ESMO 2021: High- Versus Low-Dose Pre-Operative Ipilimumab and Nivolumab in Locoregionally Advanced Urothelial Cancer: NABUCCO Cohort 2

( The European Society of Medical Oncology (ESMO) 2021 annual meeting’s non-prostate cancer mini-oral session included a presentation by Dr. Jeroen Van Dorp discussing results of NABUCCO Cohort 2 assessing high- versus low-dose pre-operative ipilimumab and nivolumab in locoregional advanced urothelial cancer. The prognosis of stage III (cT3-4aN0M0 or cT1-4aN1-3M0) urothelial carcinoma is poor, with a 5-year overall survival rate of only 25-47% after radical cystectomy. The current standard treatment for these patients is cisplatin-based chemotherapy followed by radical surgery, however a substantial number of patients are unfit for cisplatin-based chemotherapy, and there are no therapeutic options to improve prognosis for these patients. In NABUCCO cohort 1, 24 patients were treated with pre-operative day 1 ipilimumab 3 mg/kg, day 22 ipilimumab 3 mg/kg + nivolumab 1 mg/kg, and day 43 nivolumab 3 mg/kg, showing encouraging efficacy results: 46% pathological complete response, ypT0N0 and 58% pathologic complete response + non-invasive disease.1

Recent data in pre-operative trials for other cancer types (ie. melanoma) suggests that a lower dose of ipilimumab has equal activity and is better tolerated. In cohort 2, Dr. Van Dorp and colleagues aimed to identify if a lower dose of ipilimumab is also true in stage III urothelial cancer by testing two different dosing schedules for ipilimumab + nivolumab.

NABUCCO is a multicenter, phase Ib/II, pre-operative trial. In cohort 2, thirty stage III, cisplatin-ineligible (or refusal) urothelial cancer patients were randomly assigned (1:1) to arm A: two cycles ipilimumab 3 mg/kg + nivolumab 1 mg/kg (day 1, 22) and nivolumab 3 mg/kg (day 43) versus arm B: two cycles ipilimumab 1 mg/kg + nivolumab 3 mg/kg (day 1, 22) and nivolumab 3 mg/kg (day 43). The trial schema for NABUCCO is as follows: 



The primary endpoint was pathological complete response rate. Secondary endpoints include feasibility (resection within 12 weeks) and grade 3–4 immune-related adverse events.

 Among the 30 patients randomly assigned in Cohort 2, 15 were randomized to arm A and 15 to arm B. Of these patients, 26 (87%) received all 3 treatment cycles, and four patients missed one or more cycles of therapy due to immune-related adverse events. Overall 26 (87%) patients underwent radical surgery, 24 within 12 weeks after start of treatment. One patient (arm B) progressed before surgery (evaluable, non-response) and three patients (1x arm A and 2x arm B) refused radical surgery while responding radiologically. One of these patients (arm B, baseline cT4aN3) had a lymph node dissection showing a micrometastasis (evaluable, non-response). Response was evaluable in 28 patients:

  • Arm A: 6/14 (43%) patients had a pathological complete response, and 8/14 (57%) had a pathological complete response or ypTisN0
  • Arm B: 1/14 (7%) had a pathological complete response whereas 3/14 (21%) had a pathological complete response or ypTisN0


The following figure highlights the pathologic response rates, comparing Cohort 1, Cohort 2A, and Cohort 2B:


The grade 3/4 adverse event rate in cohort A was 33% compared to 20% for cohort B, with one patient in cohort A experiencing 30-day mortality, whereas no patient in cohort B died within 30 days.

Dr. Van Dorp concluded his presentation of cohort 2 of the NABUCCO trial with the following take-home messages:

  • This data suggests that ipilimumab 3 mg/kg + nivolumab 1 mg/kg (arm A) is more efficacious than ipilimumab 1 mg/kg + nivolumab 3 mg/kg (Arm B) as preoperative treatment for stage III urothelial carcinoma
  • These findings are in contrast to the melanoma literature, where ipilimumab 1 mg/kg + nivolumab 3 mg/kg has shown equal efficacy compared to ipilimumab 3 mg/kg + nivolumab 1 mg/kg with better tolerability
  • Further translational work is currently ongoing 

Presented by: Jeroen Van Dorp, PhD, Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.


  1. van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 202 0 Dec;26(12):1839-1844.