Gene Therapy for NMIBC: Efficacy & Safety Considerations

Emerging gene therapy strategies and evolving considerations for trial design are reshaping the research and treatment paradigms for patients with BCG-unresponsive,high-risk non-muscle-invasive bladder cancer (NMIBC),according to Alberto Martini,MD.

In an interview with OncLive^®, Martini discussed the favorable safety profiles of the intravesical therapies nadofaragene firadenovec-vncg (Adstiladrin), nogapendekin alfa inbakicept-pmln (Anktiva), and gemcitabine/docetaxel compared with pembrolizumab (Keytruda), which has been associated with higher rates of grade 3/4 adverse effects (AEs). He also highlighted novel investigational immune-activating agents, including the nonviral gene therapy detalimogene voraplasmid (EG-70), currently being investigated in the phase 1/2 EG-70-101 study (NCT04752722), and the oncolytic adenovirus therapy cretostimogene grenadenorepvec (CG0070), under evaluation in the phase 2 BOND2 trial (NCT02365818).

“It is indeed difficult to navigate the complex space of novel intravesical therapies,” Martini said.”When comparing the data, we should keep in mind that the trials were not designed the same way, and some results that might look better [than others] may be due to differences in trial design.”

Martini is an assistant professor in the Department of Internal Medicine at the University of Cincinnati College of Medicine and a genitourinary medical oncologist at the University of Cincinnati cancer Center in Ohio.

Read the first portion of OncLive‘s interview with Martini, where he discussed the current treatment arena for localized urothelial carcinoma, the role of intravesical chemotherapy in this population, and key data from pivotal clinical trials that have studied available therapies.

OncLive: What safety concerns have been observed with nadofaragene firadenovec, nogapendekin alfa inbakicept, gemcitabine/docetaxel, and pembrolizumabin patients with NMIBC?

Martini: These intravesical agents are generally well tolerated, with minimal toxicity. The rates of grade 3/4 AEs are less than 5% with nadofaragene firadenovec, nogapendekin alfa inbakicept, and the combination of gemcitabine and docetaxel.

This contrasts with pembrolizumab, which is associated with higher rates of grade 3 or 4 AEs. The initial publication of the phase 2 KEYNOTE-057 trial (NCT02625961) reported grade 3/4 AEs in 13%¹ of patients with carcinoma in situ, and 14%² of patients with high-grade Ta disease. These rates are higher than those seen with the intravesical agents and are not negligible.

What role might detalimogene voraplasmid play in advancing the treatment paradigm for patients with BCG-unresponsive NMIBC based on its mechanism of action?

Detalimogene voraplasmid is a nonviral gene therapy employing a dual approach to stimulate both the innate and adaptive immune systems.It delivers a double-stranded RNA, which is not found in human eukaryotic cells, triggering an innate response. It also delivers the gene for interleukin-12, which is then produced by cells, promoting immune activation. This is administered without surfactant of the glycocalyx. The EG-70-101 trial is being conducted at the University of Cincinnati Cancer Center, and we have observed encouraging results with this medication.

What role might cretostimogene grenadenorepvec play in the management of BCG-unresponsive NMIBC? How does the oncolytic adenovirus mechanism of action of this agent set it apart from other gene therapies?

Cretostimogene grenadenorepvec is another promising medication with encouraging published results. It is a form of gene therapy that differs from nadofaragene firadenovec in that it uses