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

• Published in: Nature medicine Vol. 26; no. 11; pp. 1733 - 1741
• Main Authors: Motzer, Robert J., Robbins, Paul B., Powles, Thomas, Albiges, Laurence, Haanen, John B., Larkin, James, Mu, Xinmeng Jasmine, Ching, Keith A., Uemura, Motohide, Pal, Sumanta K., Alekseev, Boris, Gravis, Gwenaelle, Campbell, Matthew T., Penkov, Konstantin, Lee, Jae Lyun, Hariharan, Subramanian, Wang, Xiao, Zhang, Weidong, Wang, Jing, Chudnovsky, Aleksander, di Pietro, Alessandra, Donahue, Amber C., Choueiri, Toni K.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 631/67/589/1588/1351; 692/308/53; Adolescent; Adult; Aged; Analysis; Angiogenesis; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antigenic determinants; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Apoptosis; Axitinib; Axitinib - administration & dosage; Axitinib - adverse effects; Biological markers; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Renal cell; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Care and treatment; Cell death; Development strategies; Drug therapy; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunomodulation; Immunotherapy; Infectious Diseases; Kidney - drug effects; Kidney - pathology; Kidney cancer; Male; Metabolic Diseases; Middle Aged; Molecular Medicine; Monoclonal antibodies; Neurosciences; Nucleotides; PD-1 protein; PD-L1 protein; Progression-Free Survival; Renal cell carcinoma; Single-nucleotide polymorphism; Sunitinib - administration & dosage; Sunitinib - adverse effects; Targeted cancer therapy; Testing; Transcriptome; Tumors; Young Adult; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-020-1044-8

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. Biomarker analysis of the phase 3 JAVELIN Renal 101 trial uncovers molecular determinants of therapy-specific outcomes, which may inform personalized treatment strategies for patients with advanced renal cell carcinoma.