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Nadofaragene firadenovec, PD-1 inhibitors show synergistic activity in bladder cancer


These findings are hypothesis-generating and suggest a possible therapeutically synergistic role for immune checkpoint blockade in [patients with] BCG-unresponsive NMIBC who may have partial or short-term response to nadofaragene treatment,” said lead study author Anirban P. Mitra, MD, PhD.1

A sub-analysis of a phase 3 trial presented at 2022 AUA Annual Meeting found that there may be a potential role for immune checkpoint inhibition with agents such as pembrolizumab (Keytruda) in patients with BCG-unresponsive non–muscle invasive bladder cancer (NMIBC) who respond to nadofaragene firadenovec (Instiladrin).

Bladder-preserving therapies for BCG-unresponsive NMIBC include pembrolizumab, a systemically administered immune checkpoint inhibitor that targets PD-1 receptors. Nadofaragene firadenovec, a novel intravesical gene therapy, delivers IFNA2 to urothelial cells. Prior data from the single-arm phase 3 trial (NCT02773849) showed nadofaragene firadenovec was effective in patients with high-grade BCG-unresponsive NMIBC.

Anirban P. Mitra, MD, PhD

Anirban P. Mitra, MD, PhD

“Nadofaragene firadenovec has shown durable response in patients with BCG-unresponsive NMIBC. It is also well tolerated and has a simple and non-intense administration schedule,” lead study author Anirban P. Mitra, MD, PhD, a fellow in Urologic Oncology in the Department of Urology at The University of Texas MD Anderson Cancer Center, said.

This analysis investigated PD-1 and PD-L1 expression in transurethral resection (TUR) specimens from patients with BCG-unresponsive NMIBC who were enrolled in the phase 3 trial and treated with nadofaragene firadenovec. This analysis aimed to evaluate the potential benefits of combining IFNA2 replacement and PD-1 inhibition in this patient population.

In the phase 3 trial, 157 patients with BCG-unresponsive NMIBC were treated with nadofaragene firadenovec once every 3 months for a maximum of 4 doses. TUR of each tumor was conducted at enrollment, and a template biopsy was conducted at 12 months or study withdrawal. Of these patients, 54% (n = 85) had TUR specimens available for analysis.

Patient response was assessed at 12 months or disease recurrence, whichever happened earlier. Tumors were assayed for PD-1 and PD-L1 expression status using routine immunohistochemical protocols. Blinded PD-1 (positive, >0% cells) and PD-L1 (positive, ≥1% cells) quantification were performed for infiltrating lymphocyte and urothelial compartments in the primary tumors.

This post-treatment biopsy analysis revealed a higher proportion of PD-1 and PD-L1 overexpression in the tumor-infiltrating lymphocytes of patients who did not respond to nadofaragene firadenovec compared with responders, although these results were not seen at baseline.

Additionally, in vivo models of orthotopic MB49 tumors were generated in C57BI/6 mice. These tumors were treated intravesically with adenoviral-interferon vs control to assess PD-1 status in both populations. Analysis of these models was followed by a marker co-expression assessment on the orthotopic bladder tumors, which showed higher levels of PD-1 overexpression on T lymphocytes in control mice compared with mice that responded to treatment. These in vivo models replicated the post-treatment biopsy findings.

Treatment response was not associated with urothelial PD-1 and PD-L1 status assessed on study-entry and study-exit TUR specimens (P = .26). A total of 52% of responders and 57% of nonresponders displayed study-entry lymphocyte PD-1 positivity (= .72). A total of 77% of responders and 92% of nonresponders displayed study-entry PD-L1 positivity (P = .15). Additionally, 26% of responders and 62% of nonresponders displayed study-exit PD-1 positivity (= .002). Study-exit PD-L1 positivity was seen in 50% of responders vs 78% of nonresponders (= .024). This relative PD-1/PD-L1 overexpression in nonresponders was seen as early as 3 months after therapy for PD-1 (= .040) and PD-L1 (P = .029).

“These findings are hypothesis-generating and suggest a possible therapeutically synergistic role for immune checkpoint blockade in [patients with] BCG-unresponsive NMIBC who may have partial or short-term response to nadofaragene treatment,” Mitra concluded.


1. Mitra AP, Mokkapati S, Miest TS, et al. Evaluating intravesical nadofaragene firadenovec and immune checkpoint blockade combination therapy in BCG-unresponsive non-muscle-invasive bladder cancer: evidence from a phase 3 trial. Presented at: 2022 American Urological Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP54-05.

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