First-in-Human Phase I Study of ABBV-085, an Antibody-Drug Conjugate Targeting LRRC15, in Sarcomas and Other Advanced
George D Demetri1, Jason J Luke2, Antoine Hollebecque3
1Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute; Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts. gdemetri@dfci.harvard.edu.
Purpose:
Leucine-rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody-drug conjugate that targets LRRC15 and showed antineoplastic efficacy in preclinical experiments. Herein, we report findings of ABBV-085 monotherapy or combination therapy in adult patients with sarcomas and other advanced solid tumors.
Patients And Methods:
This first-in-human phase I study (NCT02565758) assessed ABBV-085 safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity. The study consisted of two parts: dose escalation and dose expansion. ABBV-085 was administered by intravenous infusion at 0.3 to 6.0 mg/kg every 14 days.
Results:
In total, 85 patients were enrolled; 45 patients received the recommended expansion dose of 3.6 mg/kg ABBV-085 monotherapy, including 10 with osteosarcoma and 10 with undifferentiated pleomorphic sarcoma (UPS). Most common treatment-related adverse events were fatigue, nausea, and decreased appetite. The overall response rate for patients with osteosarcoma/UPS treated at 3.6 mg/kg was 20%, including four confirmed partial responses. No monotherapy responses were observed for other advanced cancers treated at 3.6 mg/kg. One patient treated with ABBV-085 plus gemcitabine achieved partial response.
Conclusions:
ABBV-085 appeared safe and tolerable at a dose of 3.6 mg/kg every 14 days, with preliminary antitumor activity noted in patients with osteosarcoma and UPS. Given the high unmet need in these orphan malignancies, further investigation into targeting LRRC15 in these sarcomas may be warranted.
Insights
The antibody-drug conjugate ABBV-085 targeting Leucine-rich repeat containing 15 (LRRC15) showed preliminary antitumor activity in patients with osteosarcoma and undifferentiated pleomorphic sarcoma (UPS). Further investigation of LRRC15 targeting in these rare sarcomas is warranted.
Area of Science:
- Oncology
- Pharmacology
- Tumor Microenvironment
Background:
- Leucine-rich repeat containing 15 (LRRC15) is expressed in tumor microenvironments and malignant cells of various solid tumors, including sarcomas.
- LRRC15 presents a potential therapeutic target, especially in sarcomas where it is expressed by both stromal fibroblasts and malignant cells.
- ABBV-085 is an antibody-drug conjugate designed to target LRRC15, demonstrating preclinical antineoplastic effects.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of ABBV-085 in adult patients with sarcomas and other advanced solid tumors.
- To determine the recommended expansion dose for ABBV-085 in a first-in-human Phase I clinical trial.
Main Methods:
- A Phase I, first-in-human study (NCT02565758) involving dose escalation and expansion phases.
- ABBV-085 administered intravenously every 14 days at doses ranging from 0.3 to 6.0 mg/kg.
- Eighty-five patients were enrolled; 45 received the recommended expansion dose of 3.6 mg/kg, including patients with osteosarcoma and undifferentiated pleomorphic sarcoma (UPS).
Main Results:
- The recommended expansion dose of 3.6 mg/kg was found to be safe and tolerable.
- Among patients with osteosarcoma/UPS treated at 3.6 mg/kg, the overall response rate was 20%, with four confirmed partial responses.
- No monotherapy responses were observed in other advanced cancer types at the recommended dose; one patient receiving combination therapy achieved a partial response.
Conclusions:
- ABBV-085 demonstrated safety and tolerability at 3.6 mg/kg every 14 days, with preliminary antitumor activity observed in osteosarcoma and UPS.
- The findings support further investigation of LRRC15-targeted therapy in these rare sarcoma subtypes due to a high unmet medical need.
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