TY - JOUR
T1 - Angiokines associated with targeted therapy outcomes in patients with non-clear cell renal cell carcinoma
AU - Armstrong, Andrew J.
AU - Nixon, Andrew B.
AU - Carmack, Andrea
AU - Yang, Qian
AU - Eisen, Tim
AU - Stadler, Walter M.
AU - Jones, Robert J.
AU - Garcia, Jorge A.
AU - Vaishampayan, Ulka N.
AU - Picus, Joel
AU - Hawkins, Robert E.
AU - Hainsworth, John D.
AU - Kollmannsberger, Christian K.
AU - Logan, Theodore F.
AU - Puzanov, Igor
AU - Pickering, Lisa M.
AU - Ryan, Christopher W.
AU - Protheroe, Andrew
AU - George, Daniel J.
AU - Halabi, Susan
N1 - Funding Information:
reports grants from Novartis and Pfizer during the conduct of the study; grants from Abbott, Abraxis, Acceleron, Amgen, AstraZeneca, Biovex, Cerulean, Eisai, Eli Lilly, Hoffman LaRoche, Immatics, Merck, Roche, Synta, Threshold, Tracon, EMD Serono, Millenium, Schering Plough, Macrogenics, Peloton, Iovance, MedImmune, Dynavax, and Clinigen; and grants and personal fees from Argos, Aveo, Bristol Myers Squibb, Gelgene, GlaxoSmithKline, Genentech, Novartis, Pfizer, Prometheus, Wyeth outside the submitted work. I. Puzanov reports personal fees from Merck, Amgen, Iovance, and Nouscom outside the submitted work. L.M. Pickering reports personal fees from Pfizer and Novartis outside the submitted work. C.W. Ryan reports grants from Novartis and Pfizer during the conduct of the study; personal fees from Esai, Janssen, AstraZeneca, Bristol-Myers Squibb, Diciphera, and SynOx Therapeutics; grants from Xynomic, Nektar, GlaxoSmithKline/Novartis, Daiichi Sankyo, Merck, Argos Therapeutics, CytRx Corporation, Exelixis, Bristol-Myers Squibb, Genentech, Karyopharm Therapeutics, and Pfizer outside the submitted work. D.J. George reports grants and personal fees from Astellas, AstraZeneca, BMS, Exelixis, Janssen, Pfizer, and Sanofi; personal fees from Bayer, Constellation Pharma, EMD Serono, Flatiron, Ipsen, Merck, Michael J Hennessey, Millennium Med Pub, Modra Pharma, Myovant Sciences, NCI Genitourinary, Nektar Therapeutics, Physician Education Resource, Propella Therapeutics, UroGPO, UroToday, and Vizuri Health Sciences; and grants from Calithera and Novartis outside the submitted work. S. Halabi reports grants and other from Pfizer and Novartis during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
A.J. Armstrong reports grants and personal fees from Pfizer and grants from Novartis during the conduct of the study; grants and personal fees from Merck, BMS, Dendreon, Bayer, and AstraZeneca; grants from Genentech and Astellas, and personal fees from Clovis outside the submitted work. A.B. Nixon reports grants from Genentech, MedImmune/AstraZeneca, Medpacto, Seattle Genetics, HTG Molecular Diagnostics, Tracon Pharmaceuticals, Eureka Therapeutics, Leadiant Biosciences, OncoMed Pharmaceuticals, and Promega Corporation; personal fees from Eli Lilly, GlaxoSmithKline, Kanghong Pharma, Promega Corporation, and Leap Therapeutics outside the submitted work. A. Carmack reports master’s thesis project. T. Eisen reports grants and non-financial support from Cambridge Biomedical Research Centre during the conduct of the study; grants, nonfinancial support, and other from AstraZeneca and Roche; and grants from Pfizer and Bayer outside the submitted work; and is trustee with Macmillan Cancer Support and Kidney Cancer UK. W.M. Stadler reports nonfinancial support from Pfizer during the conduct of the study; personal fees from AstraZeneca, Bayer, Esai, Merck, Pfizer, Sotio, Treadwell Therapeutics, Caremark/CVS, and Roche/Genentech outside the submitted work. R.J. Jones reports personal fees from Pfizer outside the submitted work. J.A. Garcia reports grants from Pfizer during the conduct of the study; personal fees from Merck, Pfizer, Eisai, Astellas, Janssen, Sanofi-Aventis, Bayer, and MJH outside the submitted work. U.N. Vaishampayan reports personal fees from Bayer, Pfizer, Aveo, and Helsinn; grants and personal fees from BMS, Exelixis, Merck, Alkermes, and AAA outside the submitted work. J. Picus reports grants from Inventiv Health Clinical, LLC during the conduct of the study. R.E. Hawkins reports personal fees from Pfizer, Novartis, and BMS outside the submitted work. J.D. Hainsworth reports grants from Novartis/Pfizer during the conduct of the study. C.K. Kollmannsberger reports personal fees from Pfizer, Merck, Ipsen, Eisai, EMD Serono, Astellas, Bayer, and Janssen during the conduct of the study. T.F. Logan
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6
Y1 - 2021/6
N2 - Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. Patients and Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.
AB - Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. Patients and Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.
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U2 - 10.1158/1078-0432.CCR-20-4504
DO - 10.1158/1078-0432.CCR-20-4504
M3 - Article
C2 - 33593885
AN - SCOPUS:85107959659
SN - 1078-0432
VL - 27
SP - 3317
EP - 3328
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -