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

Barcelona, Spain (UroToday.com) Neoadjuvant platinum-based chemotherapy is the standard of care for high-risk resectable urothelial carcinoma (Stage III; cT3-T4aN0M0 or cT1N+M0). Though response rates are quite high, and pathologic complete responses occur in approximately 25% of patients, these tumors commonly recur such that the marginal overall survival benefit from neoadjuvant chemotherapy is only 5%. As 30-40% of patients eligible for neoadjuvant treatment are cisplatin ineligible, recent trials have examined the efficacy of neoadjuvant immunotherapy. The PURE-01 study1 showed a 42% pCR with neoadjuvant pembrolizumab, and the ABACUS study found a 29% pCR rate in cT2-T4aN0 disease.

The NABUCCO study (NCT03387761) is a phase 1b study testing neoadjuvant ipilimumab and nivolumab in cisplatin-ineligible/cisplatin-refusing patients with high-risk Stage III urothelial carcinoma, reasoning that a more intensive immunotherapy approach is justified in this higher risk group. The primary endpoint was feasibility, and secondary endpoints were pCR rate and exploratory studies including PD-L1 status, tumor mutational burden (TMB) and immune cell infiltrate parameters. The treatment regimen was designed to maximize safety based on data from melanoma regimens. Specifically, patients received 3 mg/kg ipilimumab on day 1, 3 mg/kg ipilimumab and 1 mg/kg of nivolumab on day 22, 3 mg/kg nivolumab on day 43, then resection.

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Of the 24 patients enrolled, 14 were node-negative and 10 were node-positive for carcinoma. Only 1 patient had upper tract disease. 96% of patients underwent resection within the 12-weeks of treatment initiation. The 1 patient who did meet this feasibility endpoint had their surgery delayed due to immune-mediated hemolysis. Most patients received all three immunotherapy treatments, with only 6 receiving just two treatments due to immune-related adverse events.

Of the 22 patients available for data analysis, 46% experienced a pCR, and three additional patients only had non-invasive carcinoma, resulting in a 58% rate of downstaging. Major pathologic response, defined in the melanoma literature as less than 10% tumor cells in the tumor bed was seen in 5 patients and 4 patients had no response. More patients with PD-L1 positivity experienced tumor downstaging. The response was also associated with increased tumor infiltration of CD8+ Tcells.

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The majority of patients experienced at least 1 grade 3 adverse event, but as mentioned above, these did not delay resection in the vast majority of patients. 1 patient died within 90 days of the initiation of treatment due to tumor recurrence within 6 weeks and subsequent metastatic disease.

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In summary, neoadjuvant ipilimumab and nivolumab were tolerated in high-risk urothelial carcinoma, results in downstaging of the majority of cases including those with lymph node positivity. Patients with higher immune cell infiltration and PD-L1 positivity are enriched for response. Further studies are planned to evaluate alternative dosing regimens, and explore the effect of this combination on progression-free and overall survival.

Presented by: Michiel S. Van der Heijden, MD, PhD, Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

References:
1. Necchi A. 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. Journal of Clinical Oncology. 2018 Oct. DOI: 10.1200/JCO.18.01148 Journal of Clinical Oncology 36, no. 34 (December 01, 2018) 3353-3360.

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