Nadofaragene Firadenovec: Significance of uMRD-Negative Status in Achieving Recurrence-Free Outcomes in NMIBC

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In patients with non-muscle-invasive bladder cancer (NMIBC) unresponsive to BCG who underwent nadofaragene firadenovec (Adstiladrin) treatment, those who achieved urinary minimal residual disease (uMRD)-negative status showed no recurrences, according to an analysis from a phase 2 trial presented in a poster at the 2024 ASCO Genitourinary Cancers Symposium.¹

Beyond being highly predictive of future recurrence, uMRD was also shown to enable quantitative evaluation of molecular response to nadofaragene, according to first author Vikram M. Narayan, MD, and co-investigators. Narayan is an assistant professor in the department of Urology at Emory University School of Medicine.

“uMRD profiling uses next-generation sequencing to identify mutations associated with urothelial carcinoma and can be used to predict recurrence and assess response to therapy,” Narayan and co-investigators wrote on their poster.¹

Narayan et al’s uMRD analysis was from a multicenter, parallel-arm, open-label phase 2 trial (NCT01687244) that included 43 patients with BCG-unresponsive (relapsed/refractory) NMIBC treated with the novel intravesical therapy nadofaragene. To enroll in the trial patients had to have an ECOG performance status of ≤2. Patients with upper tract urothelial carcinoma were not eligible. The primary end point of the study was high-grade recurrence-free survival (RFS) at 1 year.²

The uMRD analysis included all patients in the trial who had been treated with at least 1 dose of nadofaragene (n = 35). Patients’ urine samples were collected before induction and at 3 months’ follow-up. Narayan et al conducted the uMRD testing using the UroAmp MRD assay, which “identifies single-nucleotide variants, copy-number variants (CNVs), insertion-deletions, copy-neutral loss of heterozygosity, microsatellite instability, and aneuploidy,” according to the researchers.¹

Initial pathological stages for the 35 evaluable patients were Ta (n = 3), T1 (n = 9), and Tis (n = 23). Six patients also had concomitant carcinoma in situ (CIS). For the 32 patients with pre-treatment urine samples available, the most frequently mutated genes included TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2. CNVs occurred most commonly in SOX4 and NIT1.In both pre- and post-induction collections, “uMRD identified patients with high (72%) and low (28%) recurrence risk,” the authors wrote.¹

The 12-month pre-induction RFS rates were 71% and 20% for MRD-negatives and MRD-positives, respectively (P = .012).Also at 12 months, the post-induction RFS rates were 100% and 20% for MRD-negatives and MRD-positives, respectively (P= .035).

The investigators measured quantitative drug response using pre- and post-induction urine (n = 15) and categorized patients’ MRD status as negative (7%), complete responder (13%), partial responder (27%), stable (20%), or refractory (33%).The researchers then determined a broad correlation between recurrence and responses groups, with no recurrence in the MRD negative and complete responder groups and recurrence in 7 of the 12 patients that comprised the other groups.

“uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials,” Narayan et al wrote in their poster conclusion.¹

Earlier this month, Ferring Pharmaceuticals, the developer of nadofaragene, announced that the therapy is now fully available across the United States for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.³ In December 2022, the FDA approved nadofaragene firadenovec for use in this patient population.⁴

REFERENCES:

1. Narayan VM, Tholomier C, Mokkapati S, et al. Urinary minimal residual disease detection predicts recurrence in BCG-unresponsive NIMBC and quantifies molecular response to nadofaragene firadenovec. J Clin Oncol 42, 2024 (suppl 4; abstr 635). doi: 10.1200/JCO.2024.42.4_suppl.63

2. NIH US National Library of Medicine Clinical Trials.gov. Intravesical Administration of rAd-IFN/Syn3 in Patients With BCG-Refractory or Relapsed Bladder Cancer. Last updated July 24, 2017.Accessed January 25, 2024. https://www.clinicaltrials.gov/NCT01687244

3. Ferring announces full availability of ADSTILADRIN (nadofaragene firadenovec-vncg) in the U.S. News release. Ferring Pharmaceuticals. Published online and accessed January 25, 2024. http://tinyurl.com/4ep48auh

4. FDA approves first gene therapy for the treatment of high-risk, non-muscle-invasive bladder cancer. News release. FDA. December 16, 2022. Accessed January 25, 2024. http://tinyurl.com/mry9j983