The authors enrolled patients with cT2-T3N0M0 urothelial carcinoma of the bladder who had ECOG performance status 0-1 and creatinine clearance l≥50 mL/min. These patients underwent NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC). Prior to initiating NAC, TURBT specimens were sequenced (Caris Life Sciences) to identify mutations, either pathogenic or variants of unknown significance in ATM, ERCC2, FANCC or RB1.
Following NAC, patients who had at least one mutation and no clinical evidence of disease by restaging TUR and imaging began a pre-defined active surveillance (AS) regime. The remaining patients who did not meet these criteria underwent bladder-directed therapy: intravesical therapy ( < cT2 post-NAC), CRT or RC. The primary endpoint is metastasis-free survival (MFS) at 2 years, the data for which is not mature, but the authors report key interim results of clinically-meaningful intermediate endpoints.
The authors enrolled 77 patients in the intention-to-treat population over 33 months at four academic centers. The median age of enrolled patients was 70 years (47-83), 74% were male, 92% were Caucasian, 81% had ECOG PS 0 and 79% had cT2 disease.
90% of enrolled patients completed 3 cycles of NAC, with 17% experiencing grade 3-4 TRAEs and one death during AMVAC.
As of a data cut-off of September 11, 2020, for the ITT pts, 32 pts have undergone radical cystectomy, 5 underwent CRT and 7 underwent intravesical therapy, at some point during the trial. 
Among 77 enrolled patients, 33 patients (46%) had a mutation of interest and 28 pts (39%) started AS (2 of the 28 pts on AS did not have a mutation but elected to start AS after achieving cT0 post AMVAC). 76% of those with a mutation had no residual disease (cT0) at the time of post-NAC TURBT. With a median follow-up of 14.9 months (range: 3.1-35.3 months), 14 patients who underwent AS had evidence of recurrence (50%). Among 14 recurrences, 2 recurred with locally advanced or metastatic disease and have died, 5 recurred with MIBC with one eventual metastatic recurrence, and 7 recurred with NMIBC.
Six (14%) patients who did not undergo AS have died. Out of the 40 pts who did not undergo upfront radical cystectomy [AS (N = 28), CRT (N = 5), intravesical tx (N = 7)], 3 patients (7.5%) all of whom underwent AS eventually underwent radical cystectomy.
Overall, 55% of patients in the ITT cohort and 89% of patients in the AS group had successful bladder preservation. In terms of overall survival, the majority of patients were alive and without metastasis at median follow-up between 18 and 20 months, in both the ITT and AS populations.
In the AS cohort, mutations were seen in RB1 (50%), ATM (42%), ERCC2 (31%), FANCC (4%) with differences in recurrence rates based on mutation status: ERCC2 (25% recurrence) vs RB1 (62% recurrence).
The authors conclude that, based on these interim results, a risk adapted approach allows active surveillance of a subset of patients with MIBC who achieve pathologic complete response from NAC, thus sparing the toxicity of consolidative therapy.
Presented by: Daniel M. Geynisman, MD, Associate Professor, Department of Hematology/Oncology, NCCN, Testicular Cancer Panel Member, Fox Chase Cancer Center