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), which is being investigated in the phase 1/2 EG-70-101 study (NCT04752722), and the oncolytic adenovirus therapy cretostimogene grenadenorepvec (CG0070), which is under evaluation in the phase 2 BOND2 trial (NCT02365818).
“It is difficult to navigate the complex space of novel intravesical therapies,” Martini said in the interview. “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.
Revisit 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.
We need to differentiate that from [the safety profile of] pembrolizumab, which is associated with [higher] rates of grade 3 or 4 AEs. The first publication [of the phase 2 KEYNOTE-057 trial (NCT02625961) with this agent] in patients with carcinoma in situ reported [grade 3/4 AEs at a rate of] 13%,1 and [this rate was] 14% in patients with high-grade Ta disease.2 [These rates are higher] than [those seen with the] the intravesical agents, and this seems consistent across both studies. [These AEs are] not negligible, and we should keep that in mind.
What role might detalimogene voraplasmidplay in advancing the treatment paradigm for patients with BCG-unresponsive NMIBC based on its mechanism of action?
[Detalimogene voraplasmid] is a nonviral gene therapy that uses a dual approach aimed at stimulating both the innate and adaptive immune systems. It works by delivering a double-stranded RNA, which does not exist in human eukaryotic cells and triggers an innate response. It also delivers the gene for interleukin-12, which is then produced by the cells and promotes immune activation. This administered without surfactant of the glycocalyx. [The EG-70-101] trial is 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?
Another medication, results with which have already been published and are encouraging, is called cretostimogene grenadenorepvec. This is another form of gene therapy. It differs from nadofaragene firadenovec in that the viral vector it uses is also an adenovirus, but it is an oncolytic adenovirus.
That means [cretostimogene grenadenorepvec] replicates in bladder cancer cells, specifically in those that are RB deficient—RB being a gene responsible for cell cycle regulation. The virus replicates in those cells and has a direct killing effect. It also carries the transgene for granulocyte-macrophage colony-stimulating factor, which is intended to activate the immune system in this context as well.
References
- Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930. doi:10.1016/S1470-2045(21)00147-9
- Necchi A, Roumiguié M, Kamat AM, et al. Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2024;25(6):720-730. doi:10.1016/S1470-2045(24)00178-5