Intratumoral Expression of a Composite B Cell / CD8 T Cell Biomarker Stratifies Overall Survival by Circulating Tumor DNA Status and Benefit From Adjuvant Immunotherapy in High-Risk Muscle-Invasive Urothelial Carcinoma.

Abstract

Identifying biomarkers to determine patients who benefit from immune checkpoint inhibitor therapy is critical to avoid overtreatment. Thus, we determined whether tumor expression of a pan-B cell gene signature (BGS), and a CD8 T effector cell gene signature (CD8TGS), was associated with greater overall survival (OS) in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) and circulating tumor DNA (ctDNA)(+) status on C1D1, who received adjuvant atezolizumab. We used transcriptomic profiles derived from bulk RNA sequencing of tumors, and plasma ctDNA, from patients in the IMvigor010 trial of adjuvant atezolizumab vs observation in resected high-risk MIUC. Tumor RNA sequencing expression defined patient groups with high (Hi) and low (Lo) BGS and CD8TGS (eg, B8T). We stratified patients by ctDNA status, then assessed OS based on receipt of atezolizumab. We interrogated tumor B8T in patients with MIUC who received neoadjuvant atezolizumab in the ABACUS trial. Patients who had high BGS and high CD8TGS (B8T Hi/Hi) tumors had high OS, and adjuvant atezolizumab did not provide additional benefit. Conversely, in patients with B8T Hi/Lo tumors, atezolizumab was associated with longer OS, regardless of ctDNA status. Neoadjuvant atezolizumab induced a high proportion of B8T Hi/Hi tumors at cystectomy. While tumor B8T Hi/Hi was prognostic regardless of ctDNA status, B8T Hi/Lo was predictive for atezolizumab benefit independent of ctDNA status. Thus, the B8T identified patients with ctDNA(-) status who benefited, and patients who were ctDNA(+) who did not benefit, from adjuvant atezolizumab.