ADC/ICI Combo Effective in BCG-Unresponsive NMIBC

Targeted Therapies in Oncology, July 2, 2022, Volume 11, Issue 10
Pages: 39

Results from a phase 3 study of pembrolizumab and nadofaragene firadenovec in patients with BCG-unresponsive non–muscle invasive bladder cancer suggests that immune checkpoint inhibitors have synergy with antibody drug conjugates.

Patients with Calmette–Guérin (BCG)-unresponsive non–muscle invasive bladder cancer (NMIBC) were responsive to the combination of pembrolizumab (Keytruda) and nadofaragene firadenovec (Instiladrin) in a single-arm phase 3 trial (NCT02773849), according to results presented at the 2022 American Urological Association Annual Meeting.1

Nadofaragene firadenovec, a novel intravesical gene therapy, delivers IFNA2 to urothelial cells. Prior data from the phase 3 trial showed nadofaragene firadenovec was effective in patients with high-grade BCG-unresponsive NMIBC.

“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,” said 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.

Combination Explored

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. Investigators analyzed the potential benefits of combining IFNA2 replacement and PD-1 inhibition in this patient population.

A total of 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 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 was performed for infiltrating lymphocyte and urothelial compartments in the primary tumors.

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

Orthotopic MB49 Tumors

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 based on urothelial PD-1 and PD-L1 status, assessed on study-entry and study-exit specimens (P = .26). A total of 52% of responders and 57% of nonresponders displayed study-entry lymphocyte PD-1 positivity (P = .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 (P = .002). Study-exit PD-L1 positivity was seen in 50% of responders vs 78% of nonresponders (P = .024). This relative PD-1/PD-L1 overexpression in nonresponders was seen as early as 3 months after therapy for PD-1 (P = .040) and PD-L1 (P = .029).

Hypothesis Generating

“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 shortterm response to nadofaragene treatment,” Mitra concluded.

REFERENCE:

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. Accessed June 15, 2022. Abstract MP54-05. https://bit.ly/3MQcC8h