Abstract CT178: Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update and association between biomarkers and overall survival in CheckMate 275
Authors: Sharma Padmanee , Baron Ari , Necchi Andrea , Plimack Elizabeth R. , Pal Sumanta K. , Bedke Jens , Arranz Jose A. , Vaena Daniel , Grimm Marc-Oliver , Bracarda Sergio , Retz Margitta , Siefker-Radtke Arlene , Ohyama Chikara , Grossfeld Gary , Lu Haolan , Saci Abdel , Tang Hao , Galsky Matthew D. 
Published: August 2018

Abstract
Introduction: Nivolumab monotherapy has already shown efficacy and safety in the open-label, single-arm, phase II CheckMate 275 trial (objective response rate [ORR], 19.6%). Here, we report updated results with a minimum follow-up of 21.3 months together with additional exploratory biomarker analyses.
Methods: Patients received nivolumab 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed ORR by blinded independent review committee (per Response Evaluation Criteria in Solid Tumors v.1.1). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). ORR was further examined by the duration of response (DoR) and time to response. Outcomes were evaluated in all patients and by tumor cell programmed death-1 ligand 1 (PD-L1) expression (cutoff ≥1% by Dako immunohistochemical staining). Myeloid-derived suppressor cells (MDSCs), defined as Lin− CD14+ HLA-DR-low/negative monocytic myeloid cells, were measured by flow cytometry in the circulation at baseline, and archival pretreatment biopsies were assessed for interferon gamma (IFN-γ) gene expression signature to assess associations with OS.
Results: There were 270 treated patients. Median follow-up was 24.5 months. ORR was 20.4% for all treated patients. There were nine additional complete responses (CRs) since results with median follow-up of 11.5 months were reported (17; 6.3%). Of the 55 responders, 72.7% had DoR ≥6 months, 54.5% had DoR ≥12 months, and 30.9% had an ongoing response. Median (95% confidence interval [CI]) DoR for all treated patients was 17.7 (11.5-22.0) months. Median (95% CI) PFS and OS were 1.9 (1.9-2.3) and 8.6 (6.1-11.3) months, respectively. OS benefit was observed across tumor PD-L1 expression levels. The 1-year and 2-year OS rates (95% CI) were 40.3% (34.4-46.2) and 29.4% (23.9-35.1), respectively. The most common any-grade treatment-related adverse events were fatigue (18.1%), diarrhea (12.2%), pruritus (11.5%), and decreased appetite (9.3%). Lower vs higher baseline MDSCs were associated with longer OS in all patients and independent of tumor PD-L1 expression (&lt;1% and ≥1%; P &lt; 0.05). Patients with higher tumor IFN-γ and lower circulating MDSC levels experienced the longest OS (P &lt; 0.05) and patients with both higher IFN-γ scores and high baseline MDSC levels experienced a lower survival benefit with nivolumab.
Conclusions: In this updated analysis of CheckMate 275, durable efficacy was observed with additional CRs since the previous report. No new safety signals were observed. A combination of immune-associated tumor and circulating biomarkers (as defined in this study) may identify patients with particularly favorable outcomes with nivolumab.
Citation Format: Padmanee Sharma, Ari Baron, Andrea Necchi, Elizabeth R. Plimack, Sumanta K. Pal, Jens Bedke, Jose A. Arranz, Daniel Vaena, Marc-Oliver Grimm, Sergio Bracarda, Margitta Retz, Arlene Siefker-Radtke, Chikara Ohyama, Gary Grossfeld, Haolan Lu, Abdel Saci, Hao Tang, Matthew D. Galsky. Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update and association between biomarkers and overall survival in CheckMate 275 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT178.