IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers

Figures

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  Figure 1. (A) Meta-analysis of five trials indicates that combined IGF-1R/mTORi-based therapy leads to superior clinical outcomes compared to single-agent IGF-1R mAb treatment. A Venn diagram of five IGF-1R-related clinical trials conducted at MDACC. (B) The two R1507 trials have been grouped for statistical analysis. (C) Patients treated with either R1507 or Robatumumab IGF-1R mAbs were analyzed together. Five patients received an IGF-1R/mTOR inhibitor combination after they progressed on IGF-1R Abs and were excluded from the statistical analysis. (D) Best clinical response by RECIST following treatment with an IGF-1R Ab vs. IGF-1R/mTOR inhibitor combination. (E) Similar data categorized by clinical benefit (e.g., complete or partial response and stable disease vs. progression). (F) Violin plot summarizing progression-free survival for all patients. Most patients progressed after 2 cycles at 6 weeks (red), whereas PFS was significantly improved in patients that achieved a partial response (green) or stable disease (blue). Each dot represents an individual patient, and the circle diameter indicates the patient’s OS duration. The superimposed box plot indicates the interquartile range. (G)…

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  Figure 2. CT and PET imaging (obtained between 7–14 days following treatment with IGF-1R Abs +/− mTOR inhibitor) are predictive of each patient’s best clinical response. CT measures of response included WHO and RECIST criteria (Panels A and B, respectively). PET measures of clinical response included EORTC (Panel C), PERCIST (Panel D), and TLG (Panel E). Dot plots and density plots are shown for each measurement parameter. The dot plots indicate each patient’s percent response compared to the pre-treatment baseline tumor measurements, color-coded by their clinical response; progressive disease (PD; red), stable disease (SD; blue), and partial response (PR; green). The density plots beneath each dot plot show the relative probability distributions of achieving a partial response (green), stable disease (blue), or progression (red) across the entire spectrum of CT or PET responses represented by the data set. No patient achieved a complete response.

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  Figure 3. Negative pIGF-1R in pretreatment tumor specimens was associated with a better radiological response in the early PET/CTs performed within the first two-weeks of IGF-1R mAb-based therapy. (A) Immunocytochemical analysis (IHC) of eighteen available pre-treatment clinical specimens for phosphorylated and total IGF-1R. Post-treatment research images (performed between days 7 and 14), as assessed by the WHO response. ES specimens from two patients are shown as representative examples. The tumors from patients 1 and 2 show high levels of expression of IGF-1R (membranous and cytoplasmic). Patient 1 had significant levels of expression of pIGF-1R (membranous and cytoplasmic, as well as scattered cells with nuclear localization). This patient had poor therapeutic response. In contrast, patient 2 had almost a total lack of expression of pIGF-1R, which was associated with a superior response to therapy. Panels B–F: Radiological response stratified by p-IGF-1R status using (B) the WHO response, (C) RECIST response, (D) EORTC measures of PET response (E) PERSIST measures of PET response and (F) total lesion glycolysis (TLG), which is a PET volumetric parameter that reflects the total…