Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial

Abstract

In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432), avelumab/best supportive care (BSC) significantly prolonged overall survival (OS) relative to BSC alone as maintenance therapy following first-line chemotherapy. Tumor molecular profiling revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity, and the number of alleles encoding high-affinity variants of activating Fc receptors. Gene expression signatures connected to tissue growth were potentially associated with reduced OS in avelumab/BSC. Individual biomarkers did not comprehensively identify patients who could benefit from therapy. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial carcinoma and suggest that multiple biomarkers may be needed to identify patients that would benefit from treatment.

Immune-Checkpoint Inhibitors in Advanced Bladder Cancer: Seize the Day

“…Responses to avelumab and pembrolizumab were independent from PD-L1 status (Dako 73–10 and 22C3, respectively) [ 24 , 25 , 31 , 32 , 35 , 36 ]. Albeit a greater effect in PD-L1 positive patients (Ventana SP263), avelumab maintenance improved survival also in PD-L1 negative patients [ 40 , 75 ]. Baseline tumor dimensions and high PD-L1 were positively associated with durvalumab response and OS in Study 1108, as if smaller tumor size permitted higher penetration of immune cells [ 76 ].…”

“…Together with PD-L1 expression, novel biomarkers should be included in a multi-marker classification, as it seems unlikely that a single biomarker would effectively guide all treatment decisions [ 75 , 78 ]. V-domain IG suppressor of T-cell activation (VISTA) is a ligand for APCs of B7 family, expressed in myeloid cells, granulocyte, and T-cells, acting as a negative regulator of T-cells activation, proliferation, and cytokine production.…”

“…In JAVELIN Bladder 100, the HR with avelumab maintenance was lower in patients with higher TMB ( p = 0.26). A possible contribution to increased TMB derives from specific mutations linked to the APOBEC signature, associated with improved OS to avelumab maintenance ( p = 0.02) [ 75 ]. Additionally, for TMB, there is a need for unifying criteria for defining high and low levels and their predictive value.…”

“…More recently, molecular classifications have also focused on TME, and gene-expression profiling (GEP) analysis distinguished four immune subtypes of BCa (C1–C4), which differ for behavior and therapy sensitivity, ranging from C2 subtype—immune-infiltrated, associated with longer OS and PFS, and sensitive to ICIs and chemotherapy, to C4 subtype—deprived of CD8 + T-cells, with the worst prognosis, inadequate response to ICIs, sensitive to chemotherapy [ 82 , 83 ]. In CheckMate 275, KEYNOTE-052, Study 1108, and JAVELIN Bladder 100, gene-expression profiling (GEP) analysis showed that expression of immune genes related to γ-IFN correlated with nivolumab, pembrolizumab, durvalumab, and avelumab responses, confirming this group of genes as a critical pathway for innate and adaptive immune responses [ 26 , 30 , 35 , 75 ]. IFN-mediated responses are also induced after DNA-damage response (DDR) gene mutations, which therefore could predict ICIs response [ 75 , 84 , 85 ].…”

“…In CheckMate 275, KEYNOTE-052, Study 1108, and JAVELIN Bladder 100, gene-expression profiling (GEP) analysis showed that expression of immune genes related to γ-IFN correlated with nivolumab, pembrolizumab, durvalumab, and avelumab responses, confirming this group of genes as a critical pathway for innate and adaptive immune responses [ 26 , 30 , 35 , 75 ]. IFN-mediated responses are also induced after DNA-damage response (DDR) gene mutations, which therefore could predict ICIs response [ 75 , 84 , 85 ]. Effectively, BCa—mainly basal squamous types—displays a genetic complexity associated with DDR genes, increased TILs, and enhanced platinum and immune responsiveness [ 85 , 86 ].…”