TY - JOUR
T1 - Circulating tumor cells and biomarker modulation with olaratumab monotherapy followed by olaratumab plus doxorubicin
T2 - Phase ib study in patients with soft-tissue sarcoma
AU - Martín-Broto, Javier
AU - Pousa, A. L.
AU - Brohl, Andrew S.
AU - van Tine, Brian A.
AU - Powers, Benjamin
AU - Stacchiotti, Silvia
AU - Blay, Jean Yves
AU - Hu, James S.
AU - Oakley, Gerard J.
AU - Wang, Hong
AU - Szpurka, Anna M.
AU - Levy, Donna E.
AU - Mo, Gary
AU - Ceccarelli, Matteo
AU - Jones, Robin L.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1–2; 15 mg/kg, cycles 3–7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRa [n ¼ 31 (72.1%)] and PDGFRb [n ¼ 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRa, n ¼ 30 (69.8%); PDGFRb, n ¼ 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRa at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRa expression and clinical outcome.
AB - This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1–2; 15 mg/kg, cycles 3–7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRa [n ¼ 31 (72.1%)] and PDGFRb [n ¼ 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRa, n ¼ 30 (69.8%); PDGFRb, n ¼ 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRa at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRa expression and clinical outcome.
UR - http://www.scopus.com/inward/record.url?scp=85100478920&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-20-0441
DO - 10.1158/1535-7163.MCT-20-0441
M3 - Article
C2 - 33177152
AN - SCOPUS:85100478920
SN - 1535-7163
VL - 20
SP - 132
EP - 141
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 1
ER -