Abstract CT009: A Phase Ib study assessing biomarker modulation in soft tissue sarcoma patients treated with olaratumab followed by olaratumab plus doxorubicin
Authors: Martin-Broto Javier , Pousa Antonio Lopez , Brohl Andrew , Tine Brian A. Van , Powers Benjamin , Stacchiotti Silvia , Blay Jean-Yves , Hu James S. , Oakley Gerard J. , Wang Hong , Szpurka Anna , Levy Donna E. , Mo Gary , Ceccarelli Matteo , Jones Robin 
Published: August 2019

Abstract
Background: Olaratumab (olara), an IgG1 monoclonal antibody, blocks platelet-derived growth factor receptor (PDGFR) α activation. In a randomized Phase 2 study, olara plus doxorubicin (dox) improved overall survival in advanced soft tissue sarcoma (STS) patients (pts). The aim of this study (JGDM, NCT02783599) was to further evaluate potential biomarkers and the mechanism of action of olara in pts with STS.
Methods: Pts with potentially resectable STS received olara monotherapy for one cycle followed by up to 6 cycles of olara plus dox (75 mg/m2 on Day 1). Olara was administered at 20 mg/kg (Cycles 1 and 2) and 15 mg/kg (Cycles 3-7) on Days 1 and 8 of a 21-day cycle. Co-primary objectives were enumeration of circulating tumor cells (CTCs) and PDGFR biomarker expression in tumor tissue pre- and post-olara monotherapy. PDGFR protein expression was analyzed by a validated immunohistochemistry (IHC) assay; Epic Sciences performed CTC enumeration. Secondary objectives included antitumor activity, safety, and pharmacokinetics (PK).
Results: Of the 51 pts enrolled, 35 were evaluable for CTC enumeration and 43 were evaluable for PDGFR expression. Median number of CTCs detected before and after olara monotherapy were 1.0/mL (range: 0.1-9.2) and 0.1/mL (range: 0.1-18.7), respectively, in the analysis population. The proportion of pts with a decrease in CTC counts post-olara monotherapy in Cycle 1 was higher in pts with disease control (58%; 11 of 19 pts) compared with pts with no disease control (31%; 5 of 16 pts) after Cycle 2 (p=0.22). In the 43 pts evaluable for tumor tissue PDGFR analysis, IHC staining at baseline was positive in 31 (72.1%) pts for PDGFRα and 36 (83.7%) pts for PDGFRβ. Post-olara monotherapy samples showed similar rates of qualitative IHC expression for PDGFRα (n=30, 69.8%) and PDGFRβ (n=33, 76.7%). Qualitative IHC expression for either marker did not appear to correlate with clinical outcome in the analysis population. Clinically, overall response rate (CR+PR) was 11.8% (n=6), 27% of pts (n=14) had a decrease in size of target lesions, and 35.3% of pts (n=18) underwent tumor resection following systemic treatment. The safety and PK profiles of olara in combination with dox were consistent with previous reports.
Conclusions: CTC enumeration in STS pts is feasible and disease control after Cycle 2 was associated with a statistically non-significant decrease in CTC following olara monotherapy in Cycle 1. Qualitative detection of PDGFRα in pre-treatment samples showed no association with clinical outcome and similar rates of qualitative detection in post-treatment samples. Further quantitative exploration of tissue biopsy results and correlations with exploratory findings in CTCs is ongoing.
Citation Format: Javier Martin-Broto, Antonio Lopez Pousa, Andrew Brohl, Brian A. Van Tine, Benjamin Powers, Silvia Stacchiotti, Jean-Yves Blay, James S. Hu, Gerard J. Oakley, Hong Wang, Anna Szpurka, Donna E. Levy, Gary Mo, Matteo Ceccarelli, Robin Jones. A Phase Ib study assessing biomarker modulation in soft tissue sarcoma patients treated with olaratumab followed by olaratumab plus doxorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT009.