MP54-05 EVALUATING INTRAVESICAL NADOFARAGENE FIRADENOVEC AND IMMUNE CHECKPOINT BLOCKADE COMBINATION THERAPY IN BCG-UNRESPONSIVE NON-MUSCLE-INVASIVE BLADDER CANCER: EVIDENCE FROM A PHASE 3 TRIAL

Abstract

You have accessJournal of UrologyCME1 May 2022MP54-05 EVALUATING INTRAVESICAL NADOFARAGENE FIRADENOVEC AND IMMUNE CHECKPOINT BLOCKADE COMBINATION THERAPY IN BCG-UNRESPONSIVE NON-MUSCLE-INVASIVE BLADDER CANCER: EVIDENCE FROM A PHASE 3 TRIAL Anirban P. Mitra, Sharada Mokkapati, Tanner S. Miest, Vikram M. Narayan, Richard Philipson, Seppo Yla-Herttuala, David Sawutz, Nigel R. Parker, David J. McConkey, and Colin P.N. Dinney Anirban P. MitraAnirban P. Mitra More articles by this author , Sharada MokkapatiSharada Mokkapati More articles by this author , Tanner S. MiestTanner S. Miest More articles by this author , Vikram M. NarayanVikram M. Narayan More articles by this author , Richard PhilipsonRichard Philipson More articles by this author , Seppo Yla-HerttualaSeppo Yla-Herttuala More articles by this author , David SawutzDavid Sawutz More articles by this author , Nigel R. ParkerNigel R. Parker More articles by this author , David J. McConkeyDavid J. McConkey More articles by this author , and Colin P.N. DinneyColin P.N. Dinney More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: There are few efficacious bladder-preserving therapies for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). Pembrolizumab, an immune checkpoint inhibitor (ICI) targeting programmed cell death 1 (PD1) receptor, is approved in this setting. Nadofaragene firadenovec is an intravesical adenoviral vector-based therapy that delivers IFNA2 to urothelial cells, and has shown durable response in a multicenter phase 3 trial for BCG-unresponsive NMIBC. We evaluated the status of PD1 and its ligand (PD-L1) in transurethral resection (TUR) specimens from patients treated with nadofaragene, and examined the role for combining nadofaragene with anti-PD1 therapy in BCG-unresponsive NMIBC. METHODS: TUR specimens were available for 85 patients treated on a single-arm phase 3 trial with nadofaragene once every three months for up to four doses. Response was assessed at 12 months or disease recurrence, whichever was earlier. TUR of tumor was done at enrollment, and a templated biopsy at 12 months or study withdrawal. PD1/PD-L1 status were assayed per routine immunohistochemical protocols. PD1 (positive, >0% cells) and PD-L1 (positive, ≥1% cells) quantification were performed for urothelial and infiltrating lymphocyte compartments. Orthotopic tumors in C57Bl/6 mice were treated with intravesical adenoviral-IFN versus control, and PD1/PD-L1 status was assessed. RESULTS: Urothelial PD1 and PD-L1 status assessed on study-entry (Sin) and study-exit (Sout) TUR specimens were not associated with treatment response (all, p ≥0.26). Sin lymphocyte PD1+ was seen in 52% responders (R) and 57% nonresponders (NR) (p=0.72). Sin lymphocyte PD-L1+ was seen in 77% R and 92% NR (p=0.15). 62% NR had Sout lymphocyte PD1+ compared with 26% R (p=0.002). Sout lymphocyte PD-L1+ was also higher in NR compared with R (78% versus 50%, p=0.024). Differences in Sout lymphocyte positivity status between R and NR were evident as early as three months after therapy for PD1 (p=0.040) and PD-L1 (p=0.029). Co-expression assays on orthotopic bladder tumors showed PD1 overexpression on T lymphocytes in control mice compared with those that responded to intravesical adenoviral-IFN. CONCLUSIONS: Nadofaragene NR patients had relative PD1/PD-L1 overexpression in tumor-infiltrating lymphocytes, although this was not seen at baseline. In vivo models replicated these findings. Taken together, this suggests a role for ICI in BCG-unresponsive NMIBC who may have partial or short-term response to nadofaragene. Source of Funding: FKD Therapies. Clinical trial # NCT02773849 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e927 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anirban P. Mitra More articles by this author Sharada Mokkapati More articles by this author Tanner S. Miest More articles by this author Vikram M. Narayan More articles by this author Richard Philipson More articles by this author Seppo Yla-Herttuala More articles by this author David Sawutz More articles by this author Nigel R. Parker More articles by this author David J. McConkey More articles by this author Colin P.N. Dinney More articles by this author Expand All Advertisement PDF DownloadLoading ...