First-in-Human Phase I Study of ABBV-085, an Antibody–Drug Conjugate Targeting LRRC15, in Sarcomas and Other Advanced Solid Tumors

Abstract

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.Materials 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.

Elevated expression of LRRC15 Shows Putative Tumor-promoting Characteristics in tumor microenvironment of breast cancer

“…LRRC15 is capable of binding collagen, which sustains its role in tissue structure and cell-to-cell adhesion [7]. It has been proposed that extracellular matrix (ECM) proteins generated by CAF prevent the effective uptake of traditional chemotherapeutics, and contribute to the immunosuppressive environment and chemoresistance in most solid tumors [8,30,31]. As a biomarker of CAF, LRRC15 might be an important contributor, and also an effective therapeutic target of immunosuppression and chemoresistance.…”

“…Leucine-rich repeat containing 15 (LRRC15), a 581 amino acid type I transmembrane protein, belongs to the LRR superfamily and has emerged as a marker of cancer-associated broblasts (CAFs) recently [7]. Remarkably, LRRC15 was highly expressed on stromal broblasts in multiple solid tumors, such as breast, head and neck, lung and pancreas, while was lowly expressed in most normal tissues [7,8]. The LRR family generally regulates a broad repertoire of functions, including signal transduction, cell adhesion, DNA repair, and RNA processing [9].…”

Origin and Therapies of Osteosarcoma

“…A phase I clinical trial was designed to evaluate the efficacy, the safety and pharmacokinetics of ABBV-085 (Samrotamab vedotin), an antibody drug conjugate, in solid tumors, especially sarcomas (NCT02565758). ABBV-085 was safe and well tolerable with promising antitumor activity in OS patients [ 187 ].…”

Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies

“…In pancreatic cancer, leucine-rich repeat-containing 15 (LRRC15) positive CAFs, induced by TGFβ, have been associated with inferior survival upon ICB [ 109 ]. In these regards, LRRC15 targeting by Samrotamab vedotin, ABBV-085, an anti-LRRC15 monomethyl auristatin E (MMAE)-loaded antibody-drug conjugate (ADC), has shown robust preclinical activity and has been tested in phase I clinical trial in patients with advanced solid tumors, showing tolerability and preliminary activity [ 110 , 111 ]. Another molecular pathway identified in myofibroblastic, as opposed to inflammatory, CAFs in pancreatic cancer is sonic hedgehog (SHH) signaling.…”