ESMO 2019: Pre-Operative Ipilimumab and Nivolumab in Locoregionally Advanced, Stage III, Urothelial Cancer - NABUCCO

Barcelona, Spain ( Stage III (cT3-4aN0M0 or ≥cT1N+M0) urothelial cancer patients have a poor prognosis, and despite high response rates, pre-operative chemotherapy shows limited survival benefit. Furthermore, the overall survival benefit of preoperative cisplatin-based chemotherapy is only 5%, with 30-40% being cisplatin ineligible. Immunotherapy targeting PD-1/PD-L1 is active in metastatic urothelial carcinoma and the combination of ipilimumab and nivolumab appears to increase response rates. Encouraging pathological complete response (pCR) rates (29-42%) have been observed in trials testing neoadjuvant anti-PD-1/PD-L1, however these have been mostly cT2-T3N0 patients. At the ESMO 2019 annual congress, Dr. Van der Heijden and colleagues presented initial findings assessing preoperative ipilimumab + nivolumab in patients with locally advanced urothelial cancer.

NABUCCO was a single-arm phase IB trial testing the feasibility of pre-operative ipilimumab + nivolumab in stage III urothelial carcinoma patients who were either cisplatin ineligible or refused chemotherapy. To mitigate the risk of immune-related toxicity, the patients were treated with (based on melanoma data): ipilimumab 3 mg/kg (day 1), ipilimumab 3 mg/kg + nivolumab 1 mg/kg (day 22), and nivolumab 3 mg/kg (day 43), followed by radical cystectomy. The primary endpoint was feasibility and secondary endpoints were efficacy (pCR) and translational parameters: PD-L1 expression, tumor mutational burden, and immune cell infiltrates at baseline vs on-treatment using multiplex immunofluorescence (pan-CK/CD3/CD8/FOXP3/CD20/CD68).

There were 24 patients (14 cT3-4N0; 10 cN+) enrolled to this study, of whom 23 (96%) had a radical cystectomy <12 weeks from first cycle. One patient, responding radiologically, had a delay in surgery because of an immune related adverse event (hemolysis). 18/24 patients received all three cycles of therapy, while six patients received two cycles due to immune related adverse event. Grade 3/4 immune related adverse event occurred in 54% of patients, however only 42% when excluding clinically insignificant lab deviations. Among 22 patients available for efficacy assessment 10 patients (45%) achieved a pCR. There were also 3 additional patients (14%) that had noninvasive cancer at the time of radical cystectomy (2 ypTis, 1 ypTa), resulting in an overall path downstaging (≤ypT1N0) rate of 59%. Response was associated with massive infiltration of CD8+ T-cells in the tumor bed, and were higher for PD-L1 positive patients: 

One patient recurred six weeks after surgery and subsequently died of metastatic disease.

Dr. Van der Heijden concluded this first reporting of NABUCCO with the following concluding statements:

  • All patients had surgical resection with 96% having surgery within 12 weeks of initiating treatment
  • There were robust response rates (pCR 45%; 59% noninvasive disease) observed with the current treatment schedule in locoregionally advanced urothelial carcinoma
  • Additional patients had major pathological responses, the clinical significance of these responses is yet unknown
  • A follow-up study will assess high vs low dose ipilimumab and frontline nivolumab to attempt to achieve similar pathological response rates with less toxicity

Clinical trial identification NCT03387761

Presented by: Michiel S. Van der Heijden, Netherlands Cancer Institute, Amsterdam, NL

Co-Authors: N. Van Dijk 2, L. Smit 1, K. Hendricksen 1, J. De Feijter 1, E. Bekers 1, E. Hooijberg 3, C. Van Rooijen 1, A. Broeks 4, Y. Lubeck 1, K. Sikorska 4, T. Schumacher 5, P. Kvistborg 5, T. Boellaard 1, C. Blank 4, B. Van Rhijn 1

1. Netherlands Cancer Institute, Amsterdam, NL

2. Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, N

3. Vrije University Medical Centre (VUMC), Amsterdam, NL

4. Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), Amsterdam, NL

5. The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, NL

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain 


  1. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018 Oct 20 [Epub ahead of print].
  2. Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). ASCO 2018 abstr 4506.

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