Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial

Robert J Motzer; Paul B Robbins; Thomas Powles; Laurence Albiges; John B Haanen; James Larkin; Xinmeng Jasmine Mu; Keith A Ching; Motohide Uemura; Sumanta K Pal; Boris Alekseev; Gwenaelle Gravis; Matthew T Campbell; Konstantin Penkov; Jae Lyun Lee; Subramanian Hariharan; Xiao Wang; Weidong Zhang; Jing Wang; Aleksander Chudnovsky; Alessandra di Pietro; Amber C Donahue; Toni K Choueiri

doi:10.1038/s41591-020-1044-8

Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial

Nat Med. 2020 Nov;26(11):1733-1741. doi: 10.1038/s41591-020-1044-8. Epub 2020 Sep 7.

Authors

Robert J Motzer^#¹, Paul B Robbins^#², Thomas Powles³, Laurence Albiges⁴, John B Haanen⁵, James Larkin⁶, Xinmeng Jasmine Mu⁷, Keith A Ching⁷, Motohide Uemura⁸, Sumanta K Pal⁹, Boris Alekseev¹⁰, Gwenaelle Gravis¹¹, Matthew T Campbell¹², Konstantin Penkov¹³, Jae Lyun Lee¹⁴, Subramanian Hariharan¹⁵, Xiao Wang^{7

16}, Weidong Zhang^{17

18}, Jing Wang¹⁷, Aleksander Chudnovsky^{19

20}, Alessandra di Pietro²¹, Amber C Donahue²², Toni K Choueiri²³

Affiliations

¹ Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. motzerr@mskcc.org.
² Translational Oncology, Pfizer, San Diego, CA, USA.
³ Department of Genitourinary Oncology, Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew's Hospital, London, UK.
⁴ Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
⁵ Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁶ Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, London, UK.
⁷ Computational Biology, Pfizer, San Diego, CA, USA.
⁸ Graduate School of Medicine, Osaka University Hospital, Osaka, Japan.
⁹ Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹⁰ Deputy Director for Science, Moscow Scientific Research Oncology Institute, Moscow, Russian Federation.
¹¹ Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France.
¹² Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Private Medical Institution, Euromedservice, St. Petersburg, Russian Federation.
¹⁴ Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
¹⁵ Oncology, Pfizer, New York, NY, USA.
¹⁶ Lyell Immunopharma, South San Francisco, CA, USA.
¹⁷ Biostatistics, Pfizer, Cambridge, MA, USA.
¹⁸ Jounce Therapeutics, Cambridge, MA, USA.
¹⁹ Oncology, Pfizer, Cambridge, MA, USA.
²⁰ Ipsen, Cambridge, MA, USA.
²¹ Immuno-Oncology, Pfizer, Milan, Italy.
²² Translational Oncology, Pfizer, La Jolla, CA, USA.
²³ Department of Medical Oncology, The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA. toni_choueiri@dfci.harvard.edu.

^# Contributed equally.

Abstract

We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (n = 886; NCT02684006 ), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / adverse effects
Antibodies, Monoclonal, Humanized / administration & dosage*
Antibodies, Monoclonal, Humanized / adverse effects
Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Axitinib / administration & dosage*
Axitinib / adverse effects
Biomarkers, Tumor / genetics*
Carcinoma, Renal Cell / drug therapy*
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / pathology
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Kidney / drug effects
Kidney / pathology
Male
Middle Aged
Progression-Free Survival
Sunitinib / administration & dosage*
Sunitinib / adverse effects
Transcriptome
Young Adult

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Biomarkers, Tumor
Axitinib
avelumab
Sunitinib

Associated data

ClinicalTrials.gov/NCT02684006

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States