NABUCCO Update: Efficacy, Biomarker Analysis of Preoperative Ipilimumab Plus Nivolumab

Chantal Stockem, MD, of the Netherlands Cancer Institute, and colleagues shared an update on clinical efficacy and an exploratory biomarker analysis from the NABUCCO trial for preoperative ipilimumab plus nivolumab in patients with stage III (cT3-4aN0M0 or cT1-4aN1-3M0) urothelial cancer (UC).

Their results are being presented at the 2024 American Society of Clinical Oncology Annual Meeting.

In cohort 1 of the NABUCCO trial, 11 of 24 (46%) patients achieved complete pathological response (ypT0N0) from ipilimumab/nivolumab. In cohort 2, 30 additional patients were sampled with 2 different ipilimumab/nivolumab dosing regimens (ipilimumab 3 + nivolumab 1 [ipi-high], ipilimumab 1 + nivolumab 3 [ipi-low]), and a higher ipilimumab dosage of 3 mg/kg was found to be more effective.

Whole-exome sequencing was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) tumor tissue and peripheral blood to identify somatic variants. RNA from FFPE tissue was isolated and sequenced. PD-L1 immunohistochemistry was performed on baseline FFPE tumor tissue and manually scored using the combined positivity score, tumor positivity score, and immune score.

To profile the tumor microenvironment, Dr. Stockem and colleagues stained pre- and post-treatment FFPE slides with 3 multiplex immunofluorescence panels consisting of antibodies against CD3, CD20, FoxP3, PanCK, CD68, CD206, IRF8, CD8, CD103, and TCF1.

After a median follow-up of 48 months, the 2-year overall survival (OS) was 90% in the ipi-high group and 73% in the ipi-low group. Progression-free survival (PFS) at 2 years was 75% and 67%, respectively. Researchers also found that tumor mutational burden was higher in responding patients across treatment arms.

Treatment response was associated with PD-L1 positivity, they added, and increased RNA expression of immune-related genes, such as IDO1, CTLA4, and PD-L1, and signatures of T-helper 1- and T-follicular helper cells at baseline were associated with response in patients treated in the ipi-low arm, but not in the ipi-high arm.

Increased baseline RNA expression of a TGFβ signature was associated with nonresponse, and patients who did not respond to ipilimumab/nivolumab demonstrated enhanced RNA expression of CD8 T-cell and stromal signatures.

“Both OS and PFS at 2 years were numerically better in patients treated with a high [ipilimumab] dose,” study authors concluded. “Overall, tumor mutation burden and PD-L1 positivity were associated with treatment response regardless of [ipilimumab] dose, [and] preexisting intratumoral T-cell immunity appears to be required to induce an antitumor response in patients treated with [low-dose ipilimumab].”