Integrative analyses of tumor and peripheral biomarkers in the treatment of advanced renal cell carcinoma Journal Article
| Authors: | Choueiri, T. K.; Donahue, A. C.; Braun, D. A.; Rini, B. I.; Powles, T.; Haanen, J. B. A. G.; Larkin, J.; Mu, X. J.; Pu, J.; Teresi, R. E.; Di Pietro, A.; Robbins, P. B.; Motzer, R. J. |
| Article Title: | Integrative analyses of tumor and peripheral biomarkers in the treatment of advanced renal cell carcinoma |
| Abstract: | The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non–T-cell–mediated and non–natural killer cell–mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes. SIGNIFICANCE: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. © 2023 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | vasculotropin; controlled study; treatment response; gene mutation; human cell; major clinical study; overall survival; genetics; sunitinib; cd8+ t lymphocyte; tumor associated leukocyte; biomarkers; biological marker; cancer immunotherapy; progression free survival; gene expression; gelatinase b; granulocyte macrophage colony stimulating factor; interleukin 13; interleukin 1beta; renal cell carcinoma; kidney neoplasms; regulatory t lymphocyte; myelodysplastic syndrome; immune response; immunotherapy; gamma interferon; kidney tumor; carcinoma, renal cell; brain derived neurotrophic factor; cd4+ t lymphocyte; tumor immunity; integrative medicine; phase 3 clinical trial; interleukin 17; axitinib; enzyme linked immunospot assay; granulocyte colony stimulating factor; intercellular adhesion molecule 1; monocyte chemotactic protein 1; tumor necrosis factor; programmed death 1 ligand 1; programmed death 1 receptor; tumor microenvironment; mc1r gene; amino terminal pro brain natriuretic peptide; limit of quantitation; intention to treat analysis; humans; human; article; foxo1 gene; whole exome sequencing; avelumab; abca1 gene; cd163l1 gene; crocc2 gene; dnmt1 gene; loc728763 gene; myh7b gene; stab2 gene |
| Journal Title: | Cancer Discovery |
| Volume: | 14 |
| Issue: | 3 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-03-01 |
| Start Page: | 406 |
| End Page: | 423 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-23-0680 |
| PUBMED: | 38385846 |
| PROVIDER: | scopus |
| PMCID: | PMC10905671 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
