The phase III DANUBE study assessed the efficacy of the PD-L1 inhibitor durvalumab (D), alone or in combination with the CTLA-4 inhibitor tremelimumab (T), versus standard of care chemotherapy (SoC) for the first-line treatment of unresectable, locally advanced or metastatic UC. Among 1032 patients randomised in DANUBE...For D vs SoC, bTMB and tTMB were not associated with OS or PFS at any cutoff. For D+T, stronger associations between bTMB and OS as well as PFS were observed with increasing bTMB cutoffs (table 1). At the bTMB cutoff ≥ 24 mut/Mb, 12-month OS rates were 76.7% for D+T and 54.3% for SoC, whereas for bTMB < 24 mut/Mb, 12-month OS rates were 53.4% for D+T and 51.2% for SoC. Similar trends for both OS and PFS were observed with tTMB. Both bTMB and tTMB are potentially useful biomarkers for enriching responses to D+T in previously untreated, advanced UC. Neither bTMB nor tTMB was associated with better outcomes for D monotherapy.

TMB high for Arm E; 38% (Vistusertib + durvalumab) vs 5% in Arm A (AZD4547 + durvalumab), 20% in AZD4547 arm and 17% in Arm D; durvalumab). D monotherapy (n = 29) had an ORR of 28%, Vistusertib + durvalumab (21%), AZD4547 + durvalumab (39%), and AZD4547 (20%).