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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

  • Stephen A Boorjian,
  • Mehrdad Alemozaffar,
  • Badrinath R Konety,
  • Neal D Shore,
  • Leonard G Gomella,
  • Ashish M Kamat,
  • Trinity J Bivalacqua,
  • Jeffrey S Montgomery,
  • Seth P Lerner,
  • Joseph E Busby,
  • Michael Poch,
  • Paul L Crispen,
  • Gary D Steinberg,
  • Anne K Schuckman,
  • Tracy M Downs,
  • Robert S Svatek,
  • Joseph Mashni Jr,
  • Brian R Lane,
  • Thomas J Guzzo,
  • Gennady Bratslavsky,
  • Lawrence I Karsh,
  • Michael E Woods,
  • Gordon Brown,
  • Daniel Canter,
  • Adam Luchey,
  • Yair Lotan,
  • Tracey Krupski,
  • Brant A Inman,
  • Michael B Williams,
  • Michael S Cookson,
  • Kirk A Keegan,
  • Gerald L Andriole Jr,
  • Alexander I Sankin,
  • Alan Boyd,
  • Michael A O'Donnell,
  • David Sawutz,
  • Richard Philipson,
  • Ruth Coll,
  • Vikram M Narayan,
  • F Peter Treasure,
  • Seppo Yla-Herttuala,
  • Nigel R Parker,
  • Colin P N Dinney

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 × 10 11 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.govNCT02773849.

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.

Commentary by Dr. Evanguelos Xylinas

The optimal management of patients with BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) represents a challenging clinical dilemma and unmet need, with few effective therapeutic options available outside of radical cystectomy. Radical cystectomy, while being the most effective therapeutic strategy, comes with a certain degree of morbidity and mortality, therefore excluding a certain percentage of patients from this therapeutic option either due to medical comorbidities or due to their decision to decline surgery. Several alternative therapies have been investigated in the BCG-failure setting, including intravesical chemotherapy (Gemcitabine, Docetaxel monotherapy, combinations including Gemcitabine plus Mitomycin and Gemcitabine plus Docetaxel and Nab-paclitaxel) and chemohyperthermia (EMDA, RITE Synergo, HIVEC). Widespread adoption of these agents has been hampered by small sample sizes, heterogeneous cohorts, and lack of industry-sponsored prospective trials. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, was the first approved drug in the US in the BCG-unresponsive setting, owing to the positive results of a phase-2 trial (Keynote-057). This option is still pending approval outside the US due to the lack of phase-3 data.

Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers the human interferon alfa-2b cDNA into the bladder epithelium. It is a novel intravesical therapy for BCG-unresponsive NMIBC. Boorjian et al. led a phase-3, multicentre (n=33), open-label trial (NCT02773849) between September 19, 2016, and May 24, 2019, in which 157 patients with BCG-unresponsive NMIBC received a single-intravesical, 75-mL dose of nadofaragene firadenovec (3 × 10 11 viral particles per mL). Dosing was repeated at months 3, 6, and 9 provided that no high-grade recurrence had developed. Patients were excluded (n=41) if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. 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): an endpoint that was defined in accordance with the US Food and Drug Administration. The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses of the per-protocol population were performed to only include patients strictly meeting the BCG-unresponsive definition (n=151). Safety analyses were done in all patients who received at least one dose of treatment.

In terms of oncological efficacy, 55 (53.4%) out of 103 patients (95%CI 43.3-63.3) in the carcinoma-in-situ cohort had a complete response, with all complete responses noted at month 3. Median follow-up for this cohort was 19.7 months (IQR 16.0-24.8). The pre-specified null hypothesis of a complete response rate no more than 27% is therefore rejected at p<0.0001. Median duration of complete response in patients with carcinoma in situ was 9.69 months (95%CI 9-17), with 25 out of 103 patients (24.3%; 95%CI 16.4-33.7) remaining high-grade-recurrence-free at month 12. 25 (45.5%) out of the 55 patients with an initial complete response in the carcinoma-in-situ cohort remained free from high-grade recurrence at month 12. In the high-grade Ta or T1 cohort, 35 out of 48 patients (72.9%; 95%CI 58.2-84.7) were high-grade-recurrence-free at month 3, and 21 patients (43.8%; 29.5-58.8) were recurrence-free at month 12. Thus, 21 (60%) out of 35 patients with high-grade Ta or T1 NMIBC who had been high-grade-recurrence-free at month 3 maintained that status at month 12. Median follow-up for the high-grade Ta or T1 cohort was 20.2 months (IQR 17.2-25.5). Median duration of high-grade-recurrence-free survival was 12.35 months (95%CI 6.67 to not estimable).

Progression to muscle invasion was a rare event, occurring in 5% of the patients in the carcinoma-in-situ cohort and 6% of the patients in the high-grade Ta or T1 cohort. Noteworthily, these rates of progression are lower than those previously reported in patients with BCG-unresponsive NMIBC treated with radical cystectomy, suggesting that nadofaragene firadenovec did not put patients at an increased risk of progression and subsequent death from bladder cancer, and might have prevented disease progression. Moreover, cystectomy-free survival at 24 months was 64.5% of the total study population, indicating that most patients with this difficult-to-treat condition chose to avoid surgery.

In terms of safety, 146 (93%) out of 157 patients experienced adverse events during the study. 110 (70%) patients experienced events that were study-drug-related. The most frequently reported drug-related adverse events were problems around the catheter during instillation, fatigue, bladder spasms, and micturition urgencies. For most patients, the adverse events were transient and classified as either grade 1 or 2. Grade 3 or 4 adverse events occurred in 29 (18%) out of 157 patients, of whom only six (4%) experienced events that were study-drug-related (two cases of micturition urgency, and one case of bladder spasm, urinary incontinence, syncope, and hypertension respectively). A grade-4 event of sepsis was considered study-drug-unrelated but was procedure-related. There were no grade-5 adverse events.

In conclusion, intravesical nadofaragene firadenovec for patients with BCG-unresponsive NMIBC showed significant efficacy with a manageable safety profile and delivery schedule, resulting in a favourable benefit/risk profile.