2364MO Durvalumab (D) +/- tremelimumab (T) in combination with dose-dense MVAC (ddMVAC) as neoadjuvant treatment in patients with muscle-invasive bladder carcinoma (MIBC): Results of NEMIO, a randomized phase I-II trial

Neoadjuvant cisplatin-based chemotherapy (NAC) regimen followed by local therapy is the standard of care for MIBC. However, 60-75% of these patients (pts) have residual disease after NAC. Preclinical data suggest that the use of ddMVAC regimen may induce higher immunogenic death and pathological complete response (pCR) in the NAC setting as compared to gemcitabine cisplatin regimen (GC). Thus, we aimed to evaluate the efficacy and safety of ddMVAC + D +/- T combination in a phase I/II trial. NEMIO (NCT03549715) is a multicenter open-label randomized non-comparative phase 1/2 trial evaluating neoadjuvant ddMVAC + D +/- T in pts with cT2-4N0-1 eligible for radical cystectomy (RC). The pts received 4 cycles of ddMVAC every 2 weeks with D (1500 mg) +/- T (75 mg) every 4 weeks. The co-primary endpoints were locally assessed pCR rate (ypT0N0) and grade ≥ 3 treatment related adverse events (TRAE). We assumed a pCR rate ≥ 45% to consider trial as positive. Between November 2018 and April 2022, 121 pts were enrolled in 16 centers and 119 received at least one dose of ddMVAC + D +/- T. The median age was 64 years (IQR: 58-70) with predominant ECOG PS 0 (74%). Clinical tumor stage at diagnosis was cT2, cT3 and cT4 in 86 (89%), 9 (9%) and 1 (1%), respectively, while 5 (5%) pts were cN1. Only 6 pts (6%) did not undergo RC (4 refusal and 2 progressive disease). Among the 113 pts with RC, the pCR was 47.8% (Table). All pts had at least one TRAE and 41% a G≥3 TRAE including neutropenia (12.6%) anemia (9.2%), and acute kidney injury (6.7%). ddMVAC or D +/- T were discontinued in 21 pts (17.6%), mostly due to TRAE (90.5%).Table: 2364MOddMVAC + D (N=55)ddMVAC + D + T (N=58)Pts achieved cystectomy (N=113)ypT0N027 (49.1%)27 (46.6%)54 (47.8%)ypT1, Ta, TisN012 (21.8%)8 (15.5%)21 (18.6%)ypT2-4N010 (18.2%)16 (27.6%)26 (23.0%)ypN+6 (10.9%)6 (10.3%)12 (10.6%) Open table in a new tab NEMIO is a positive trial showing one of the highest pCR achieved in the neoadjuvant setting with the use of ddMVAC + D. Nonetheless, the benefit of adding T on pathological response appears limited, pending survival outcomes.