Atezolizumab + intravesical BCG (bacillus Calmette-Guerin) upfront combination in high risk non–muscle- invasive bladder cancer (NMIBC) patients: Safety interim report of BladderGATE phase I-II study.
Authors: Castellano Daniel , de Velasco Guillermo , Carretero-González Alberto , Dueñas Marta , Paramio Jesus , De La Rosa Federico , Gomez Carmen , Hernandez Mario , Martin Maria Paz , Álvarez Pablo , Guerrero Félix 
Published: June 2023

e16590 Background: Intravesical Bacillus Calmette-Guerin (BCG) induction + BCG maintenance after transurethral resection (TURBT) is the current standard of care for patients (pt) with high-risk non-muscle invasive bladder cancer (NMIBC). Recurrence rate at 2 years is around 30%, which is clearly unsatisfactory. Atezolizumab is a humanized IgG1 monoclonal antibody targeting PD-L1 and is associated with long-term durable remissions in pts with metastatic urothelial cancer (Powles T. Lancet. 2018). Pembrolizumab (KN-057-FDA approved) and Atezolizumab (SWOG S-1605 Ph2 study) were recently evaluated for pts with unresponsive NMIBC ineligible for radical cystectomy with excellent results. Atezolizumab in combination with standard BCG could provide synergistic benefit for pts with NMIBC. BladderGATE (NCT04134000) is a phase Ib-II study which evaluates the safety and efficacy of Atezolizumab + intravesical BCG in pts with high-risk NMIBC. Methods: Pt had confirmed histopathology of high-risk NMIBC, BCG naïve or stopped > 2 years ago, WHO PS 0-2 and adequate hematologic and end-organ function. De-escalation design to identify DLT and MTD to evaluate safety and efficacy in an expansion cohort. Pt will receive induction BCG, 1 instillation every week (qw) (dose level 0) or BCG, 1/2 instillation qw (dose level -1) + intravenously atezolizumab 1200 mg every 3 w (q3w), during 6 w. After induction, BCG was administered at weeks 13-15, 25-27 and 49-51 and atezolizumab up to 1 year. Pt were accrued to each dose level in cohorts of 10 pt until the MTD is achieved (dose at which < 4 out of 10 pt experience DLT). DLT was evaluated during induction treatment. Additional pt will be included in the expansion cohort. Results: 34 pt are included in this interim analysis, median age 70 years, 82% men, 82% ECOG 0 and 79% had previous transurethral resection. Median treatment exposure was 28 weeks. No DLTs were reported in the first 10 patients included in dose level 0. Most frequent adverse events (AEs) all grades were: asthenia (24%), pruritus (21%), pyrexia (18%), hypothyroidism (15%), urinary tract infection (15%), hyperthyroidism (9%), hypertransaminitis (9%), back pain (9%), myalgia (9%) and dysuria (9%). Most frequent AES G 3-4 were mainly IRAEs: myocarditis (3%), asthenia (9%), immune-mediated hepatitis (3%), hyponatremia (3%), encephalopathy (3%) and Guillain-Barre syndrome (3%). Two patients discontinued study treatment due to immuno-mediated hepatitis Grade 3 and immuno-mediated pneumonitis Grade 3 respectively. Conclusions: Induction treatment with BCG + atezolizumab followed by maintenance treatment seems to be feasible and have a manageable toxicity profile. The toxicity of BCG and atezolizumab appears not to be enhanced in this combination. Clinical trial information: NCT04134000 .