Feb. 05, 2021
The majority of newly diagnosed bladder cancers (75% to 80%) are classified as nonmuscle invasive bladder cancer (NMIBC). Treatment for NMIBC often includes intravesical therapies. In particular, for patients with high-risk NMIBC, including those with carcinoma in situ, high-grade T1, or large-volume or recurrent Ta tumors, guidelines recommend treatment after transurethral resection with intravesical bacillus Calmette-Guerin (BCG).
Although approximately 70% of patients will experience a complete response to induction BCG therapy, more than 50% of patients will subsequently experience tumor recurrence. While a subset will respond to a second induction course of BCG, few effective treatment options exist for those patients who develop BCG-unresponsive disease. While radical cystectomy is favored in this clinical scenario, many patients may be unfit for major surgery, and others may strongly prefer bladder preservation.
Using an adenovirus to treat high-risk BCG-unresponsive bladder cancer
In an effort to explore novel treatments in this disease space, Stephen A. Boorjian, M.D., a urologic oncologist at Mayo Clinic in Rochester, Minnesota, evaluated the potential of nadofaragene firadenovec for patients with BCG-unresponsive NMIBC as part of a multi-institutional clinical trial. Study results were published in The Lancet Oncology in 2021.
Nadofaragene firadenovec is a nonreplicating recombinant adenovirus that acts as a gene therapy. The adenovirus delivers the human interferon alfa-2b gene to the patient's bladder urothelial cells.
"There is prior evidence that intravesical interferon alfa-2b therapy can be effective in the treatment of NMIBC, but results have not been durable. It has been hypothesized that a relatively short exposure time of the urothelium to the interferon alfa-2b limits longer term treatment efficacy. The novel gene therapy approach provides a longer duration of exposure to the interferon alfa-2b, essentially converting the bladder cells into an interferon factory," says Dr. Boorjian.
Multi-institutional effort leads to successful collaboration
The study was conducted as a phase III, open-label investigation that included 33 centers. The researchers enrolled 157 patients from September 2016 to May 2019. Patients received treatment, as eligible, every three months for up to four doses. The primary endpoint assessed was complete response in patients with carcinoma in situ. Patients were surveilled by cystoscopy and cytology. Patients who remained visually free of disease underwent templated bladder biopsy at 12 months.
Of patients in the carcinoma in situ cohort, 55 of 103 (53.4%) had a complete response within three months of treatment. Furthermore, 25 of 55 maintained a durable complete response at 12 months. "These efficacy results were exciting to see, particularly in what has up to this time been a challenging disease to treat," notes Dr. Boorjian.
Treatment well-tolerated by patients
Nadofaragene firadenovec is administered every three months. Most other intravesical therapies are administered per an induction (weekly for six weeks) and maintenance schedule. "The treatment schedule, with limited dosing, is relatively favorable to patients and providers," says Dr. Boorjian. "In addition, treatment was generally very well tolerated. In fact, there were no grade 4 to 5 adverse reactions in patients receiving nadofaragene firadenovec therapy."
The most common grade 3 adverse reaction was micturition urgency (1%). The majority of patients experience a grade 1 adverse event (66%) with some of the most common events being mild fatigue (20%) and bladder spasms (15%).
Future of nadofaragene firadenovec therapy
Nadofaragene firadenovec is not yet a standard component in urologists' armamentarium for high-risk NMIBC, but the results of this phase III trial are encouraging. Dr. Boorjian notes the significance of the study findings: "We have been seeking better treatment options for patients with this challenging clinical scenario. We are optimistic that nadofaragene firadenovec represents a potential change in the paradigm for patients who develop BCG-unresponsive NMIBC."
For more information
Boorjian SA, et al. 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. 2021;22:107.