The Evolution of Nadofaragene Firadenovec: A Review and the Path Forward
Abstract:
BACKGROUND:
The intravesical gene therapy nadofaragene firadenovec (rAd-IFNα/Syn3) was FDA approved in 2022 for non-muscle invasive bladder cancer (NMIBC) unresponsive to frontline treatment with BCG, and the first gene therapy developed for bladder cancer. This non-replicating recombinant adenovirus vector delivers a copy of the human interferon alpha-2b gene into urothelial and tumor cells, causing them to express this pleotropic cytokine with potent antitumor effects.
OBJECTIVE:
To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC.
METHODS:
We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC.
RESULTS:
The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon’s direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene.
CONCLUSIONS:
Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.
Non-Muscle Invasive Bladder Cancer: Many More Patients Die With It Than Of It
Abstract:
BACKGROUND:
The National Cancer Institute SEER Program regularly publishes bladder-cancer specific survival statistics. However, this data is for all bladder cancers, and information for non-muscle invasive bladder cancer (NMIBC) is difficult to obtain.
OBJECTIVE:
To quantify 5-year overall and bladder cancer-specific survival in a cohort of Department of Veterans Affairs (VA) patients diagnosed with NMIBC.
METHODS:
We identified VA patients diagnosed with NMIBC who underwent a transurethral resection from 2003-2013. The patient demographics and Charlson Comorbidity Index were categorized. We acquired the patients’ date of death from the Veterans Health Administration’s Death Ascertainment File and their cause of death from the Mortality Data Repository. We calculated Kaplan Meier estimates of survival.
RESULTS:
A total of 27,008 patients were included; median age was 69 and almost all were male (99%). The median comorbidity score was 4. The most prevalent comorbidity indicators included Chronic Pulmonary Disease (48%), cancer other than Bladder (41%), and diabetes (40%). This cohort was found to have a 5-year overall survival of 68% (99% CI 67% –69%) and a 5-year bladder cancer-specific survival of 93% (99% CI 92% –94%).
CONCLUSIONS:
The 5-year bladder cancer-specific survival in patients diagnosed with non-muscle invasive bladder cancer is substantially higher than the 5-year overall survival. This difference may be related to the severity and number of comorbidities that patients in this population must manage. This warrants further research into the necessity of currently recommended high-intensity cancer surveillance for individuals with NMIBC.
Multi-Center Assessment of Lymph-Node Density and Nodal-Stage to Predict Disease-Specific Survival in Patients with Bladder Cancer Treated by Radical Cystectomy
Abstract:
BACKGROUND:
Prognostic tools in pathological-node (pN) patients after radical cystectomy (RC) are needed.
OBJECTIVES:
To evaluate the prognostic impact of lymph node (LN)-density on disease-specific survival (DSS) in patients with bladder cancer (BC) undergoing RC with pelvic lymph node dissection.
METHODS:
We analyzed a multi-institutional cohort of 1169 patients treated with upfront RC for cT1-4aN0M0 urothelial BCat nine centers. LN-densitywas calculated as the ratio of the number of positive LNs×100% to the number of LNs removed. The optimal LN-density cut-off value was defined by creating a time-dependent receiver operating characteristic (ROC) curve in pN patients. Univariable and multivariable Cox’ regression analyses were used to assess the effect of conventional Tumor Nodes Metastasis (TNM) nodal staging system, LN-density and other LN-related variables on DSS in the pN-positive cohort.
RESULTS:
Of the 1169 patients, 463 (39.6%) patients had LN-involvement. The area under the ROC curve was 0.60 and the cut-off for LN-density was set at 20%, 223 of the pN-positive patients (48.2%) had a LN-density ≥ 20%. In multivariable models, the number of LN-metastases (HR 1.03, p = 0.005) and LN-density, either as continuous (HR 1.01, p = 0.013) or as categorical variable (HR 1.37, p = 0.014), were independently associated with worse DSS, whereas pN-stage was not.
CONCLUSIONS:
LN-density ≥ 20% was an independent predictor of worse DSS in BC patients with LN-involvement at RC. The integration of LN-density and other LN-parameters rather than only conventional pN-stage may contribute to a more refined risk-stratification in BC patients with nodal involvement.
Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis
Abstract:
BACKGROUND:
Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed.
OBJECTIVE:
We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole transcriptome RNA sequencing.
METHODS:
A single-institution, retrospective analysis of muscle-invasive SBC patients treated with neoadjuvant CGD with molecular analysis. Patients received cisplatin 35 mg/m2 + gemcitabine 800 mg/m2 + docetaxel 35 mg/m2 intravenously on days 1 and 8 + pegfilgrastim 6 mg subcutaneously on day 9 every 3 weeks for 4 cycles followed by cystectomy. The primary endpoint was pathologic complete response (ypCR) rate.
RESULTS:
Sixteen patients with SBC received neoadjuvant CGD with a ypCR rate of 38% and a < ypT2 rate of 50%. Grade 3 and 4 toxicity occurred in 80% and 40% of patients, but was manageable with 81% of patients completing > 3 CGD cycles. Whole transcriptome RNA sequencing demonstrates co-clustering of SBC with conventional urothelial tumors. SBC tumors are characterized by basal-squamous and stroma rich gene signatures with frequent increased expression of immune checkpoint (CD274 (PD-L1)), chemokine (CXCL9), and T-cell (CD8A) genes.
CONCLUSIONS:
SBC is a chemosensitive subtype, with ypCR rate similar to urothelial bladder cancer following CGD neoadjuvant therapy. Whole transcriptome tissue analyses demonstrate increased expression of immune checkpoint and T-cell genes with therapeutic implications.
Factors Influencing Patient Decision-Making in the Treatment of Muscle-Invasive Bladder Cancer
Abstract:
BACKGROUND:
In 2023, an estimated 82,290 individuals were diagnosed with bladder cancer in the United States. For muscle-invasive bladder cancer (MIBC), the American Urological Association recommends offering radical cystectomy with cisplatin-based neoadjuvant chemotherapy. However, patients are increasingly requesting alternative treatments.
OBJECTIVE:
To describe factors influencing selection of radical cystectomy with cisplatin-based neoadjuvant chemotherapy (NAC + RC), radical cystectomy monotherapy (RC), or tri-modality therapy (TMT) among patients with MIBC.
METHODS:
Individual, semi-structured phone interviews were conducted with 18 adults who underwent MIBC treatment at the University of North Carolina, recruiting six patients each from three treatment groups: 1) NAC + RC, 2) RC, and 3) TMT. Interview transcriptions were qualitatively analyzed using QSR NVivo, with major themes and sub-themes extracted. Patients also completed the Shared Decision-Making Questionnaire (SDM-Q-9; range 0–100).
RESULTS:
Concern for survival and risks, quality of life, and varied patient preferences for involvement influenced the decision-making process. Concern surrounding sexual function, bladder preservation, and urostomy bags drove patients towards TMT. High levels of shared decision-making were observed overall, with a median SDM-Q-9 score of 95 (IQR 89–100). Patients undergoing TMT reported the highest median SDM-Q-9 score (97, IQR 94–100), while those receiving radical cystectomy alone had the lowest (66, IQR 37–96).
CONCLUSIONS:
Patients with MIBC described a multifaceted treatment decision-making process, highlighting key influences, concerns, and unmet needs. Understanding this process can help address misconceptions and align treatment choices with patient goals. Physicians can use these insights to engage in shared decision-making, ultimately improving patient experiences and outcomes.
