NABUCCO Trial Pursues Neoadjuvant Nivolumab/Ipilimumab in Advanced Urothelial Cancer

The combination of preoperative nivolumab and ipilimumab demonstrated preliminary feasibility and safety in patients with locoregionally advanced urothelial cancer.

The combination of preoperative nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated preliminary feasibility and safety in patients with locoregionally advanced (stage III) urothelial cancer, according to findings from the phase 1 NABUCCO trial (NCT03387761).

All patients who received the combination underwent resection (n = 24), and all but 1 (n = 23; 96%) did so within 12 weeks after starting neoadjuvant therapy, meeting the primary end point of the study. 

“We found that ipilimumab plus nivolumab is feasible and highly active as preoperative treatment in urothelial cancer. Moreover, high pCR rates were observed in patients with locoregionally advanced disease,” wrote Nick van Dijk, MD, PhD, of The Netherlands Cancer Institute, and study co-authors.

In the single-arm trial, 24 patients with stage III urothelial cancer received 3 mg/kg of ipilimumab on day 1, 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab on day 22, and 3 mg/kg of nivolumab on day 43, followed by resection.

The primary end point of the study was the viability of surgical resection within 12 weeks from the start of treatment. 

At baseline, 14 patients (58%) had node-negative disease (cT3-4aN0M0), and 10 patients (42%) had lymph node metastases (cT2-4aN1-3M0). Patients were ineligible for cisplatin or refused cisplatin-based chemotherapy.

One patient was delayed 4 weeks due to immune-related hemolysis. 

Grade 3 or 4 immune-related adverse effects (irAEs) occurred in 55% of patients and in 41% of patients with the exclusion of clinically insignificant laboratory abnormalities––predominantly lipase elevation.

Eighteen patients (75%) received all 3 treatment cycles. Six patients (25%) received only 2 cycles due to irAEs. No treatment-related mortality was reported.

Eleven patients (46%; 95% CI, 26%-67%) had a pathological complete response (pCR; pT0N0), meeting the secondary end point of the study. Fourteen patients (58%; 95% CI, 37%-77%) had no residual invasive disease (pCR or pTisN0/pTaN0) after treatment.

Two additional patients (8%) achieved a major pathological response (MPR), defined as less than 10% residual vital tumor and pN0, with extensive immune infiltration. Patients without baseline lymph node metastases (cT3-4aN0) experienced a 50% pCR rate (95% CI, 29%-71%) versus 40% (95% CI, 12%-73%) in patients with clinically suspected node-positive disease (cT2-4aN1-3).

Four patients achieved pCR/MPR in the primary tumor, whereas a resistant micrometastasis was identified in a concurrent lymph node. No discrepant genetic resistance mechanisms were identified between the primary tumor and resistant lymph nodes with whole-exome sequencing. 

At the time of analysis, 2 patients (both non-pCR) had relapsed; 1 of these patients died of metastatic disease. 

With regard to biomarkers of response, the CR rate (pCR or CIS/pTa) in PD-L1–positive tumors [combined positive score (CPS) >10] was 73% (95% CI, 45%-92%) versus 33% (95% CI, 7%-70%) in PD-L1–negative tumors (P = .15). 

The pretreatment tumor tissue and germline DNA of patients who achieved a CR with the combination indicated a trend toward a higher tumor mutational burden (TMB) with whole-exome sequencing versus those who did not achieve a CR (P = .056).

Additionally, alterations in DNA damage response genes were more common in responding tumors than in non-CR tumors (P = .03). TGF-β expression signature was associated with non-response. 

Notably, no correlation between baseline CD8+ T-cell density and response to the combination was found using quantitative multiplex immunofluorescence. The CR rate in the lowest and highest CD8+ cell density quartile was 67%. Moreover, no difference was found between CR and non-CR tumors with regard to baseline interferon-γ, tumor inflammation signature and CD8+ T-cell effector signatures.

“In contrast to studies with anti–PD-1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8+ presence or T-effector signatures,” wrote the study authors.

Further analysis demonstrated that upregulation of B-cell-related genes at baseline was associated with non-response and increased CD20+ B-cell counts. Stromal B cells were more common in non-responding tumors compared with responding tumors (P = .043). Though, the density of B cells in the tumor was higher (P = .07). The increased B-cell expression in non-CR tumors was reported regardless of pre-existing CD8+ T-cell immunity. 

No correlation was reported between baseline tertiary lymphoid structures (TLS) numbers and response. Though, immature TLSs were higher in non-CR tumors, and on-treatment analysis showed evidence of TLS enrichment in CR tumors (P < .001), irrespective of maturation stage. 

Examined together, the expression of TLS-related genes and a signature corresponding to B cell/TLS expression increased with treatment, particularly in CR tumors. 

The use of corticosteroids for irAEs stunted TLS development (P = .014). Treatment did not have an effect on CD27+ B cells and T follicular helper cells in TLS. Though, the combination led to a reduction in regulatory T cells in TLS. 

“These exploratory findings suggest that the presence of B cells and TLSs at baseline does not predict for ipilimumab plus nivolumab response in UC, although TLS induction is observed in responding patients,” wrote the study authors.

“Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective

preoperative treatment strategy in locoregionally advanced urothelial cancer, irrespective of pre-existing CD8+ T cell activity,” concluded the study authors.


  1. van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nature Med. 2020.