Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer (NABUCCO Cohorts 1 and 2)

Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761), a single-arm feasibility trial, twenty-four stage III urothelial cancer patients received 2 doses of ipilimumab and 2 doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect <12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection; twenty-three (96%) within <12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients; 41% when excluding clinically insignificant laboratory abnormalities. 46% of patients had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8+ presence or T-effector signatures. Induction of TLS upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade may provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8+ T-cell activityEGA study EGAS00001004521