MP16-07: Urinary minimal residual disease detection predicts recurrence in BCG-unresponsive NIMBC and quantifies molecular response to nadofaragene firadenovec
Friday, May 3, 2024 1:00 PM to 3:00 PM · 2 hr. (US/Central)
221B
Abstract
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Full Abstract and Figures
Author Block
Vikram M Narayan*, Atlanta, GA, Come Tholomier, Sharada Mokkapati, Alberto Martini, Houston, TX, Vincent M Caruso, Brian C Mazzarella, Kevin G Phillips, Vincent T Bicocca, Trevor G Levin, South San Francisco, CA, David Sawutz, Seppo Yla-Herttuala, Nigel Parker, Kuopio, Finland, David J McConkey, Baltimore, MD, Colin P.N. Dinney, Houston, TX
Introduction
Urinary minimal residual disease (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. Nadofaragene firadenovec is a novel intravesical therapy recently approved for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). We evaluate the utility of uMRD to identify molecular response to Nadofaragene in patients with high-grade (HG) BCG-refractory or relapsed NMIBC.
Methods
This was an open-label, multicenter, parallel-arm, phase II study (NCT01687244) of 43 patients with BCG-unresponsive NMIBC who received intravesical nadofaragene. The primary endpoint was 12-month HG-recurrence-free survival (RFS). All patients who received at least one dose were included in the uMRD analysis. Urine samples were collected prior to induction and at 3 months. uMRD testing was done 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.
Results
Among evaluable patients (n=35), initial pathological stages were Ta (n=3), T1 (n=9), and Tis (n=23), with concomitant CIS in six patients. In pre-treatment urine (n=32), TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2 were among the most prevalently mutated genes. Most CNVs occurred in SOX4 and NIT1. uMRD identified patients with high (72%) and low (28%) recurrence risk in both pre- and post-induction collections. At 12 months, post-induction RFS rate was 100% for low-risk and 38% for high-risk patients (P = 0.038, log-rank test). Pre-induction RFS was 56% for low-risk and 22% for high-risk (P = 0.097, log-rank test). Using matched pre- and post-induction urine (n=15), quantitative drug response was measured and patients categorized as MRD Negative (7%), MRD Complete Responder (13%), MRD Partial Responder (27%), MRD Stable (20%), or MRD Refractory (33%). Recurrence correlated broadly with response groups: MRD Negative and Complete Responder groups did not recur on study, while 7 of 12 patients in the other groups recurred.
Conclusions
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.
Source Of Funding
N/A
Author Block
Vikram M Narayan*, Atlanta, GA, Come Tholomier, Sharada Mokkapati, Alberto Martini, Houston, TX, Vincent M Caruso, Brian C Mazzarella, Kevin G Phillips, Vincent T Bicocca, Trevor G Levin, South San Francisco, CA, David Sawutz, Seppo Yla-Herttuala, Nigel Parker, Kuopio, Finland, David J McConkey, Baltimore, MD, Colin P.N. Dinney, Houston, TX
Introduction
Urinary minimal residual disease (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. Nadofaragene firadenovec is a novel intravesical therapy recently approved for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). We evaluate the utility of uMRD to identify molecular response to Nadofaragene in patients with high-grade (HG) BCG-refractory or relapsed NMIBC.
Methods
This was an open-label, multicenter, parallel-arm, phase II study (NCT01687244) of 43 patients with BCG-unresponsive NMIBC who received intravesical nadofaragene. The primary endpoint was 12-month HG-recurrence-free survival (RFS). All patients who received at least one dose were included in the uMRD analysis. Urine samples were collected prior to induction and at 3 months. uMRD testing was done 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.
Results
Among evaluable patients (n=35), initial pathological stages were Ta (n=3), T1 (n=9), and Tis (n=23), with concomitant CIS in six patients. In pre-treatment urine (n=32), TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2 were among the most prevalently mutated genes. Most CNVs occurred in SOX4 and NIT1. uMRD identified patients with high (72%) and low (28%) recurrence risk in both pre- and post-induction collections. At 12 months, post-induction RFS rate was 100% for low-risk and 38% for high-risk patients (P = 0.038, log-rank test). Pre-induction RFS was 56% for low-risk and 22% for high-risk (P = 0.097, log-rank test). Using matched pre- and post-induction urine (n=15), quantitative drug response was measured and patients categorized as MRD Negative (7%), MRD Complete Responder (13%), MRD Partial Responder (27%), MRD Stable (20%), or MRD Refractory (33%). Recurrence correlated broadly with response groups: MRD Negative and Complete Responder groups did not recur on study, while 7 of 12 patients in the other groups recurred.
Conclusions
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.
Source Of Funding
N/A