase II dose (as monotherapy or in combination with standard therapies) in subjects with advanced solid tumors.
The phase I, first-in-human, 2-part study assessed the safety/tolerability of ABBV-085 in patients with advanced solid tumors.
Eligible patients (≥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.
Interim results presented at the 2019 American Society of Clinical Oncology (ASCO) include data from the trial.
As of Dec 2018, 78 patients 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%) patients reported grade 1/2 blurred vision (reversible on study discontinuation). Grade ≥3 TEAEs were reported in 56 (71.8%) patients; 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 Ib 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 patients (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). In this trial, ABBV-085 was well tolerated with durable PR observed in patients with advanced sarcomas.
 Demetri GD, Luke JJ, Hollebecque A, Powderly JD, Spira AI, Subbiah V, et al. First-in-human phase 1 study of ABBV-085, an antibody-drug conjugate (ADC) targeting LRRC15, in sarcomas and other advanced solid tumors. J Clin Oncol 37, 2019 (suppl; abstr 3004). [Abstract]