cretostimogene grenadenorepvec (CG0070)

In parallel, we highlight emerging intravesical immunotherapies for BCG-unresponsive NMIBC with carcinoma in situ, including nadofaragene firadenovec (Adstiladrin), nogapendekin alfa inbakicept-pmln (Anktiva), cretostimogene grenadenorepvec (CG0070), and detalimogene voraplasmid (EG-70). The lack of comparative data, coupled with the absence of predictive biomarkers of response, complicates treatment selection. Our review underscores that developing effective therapies for BCG-unresponsive disease will require combination strategies targeting multiple immune escape mechanisms that shape immune dynamics within the TME.

P3, N=190, Active, not recruiting, CG Oncology, Inc. | Trial completion date: Dec 2029 --> Dec 2031 | Trial primary completion date: Dec 2027 --> Jun 2030

Intermediate-risk patients could benefit from either intravesical chemotherapy or Bacillus Calmette-Guérin (BCG) instillation, with emerging therapies such as UGN-102 chemoablation showing promise...Moreover, alternative agents such as sequential gemcitabine and docetaxel instillation have demonstrated favorable outcomes in both BCG-naïve and BCG-unresponsive patients...Gene therapy (nadofaragene firadenovec), oncolytic viral therapy (CG0070), interleukin-15 superagonist (Nogapendekin alfa-inbakicept), and innovative drug delivery systems (TAR-200) have shown encouraging clinical potential in this population. This review provides an overview of current intravesical treatment strategies for NMIBC across different risk groups and highlights promising new approaches aimed at overcoming the limitations of BCG therapy.

P1, N=21, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

P3, N=367, Active, not recruiting, CG Oncology, Inc. | Trial completion date: Jan 2030 --> Feb 2029 | Trial primary completion date: Jan 2028 --> Jun 2026

P2, N=16, Recruiting, Lepu Biopharma Co., Ltd.

We highlight trials where OVs prime checkpoint response (e.g., DNX-2401→pembrolizumab in recurrent glioblastoma) and where vector design (e.g., TK-deleted vaccinia, CG0070) or payloads (e.g., IFNβ, NIS) drive measurable benefit. We conclude with actionable priorities, patient selection by IFN-pathway competence, receptor-tropism panels, and rational OV-ICI sequencing, to accelerate durable responses.

Nadofaragene firadenovec, a recombinant adenovirus delivering interferon alpha-2b (IFNα2b), is the first FDA-approved gene therapy for BCG-unresponsive NMIBC with carcinoma in situ (CIS)...Cretostimogene grenadenorepvec (CG0070), an oncolytic vector, demonstrated a 47% 6-month CR rate in a phase II study (NCT02365818). Detalimogene voraplasmid (EG-70), a nonviral gene therapy, demonstrated a 47% 6-month CR in a phase I/II study (NCT04752722). Future advances are likely to focus on patient selection, novel vectors, and combination strategies to improve treatment outcomes. Gene therapy represents a significant addition to the bladder cancer treatment landscape by offering bladder-sparing alternatives where conventional therapies are limited.

P1, N=20, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | Trial completion date: Mar 2027 --> Sep 2027 | Trial primary completion date: Mar 2027 --> Sep 2027

P3, N=367, Active, not recruiting, CG Oncology, Inc. | Recruiting --> Active, not recruiting

P3, N=190, Active, not recruiting, CG Oncology, Inc. | Recruiting --> Active, not recruiting

Emerging BSTs include immune checkpoint inhibitors like pembrolizumab and novel agents such as nadofaragene firadenovec and nogapendekin alfa inbakicept (IL-15)...Gene therapies and targeted agents like CG0070 and EG-70 are also gaining traction for their innovative mechanisms...Despite advancements, challenges remain in balancing efficacy, safety, and cost-effectiveness within diverse healthcare settings. This narrative review highlights the evolving landscape of BSTs for HR-NMIBC, emphasising the need for robust clinical evidence to refine patient selection and optimise outcomes.