Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial

Michiel S. van der Heijden*, Thomas Powles, Daniel Petrylak, Ronald de Wit, Andrea Necchi, Cora N. Sternberg, Nobuaki Matsubara, Hiroyuki Nishiyama, Daniel Castellano, Syed A. Hussain, Aristotelis Bamias, Georgios Gakis, Jae Lyun Lee, Scott T. Tagawa, Ulka Vaishampayan, Jeanny B. Aragon-Ching, Bernie J. Eigl, Rebecca R. Hozak, Erik R. Rasmussen, Meng Summer XiaRyan Rhodes, Sameera Wijayawardana, Katherine M. Bell-McGuinn, Amit Aggarwal, Alexandra Drakaki

*Corresponding author for this work

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The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab.

Original languageEnglish
Article number1878
JournalNature Communications
Issue number1
Publication statusPublished - 6 Apr 2022

Bibliographical note

Funding Information:
M.S.v.d.H. has received research support from Bristol Myers Squibb, AstraZeneca, Roche, and 4SC; and consultancy fees from BMS, Merck, Sharp & Dhome, Roche, AstraZeneca, Seattle Genetics, Janssen, and Pfizer (all paid to Institute). T.P. reports consulting honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; grants/funding (to Institution) from AstraZeneca, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; and travel expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. D.P. has received consultancy fees from Ada Cap (Advanced Accelerator Applications) Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly and Company, Exelixis, Gilead Sciences, Incyte, Janssen, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Seattle Genetics, and Urogen; grant support from Ada Cap (Advanced Accelerator Applications), Agensys Inc., *Astellas, AstraZeneca, *Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, *Eli Lilly and Company, *Endocyte, Genentech, *Innocrin, MedImmune, Medivation, Merck, Mirati, *Novartis, Pfizer, *Progenics, Replimune, Roche, *Sanofi Aventis, and Seattle Genetics (*denotes study trials have terminated); and ownership interest/investment in Bellicum (sold 7/2020) and Tyme (sold 10/2019). R.d.W. has received consultancy fees from Merck, Sanofi, Astellas, Janssen, Clovis, Orion, and Bayer; speaker fees from Astellas, Sanofi, and Merck; and has received research grants (to Institution) from Sanofi and Bayer. A.N. has a consulting role with Merck, AstraZeneca, Janssen, Incyte, Roche, Rainier Therapeutics, Clovis Oncology, Bayer, Astellas/Seattle Genetics, Ferring, and Immunomedics; has received grant/research support from Merck, Ipsen, and AstraZeneca; and travel expenses/honoraria from Roche, Merck, AstraZeneca, and Janssen. C.N.S. has served in an advisory/consultancy role for Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, Medscape, UroToday, and Foundation Medicine. N.M. reports personal fees from Chugai, Janssen, MSD, and Sanofi and grants from Astellas Pharma, Inc., AstraZeneca, Chugai, Eli Lilly and Company, Taiho, Janssen, MSD, Takeda, Amgen, and Pfizer. H.N. reports personal fees from Astellas Pharma, Inc., Chugai, Janssen, Merck, Sharp & Dhome, and Nippon Kayaku and grants from Astellas Pharma, Inc., Ono, and Chugai. S.A.H. has an advisory/consulting role with Roche, MSD, AstraZeneca, BMS, Janssen, Astellas, Bayer, Ipsen, Pfizer, Pierre Fabre, and Sotio and has received research funding from Cancer Research UK, MRC/NIHR, Janssen, and Boehringer Ingelheim. A.B. has an advisory/consulting role with Roche, Pfizer, Bristol Myers Squibb, AstraZeneca, and IPSEN Pharma; receiving honoraria from Bristol Myers Squibb, IPSEN Pharma, and Merck, Sharpe & Dohme and research support from AstraZeneca, Bristol Myers Squibb, Pfizer, IPSEN Steering Committee, and Roche. G.G. has served on an Advisory Board (last 5 years) for Bayer, MSD, Medac, IPSEN Pharma, Merck, LEO Pharma, and Astellas and has acted as an expert for Erbe Elektromedizin, IPSEN Pharma, Roche, Ferring, LEO Pharma, Merck, and Medac. S.T.T. reports research funding (to Institution) from Eli Lilly and Company and Sanofi and honoraria from Sanofi. U.V. reports research support from Astellas, Merck, and Bristol Myers Squibb and consulting and honoraria from AAA Pharmaceutical, Aveo, Bristol Myers Squibb, Bayer, Exelixis, Merck, Pfizer, and Sanofi. J.B.A.-C. serves on the Speakers’ Bureau of Astellas/Seattle Genetics and Bristol Myers Squibb and receives advisory board fees from EMD Serono, Pfizer, Aveo Pharmaceuticals, Immunomedics, AstraZeneca, Exelixis, and Merck. B.J.E. serves in an advisory/consultancy role for Merck, Janssen, AstraZeneca, Roche, Pfizer, EMD Serono, and SEAGEN. R.R.H., E.R.R., M.S.X., and S.W. are employees and shareholders of Eli Lilly and Company. K.M.B.-M. is a shareholder and former employee of Eli Lilly and Company and a shareholder and current employee of AbbVie. A.A. is a shareholder and former employee of Eli Lilly and Company and is currently an employee of Daiichi Sankyo, Inc. (US). A.D. has an advisory/consulting role with AstraZeneca, PACT Pharma, Astellas/Seattle Genetics, Janssen, Nektar, Bristol Myers Squibb, Radmetrix, Merck, Roche/Genentech, Exelixis, and Dyania Health; has received travel reimbursement from Eli Lilly and Company, AstraZeneca, and Seattle Genetics; holds stock and/or other interests in Attica Sciences and ATHOS Therapeutics; and has received research funding (to Institution unless noted otherwise) from AstraZeneca, Genentech/Roche, BMS, Merck Sharp & Dohme, Jounce Therapeutics, Infinity Pharmaceuticals, Seattle Genetics/Astellas, and Kite/Gilead (to A.D.). The disclosures reported herein, for each author, are potential conflicts only on the premise that the companies listed manufacture drugs for cancer treatment. The following authors declare no competing interests: D.C., A.B., J.L.L., R.R.

Funding Information:
This study was funded by Eli Lilly and Company. The funder provided support in the form of salaraies for authors (RRH, ERR, MSX, RR, SW, KMB-M, and AA), design of study, data collection, data analysis, decision to publish, and preparation of the manuscript. We thank the patients, their families, and the study personnel across all sites for participating in the RANGE trial. We also thank Decipher Biosciences for performing the gene expression profiling and molecular subtyping of the tumor samples, as well as insightful discussions (Elai Davicioni and Ewan Gibb). Kristi Gruver and Susan Whitman of Eli Lilly and Company provided project management support. Erika Wittchen and Antonia Baldo of Syneos Health provided medical writing and editorial support, funded by Eli Lilly and Company.

Publisher Copyright:
© 2022, The Author(s).


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