ASCO 2021: Neoadjuvant Atezolizumab with Gemcitabine and Cisplatin in Patients with Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase 2 Trial

( Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy and pelvic lymph node dissection improves survival compared to radical cystectomy and pelvic lymph node dissection alone for patients with muscle-invasive bladder cancer.1 Neoadjuvant gemcitabine-cisplatin is standard for patients with muscle-invasive bladder cancer and can result in pathologic downstaging to non-muscle-invasive bladder cancer (< pT2N0) at radical cystectomy, which correlates with improved survival. Based on the known activity of atezolizumab in metastatic bladder cancer, it is reasonable to assess the efficacy of combination gemcitabine-cisplatin + atezolizumab as neoadjuvant therapy. At the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting, Dr. Samuel Funt and colleagues presented the results of their trial testing this combination in a phase II trial among patients with muscle-invasive bladder cancer.

For this trial, eligible patients with muscle-invasive bladder cancer (cT2-T4aN0M0) received a single dose of atezolizumab (1200 mg IV) and, two weeks later, began cisplatin (as either 70mg/m2 IV on D1 or 35 mg/m2 on D1, D8), gemcitabine (1000 mg/m2 on D1, D8), and atezolizumab (1200 mg IV on D8) every 21 days for 4 cycles followed by radical cystectomy. Patients were also able to receive one additional dose of atezolizumab 3 weeks after the last dose of atezolizumab and prior to radical cystectomy. The primary endpoint was proportion of patients with < pT2N0. Patients were considered not evaluable for the primary endpoint if they received less than 2 cycles due to withdrawal of consent or unrelated adverse events. Secondary endpoints included the proportion of patients with pT0N0, recurrence-free survival (RFS), and safety. The trialists prespecified null and alternate < pT2N0 rates of 35% and 55%, respectively, with the null being rejected if at least 19 of 39 patients achieved < pT2N0. Additionally, pretreatment tumors underwent centralized PD-L1 staining (SP142; positive if ≥5% of immune cells). The trial schema for this study is as follows:


Between February 2018 and May 2020, 44 patients were enrolled from five institutions. Five patients were not evaluable (withdrawal of consent before C3, n = 4; unrelated adverse events during C1, n = 1). Among the 39 evaluable patients (cT2N0 79%, cT3N0 18%, cT4N0 3%), one patient refused surgery and was considered a non-responder. The primary endpoint was met, with 27 of 39 patients (69%) < pT2N0 at radical cystectomy, including 17 (44%) pT0N0. The detailed breakdown of pathologic response at radical cystectomy are as follows:


All patients achieving < 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), and the median time from last dose of chemotherapy to radical cystectomy was 7.8 weeks (range 5.1 – 17). RFS stratified by pathologic response is as follows:


The most common grade 3-4 treatment-related adverse events were due to chemotherapy and were neutropenia (36%), lymphopenia (16%), and anemia (11%). Possible grade 3-4 immune-related adverse events included 2 patients with asymptomatic grade 3 pancreatic enzyme elevation, 1 patient with grade 3 pancreatitis, and 1 patient with hepatitis requiring steroids. Only 4 of 39 (10%) patients had PD-L1 positive tumors, which is low compared to metastatic bladder cancer (~25% positive) and muscle-invasive bladder cancer (~40% positive) cohorts also tested with the SP142 clone. All 4 patients with PD-L1 positive tumors achieved < pT2N0, 12 of 12 (100%) non-responding patients were PD-L1 negative, and 23 of 27 (85%) responding patients were PD-L1 negative (p = 0.3).

Dr. Funt concluded this presentation with the following summary statements:

  • This study of neoadjuvant gemcitabine-cisplatin + atezolizumab met its primary endpoint with 27 of 39 patients (69%) with muscle-invasive bladder cancer achieving <pT2N0 at radical cystectomy, including (44%) achieving pT0N0
  • Neoadjuvant gemcitabine-cisplatin + atezolizumab was associated with manageable treatment-related adverse events, which did not compromise surgical resection
  • No patients who underwent radical cystectomy and achieved <pT2N0 after gemcitabine-cisplatin + atezolizumab treatment subsequently relapsed with a median follow-up of 12 months for non-relapsing patients
  • 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 gemcitabine-cisplatin + atezolizumab is ongoing

Clinical trial information: NCT02989584

Presented by: Samuel A. Funt, MD, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021


  1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.