2053 - Pre-operative ipilimumab and nivolumab in locoregionally advanced, stage III, urothelial cancer (NABUCCO)

Background

Stage III (cT3-4aN0M0 or ≥cT1N+M0) urothelial cancer (UC) patients (pts) have a poor prognosis. Despite high response rates, pre-operative chemo shows limited survival benefit. Immunotherapy targeting PD-1/PD-L1 is active in metastatic UC; the combination of ipilimumab (ipi) and nivolumab (nivo) appears to increase response rates. Encouraging path Complete Response (pCR) rates are observed in trials testing neoadjuvant anti-PD-1/PD-L1 (mostly cT2-T3N0 pts). Here, we present the first clinical trial data on preoperative ipi+nivo.

Methods

This is a single-arm phase 1B trial testing the feasibility (primary endpoint) of pre-operative ipi+nivo in stage III UC pts (cis unfit/refusal). To mitigate the risk of immune-related toxicity, pts were treated with (based on melanoma data): ipi 3 mg/kg (day 1), ipi 3 + nivo 1 mg/kg (day 22), and nivo 3 mg/kg (day 43), followed by resection. Secondary endpoints were efficacy (pCR) and translational parameters: PD-L1, TMB (by WES), and immune cell infiltrates at baseline vs on-treatment using multiplex immunofluorescence (mIF; pan-CK/CD3/CD8/FOXP3/CD20/CD68).

Results

24 pts (14 cT3-4N0; 10 cN+) were enrolled, of whom 23 (96%) had resection <12 weeks from 1st cycle. 1 pt, responding radiologically, had a delay in surgery because of an irAE (hemolysis). 18/24 pts received all 3 cycles, 6 pts received 2 cycles due to irAEs. Grade 3/4 irAEs occurred in 54% of pts; 42% when excluding clinically insignificant lab deviations. 22 pts were available for efficacy assessment (1 pt resection delayed, 1 pt had resection 1 day before abstract submission). 10/22 pts (45%) achieved a pCR. 3 additional pts (14%) had noninvasive cancer at resection (2 ypTis, 1 ypTa), resulting in an overall path downstaging (≤ypT1N0) rate of 59% (13/22). In recent neoadjuvant IO studies in melanoma and NSCLC, major path response (MPR) has been defined as ≤ 10% vital tumor cells in the tumor bed. MPR was seen in 5/22 pts (23%). Nonresponse was seen in 4/22 (17%). Response was associated with massive infiltration of CD8+ T-cells in the tumour bed.

Conclusions

Preoperative ipi+nivo is feasible (96% surgery <12 weeks) and shows promising efficacy in stage III UC pts. Updated results on all 24 pts, including mIF, PDL1 and TMB, will be presented.

Clinical trial identification

NCT03387761, January 2, 2018.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute - Antoni van Leeuwenhoek.

Funding

BMS.

Disclosure

M.S. Van der Heijden: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Janssen. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA. P. Kvistborg: Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Personalis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: GenMab; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): NanoString. B.W. van Rhijn: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ferring. All other authors have declared no conflicts of interest.