Browsing by Author "Lerner, Seth P"

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    ItemOpen Access
    Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.
    (European urology, 2021-12-18) Mitra, Anirban P; Narayan, Vikram M; Mokkapati, Sharada; Miest, Tanner; Boorjian, Stephen A; Alemozaffar, Mehrdad; Konety, Badrinath R; Shore, Neal D; Gomella, Leonard G; Kamat, Ashish M; Bivalacqua, Trinity J; Montgomery, Jeffrey S; Lerner, Seth P; Busby, J Erik; Poch, Michael; Crispen, Paul L; Steinberg, Gary D; Schuckman, Anne K; Downs, Tracy M; Svatek, Robert S; Mashni, Joseph; Lane, Brian R; Guzzo, Thomas J; Bratslavsky, Gennady; Karsh, Lawrence I; Woods, Michael E; Brown, Gordon A; Canter, Daniel; Luchey, Adam; Lotan, Yair; Krupski, Tracey; Inman, Brant A; Williams, Michael B; Cookson, Michael S; Keegan, Kirk A; Andriole, Gerald L; Sankin, Alexander I; Boyd, Alan; O'Donnell, Michael A; Philipson, Richard; Ylä-Herttuala, Seppo; Sawutz, David; Parker, Nigel R; McConkey, David J; Dinney, Colin PN
    A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.
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    ItemOpen Access
    Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non-muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis.
    (European urology oncology, 2020-06) Kamat, Ashish M; Lerner, Seth P; O'Donnell, Michael; Georgieva, Mihaela V; Yang, Min; Inman, Brant A; Kassouf, Wassim; Boorjian, Stephen A; Tyson, Mark D; Kulkarni, Girish S; Chang, Sam S; Konety, Badrinath R; Svatek, Robert S; Balar, Arjun; Witjes, J Alfred

    Context

    Currently, there is no standard of care for patients with non-muscle-invasive bladder cancer (NMIBC) who recur despite bacillus Calmette-Guerin (BCG) therapy. Although radical cystectomy is recommended, many patients decline to undergo or are ineligible to receive it. Multiple agents are being investigated for use in this patient population.

    Objective

    To systematically synthesize and describe the efficacy and safety of current and emerging treatments for NMIBC patients after treatment with BCG.

    Evidence acquisition

    A systematic literature search of MEDLINE, Embase, and the Cochrane Controlled Register of Trials (period limited to January 2007-June 2019) was performed. Abstracts and presentations from major conference proceedings were also reviewed. Randomized controlled trials were assessed using the Cochrane risk of bias tool. Data for single-arm trials were pooled using a random-effect meta-analysis with the proportions approach. Trials were grouped based on the minimum number of prior BCG courses required before enrollment and further stratified based on the proportion of patients with carcinoma in situ (CIS).

    Evidence synthesis

    Thirty publications were identified with data from 23 trials for meta-analysis, of which 17 were single arm. Efficacy and safety outcomes varied widely across studies. Heterogeneity across trials was reduced in subgroup analyses. The pooled 12-mo response rates were 24% (95% confidence interval [CI]: 16-32%) for trials with two or more prior BCG courses and 36% (95% CI: 25-47%) for those with one or more prior BCG courses. In a subgroup analysis, inclusion of ≥50% of patients with CIS was associated with a lower response.

    Conclusions

    The variability in efficacy and safety outcomes highlights the need for consistent endpoint reporting and patient population definitions. With promising emerging treatments currently in development, efficacious and safe therapeutic options are urgently needed for this difficult-to-treat patient population.

    Patient summary

    We examined the efficacy and safety outcomes of treatments for non-muscle-invasive bladder cancer after bacillus Calmette-Guerin therapy. Outcomes varied across studies and patient populations, but emerging treatments currently in development show promising efficacy.
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    Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
    (The Lancet. Oncology, 2020-11-27) Boorjian, Stephen A; Alemozaffar, Mehrdad; Konety, Badrinath R; Shore, Neal D; Gomella, Leonard G; Kamat, Ashish M; Bivalacqua, Trinity J; Montgomery, Jeffrey S; Lerner, Seth P; Busby, Joseph E; Poch, Michael; Crispen, Paul L; Steinberg, Gary D; Schuckman, Anne K; Downs, Tracy M; Svatek, Robert S; Mashni, Joseph; Lane, Brian R; Guzzo, Thomas J; Bratslavsky, Gennady; Karsh, Lawrence I; Woods, Michael E; Brown, Gordon; Canter, Daniel; Luchey, Adam; Lotan, Yair; Krupski, Tracey; Inman, Brant A; Williams, Michael B; Cookson, Michael S; Keegan, Kirk A; Andriole, Gerald L; Sankin, Alexander I; Boyd, Alan; O'Donnell, Michael A; Sawutz, David; Philipson, Richard; Coll, Ruth; Narayan, Vikram M; Treasure, F Peter; Yla-Herttuala, Seppo; Parker, Nigel R; Dinney, Colin PN

    Background

    BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.

    Methods

    In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.

    Findings

    Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.

    Interpretation

    Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.

    Funding

    FKD Therapies Oy.