AUA 2022: Evaluating Intravesical Nadofaragene Firadenovec and Immune Checkpoint Blockade Combination Therapy in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Evidence From a Phase 3 Trial

(  The 2022 Annual Meeting of the American Urological Association was host to a moderated poster session for non-invasive bladder cancer. Dr. Mitra presented the results of an exploratory analysis from the phase 3 trial of intravesical nadofaragene firadenovac evaluating the potential for immune checkpoint blockade combination therapy in BCG-unresponsive NMIBC.

Given the shortage of treatment options in the BCG-unresponsive NMIBC disease space, there has been intensified research efforts to development treatment strategies with durable responses. Radical cystectomy remains the gold standard treatment option in this disease space, but many patients are either unfit or unwilling to undergo such a morbid procedure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, has recently been FDA approved in this setting on the basis of results from the KEYNOTE-057 trial.1 Nadofaragene firadenovec, an intravesical adenoviral vector-based therapy that delivers IFNA2 to urothelial cells, has shown durable response in a multicenter phase 3 trial for BCG-unresponsive NMIBC with 53.4% complete response within 3 months of the first dose. Response was maintained by 45.5% of these patients at 12 months.2

The objective of this study was to evaluate the status of PD1 and PD-L1 in transurethral resection specimens from patients treated with nadofaragene and examined the potential role for combining nadofaragene with anti-PD1 therapy in BCG-unresponsive NMIBC.

Transurethral resection specimens from 85 patients in the single-arm phase 3 trial treated with nadofaragene once every 3 months for up to 4 doses were examined. Response was assessed at 12 months or disease recurrence, whichever occurred earlier. The transurethral resection specimen was available at enrolment and again at 12 months or at time of study withdrawal (template biopsy). 

PD1/PD-L1 status was assayed per routine immunohistochemical protocols. PD1 status was positive if >0% cells and PD-L1 positivity was defined as at least 1%. PD1 and PD-L1 status quantification was 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.
Urothelial PD1 and PD-L1 status were assessed at study-entry and study-exit. TUR specimens were not associated with treatment response (all, p = 0.26).

Study entry: Study-entry lymphocyte PD1+ status was noted in 52% of responders and in 57% of non-responders (p = 0.72). Conversely, study-entry lymphocyte PD-L1+ was seen in 77% of responders and in 92% of non-responders (p = 0.15). 

Study exit: 62% of non-responders had study-exit lymphocyte PD1+ compared with 26% of responders (p = 0.002). Study-exit lymphocyte PD-L1+ was also higher in non-responders (78%) compared with responders (50%, p = 0.024). Differences in study-exit lymphocyte positivity status between responders and non-responders 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.
The authors concluded that nadofaragene non-responding patients had relative PD1/PD-L1 overexpression in tumor-infiltrating lymphocytes, findings that were not seen at baseline. These findings have been replicated in in-vivo models. These findings suggest that BCG-unresponsive NMIBC patients who have partial or short-term response to nadofaragene may benefit from immunotherapy in this setting.


Presented By: Anirban Mitra, MD, SUO Fellow, MD Anderson Cancer Center, Houston, TX

Written By: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022. 

  1. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 201;22(7):919-930.
  2. Boorjian SA, Alemozaffar M, Konty BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117.