- Pathology after BCG: a high-grade tumor
- Timing of persistence/recurrence after the last BCG exposure: BCG refractory, or Ta/T1 high-grade recurrence within 6 months, or recurrence of CIS within 12 months
- Amount of BCG given: at least 5 doses of induction BCG plus two additional instillations as a second induction or maintenance
Treatment options for BCG unresponsive tumors include (i) radical cystectomy, which is the standard treatment, is oncologically safe, but may result in overtreatment in some cases, or (ii) alternative bladder sparing options, which may be effective in some patients, but are connected with the risk of tumor progression. These alternative options include cytotoxic treatments (new chemotherapy and chemotherapy combinations, new drug delivers, and device-assisted instillation), gene therapy, immune checkpoint inhibitors, vaccines, oncolytic adenoviruses, recombinant proteins, and photodynamic therapy.
The United States Federal Drug Administration (FDA) previously proposed a pathway to drug registration, including single-arm phase II trials, given that there are no salvage therapies to which new agents can be compared. Meaningful outcome goals were an initial complete response of 40-50% at 6 months for patients with CIS, and a durable response of >30% at 18-24 months.
KEYNOTE-057 is a single-arm phase 2 study for patients with BCG-unresponsive NMIBC who were unwilling or unfit to undergo radical cystectomy. These patients had histologically confirmed high-risk, BCG-unresponsive CIS with or without papillary disease, who received adequate BCG therapy and received pembrolizumab 200 mg Q3W for 24 months or until recurrence, progression, or unacceptable toxicity. Patients with high-risk NMIBC or progressive disease during treatment were required to discontinue pembrolizumab. The primary endpoint for this study was complete response rate and key secondary endpoint for the study were duration of response and safety. The study design is as follows:
There were 102 patients who met inclusion criteria. The median age was 73 years, 63.7% of patients had CIS alone, and the median number of prior BCG instillations was 12 (range 6.0-45.0). Updated results presented at EAU 2020 showed that among 96 patients, the complete response rate was 40.6% (95%CI 30.7%-51.1%) by central assessment. Furthermore, the duration of complete response was a median 16.2 months (range 0-30.4 months), and for responders, 46.2% had a duration of response >= 12 months. As such, this lead to FDA approval in January 2020. Dr. Babjuk notes that albeit these are encouraging outcomes, this is a systemic therapy with a non-insignificant side effect profile.
Nadofaragene firadenovec is a non-replicating recombinant type-5 adenovirus vector-based gene therapy that delivers a copy of the human IFNα2b gene. Adenoviruses provide short-term, high but transient expression of the gene of interest in a relatively broad range of host cells. The Phase III trial of nadofaragene firadenovec for BCG unresponsive NMIBC was a multi-center study to investigate the safety and efficacy of intravesical nadofaragene firadenovec 75 mL once every 3 months in 157 patients with high-grade, BCG-unresponsive NMIBC. Cytology and cystoscopy (with biopsy if clinically indicated) were performed at 3, 6, and 9 months to evaluate for recurrence of high-grade disease. At 12 months, all patients underwent urine cytology, cystoscopy, and mandatory biopsy. Patients free from high-grade recurrence were eligible for retreatment at 3-month intervals while they remained high-grade recurrence-free. The trial design is as follows:
The study met its primary endpoint with 53.4% of patients with CIS ±Ta/T1 achieving a complete response, all by 3 months, including 43.6% of these patients remaining free of high-grade recurrence at 15 months. This study was recently published in Lancet Oncology.1
There are also other agents that take advantage of sequential chemotherapy and new delivery options. Intravesical gemcitabine with docetaxel has a 1-year high-grade recurrence-free survival rate of 56%, of which 49% were deemed BCG unresponsive. Currently, there is an ongoing phase I trial (NCT02202772) looking at sequential cabazitaxel, gemcitabine, and cisplatin which was recently completed and expected to report results soon. New and enhanced drug delivery options include:
- Intravesical docetaxel-PM (nanoparticle-based formulation) + mitomycin C (NCT02982395)
- Mitomycin C imbedded in TC-3 sterile hydrogel (UroGen Pharma)
- TAR-200/gemcitabine (JNJ-17000139-ACC), which are gemcitabine minitablets and osmotic minitablets containing urea as an osmotic agent
- Paclitaxel + HA (Oncofid)
Device assisted instillations include (i) radiofrequency-induced thermo-chemotherapy (RICE), which delivers hyperthermia to the bladder wall, improving cytotoxicity and drug absorption; (ii) chemohyperthermia (HIVEC-E), which involves continuous recirculation of mitomycin C for 50-60 minutes at a temperature of 43 degrees Celsius; (iii) electromotive-drug administration (EMDA) sequentially with BCG.
Further drug investigations are as follows:
- Vaccines: PANVAC, HS-410, ALT-803
- Gene therapies: CG007, BC-819
- Recombinant proteins: recombinant BCG, oportuzumab Monatox
- Targeted therapy: fusion protein Vicinium
Dr. Babjuk concluded by highlighting and encouraging that our management of these patients must always be guideline specific:
Presented by: Marek Babjuk, MD, PhD, Department of Urology, 2nd Faculty of Medicine, Hospital Motol, Prague, Czech Republic
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 18th Meeting of the EAU Section of Oncological Urology (ESOU21), January 29-31, 2021
References:
Clinical Trial Information:
NCT02202772
NCT02982395
Related Content:
EAU 2020: Results from the phase III study of Nadofaregene Firadenovec: Safety and Efficacy in Patients with High-grade, BCG-unresponsive Non-Muscle Invasive Bladder Cancer