Neoadjuvant atezolizumab (A) with gemcitabine and cisplatin (GC) in patients (pts) with muscle-invasive bladder cancer (MIBC): A multicenter, single-arm, phase 2 trial.
Authors: Samuel Aaron Funt, Michael Lattanzi, Karissa Whiting, Hikmat A. Al-Ahmadie, Colleen Quinlan, Min Yuen Teo, Jeffrey Kamradt, Maged F. Khalil, Irina Ostrovnaya, Asia S. McCoy, Grace Hettich, Marwah Jihad, Edmund Folefac, William C. Huang, Dean F. Bajorin, Gopa Iyer, Bernard H. Bochner, Arjun Vasant Balar, Amir Mortazavi, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2021)

4517 Background: Neoadjuvant GC is standard for pts with MIBC and can result in pathologic downstaging to non-MIBC ( &lt; pT2N0) at radical cystectomy (RC), which correlates with improved survival. Based on the known activity of A in metastatic BC (mBC), we tested the combination of GC+A as neoadjuvant therapy for MIBC in a phase II trial (NCT02989584). Methods: Eligible pts with MIBC (cT2-T4aN0M0) received a single dose of A (1200 mg IV) and, two weeks later, began C (as either 70mg/m2 IV on D1 or 35 mg/m2 on D1,D8), G (1000 mg/m2 on D1,D8), and A (1200 mg IV on D8) every 21 days for 4 cycles followed by RC. Pts were also able to receive one additional dose of A 3 weeks after the last dose of A and prior to RC. The primary endpoint was proportion of pts with &lt; pT2N0. Pts were considered not evaluable for the primary endpoint if they received less than 2 cycles due to withdrawal of consent or unrelated adverse events (AEs). Secondary endpoints included the proportion of pts with pT0N0, recurrence-free survival (RFS), and safety. We prespecified null and alternate &lt; pT2N0 rates of 35% and 55%, respectively, with the null being rejected if at least 19 of 39 pts achieved &lt; pT2N0. Pretreatment tumors underwent centralized PD-L1 staining (SP142; positive if ≥5% of immune cells). Results: Between Feb 2018 and May 2020, 44 pts were enrolled from five institutions. Five pts were not evaluable (withdrawal of consent before C3, n = 4; unrelated AEs during C1, n = 1). Of the 39 evaluable pts (cT2N0 79%, cT3N0 18%, cT4N0 3%), 1 pt refused surgery and was considered a non-responder. The primary endpoint was met, with 27 of 39 pts (69%) &lt; pT2N0 at RC, including 15 (38%) pT0N0. All pts achieving &lt; pT2N0 are alive and disease free. The median RFS was not reached with a median follow-up of 16.7 months (range: 7.7-33.2). The median time from last dose of chemotherapy to RC was 7.8 weeks (range 5.1 – 17). The most common grade 3-4 treatment related AEs were due to chemotherapy and were neutropenia (36%), lymphopenia (16%), and anemia (11%). Possible grade 3-4 immune related AEs included 2 pts with asymptomatic grade 3 pancreatic enzyme elevation, 1 pt with grade 3 pancreatitis, and 1 pt with hepatitis requiring steroids. Only 4 of 39 (10%) pts had PD-L1 positive tumors, which is low compared to mBC (25% positive; Powles et al. Lancet 2017) and MIBC (40% positive; Powles et al. Nature Med 2019) cohorts also tested with the SP142 clone. All 4 pts with PD-L1 positive tumors achieved &lt; pT2N0. Twelve of 12 (100%) non-responding pts were PD-L1 negative and 23 of 27 (85%) responding pts were PD-L1 negative (p = 0.3). Conclusions: Neoadjuvant GC+A is an effective and safe regimen for the treatment of pts with MIBC. The PD-L1 positivity rate was low compared with other studies and was not predictive of pathologic downstaging. Additional interrogation of the genomic and host immune factors mediating response and resistance to GC+A is ongoing. Clinical trial information: NCT02989584.