A phase 2 trial of R1507, a monoclonal antibody to the insulin‐like growth factor‐1 receptor (IGF‐1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: Results of a Sarcoma Alliance for Research Through Collaboration study

Abstract

BACKGROUND Insulin‐like growth factor‐1 receptor (IGF‐1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi‐institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas. METHODS Eligibility criteria included age ≥2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks × 4 and every 12 weeks thereafter. RESULTS From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7‐85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%‐6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a ≥50% decrease in tumor size that lasted for <4 weeks. The median progression‐free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%). CONCLUSIONS R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted. Cancer 2014;120:2448–2456. © 2014 American Cancer Society.

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

“…While conventional cytotoxics do improve survival in Ewing sarcoma, rhabdomyosarcomas, and osteosarcoma, they confer little curative benefit in most soft-tissue sarcomas, as confirmed by a recent analysis of 2,665 cases across 11 clinical trials (1). Much recent effort has gone into targeting expressed proteins in activated oncogenic pathways, but these have had disappointing results in phase II trials (2)(3)(4), and few sarcoma studies have progressed to phase III (5). Off-label use is common but has shown little evidence of efficacy (6).…”

Insulin-like growth factor-1 receptor expression in pediatric tumors: a comparative immunohistochemical study

“…Three of eight (37%) ES/PNET specimens were defined as positive for IGF-1R in our study. Although studies with IGF-1R antibodies in ES/PNETs are limited or disappointing, there are assertions in the literature that IGF-1R inhibitors may play a role in the treatment of ES/PNETs since it is regarded as a key mechanism in proliferation (7,12,13).…”

“…IGF-1R is also involved in malignant tumor transformation and is overexpressed in a variety of human malignancies such as lung, prostate, breast, and colorectal carcinomas (2)(3)(4)(5). Studies have revealed a pronounced expression of IGF-1R in pediatric tumors, such as Ewing sarcoma/primitive neuroectodermal tumors (ES/PNETs), rhabdomyosarcomas (RMSs), osteosarcoma, and synovial sarcoma (6,7).…”

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

“…Unfortunately, the preclinical anti-RMS activity of targeted agents such as mTOR inhibitors (Hosoi et al 1999) and neutralizing IGF1 receptor antibodies (Mayeenuddin et al 2010) have not translated thus far into durable objective response rates in early-phase clinical trials (Geoerger et al 2012;Pappo et al 2014;Weigel et al 2014). However, improved event-free survival of individuals with relapsed RMS after treatment with the mTOR inhibitor temsirolimus in combination with vinorelbine and cyclophosphamide supports experimental strategies involving combinations of targeted agents and established drugs (Mascarenhas et al 2014).…”