Samrotamab vedotin | ABBV-085 (Drug Description)

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).

Clinical Trial
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.[1]

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.

[1] 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]