Nadofaragene Firadenovec Sets the Stage for Gene Therapies in NMIBC

Vikram M. Narayan, MD

As investigators parse out the unique mechanism of action of nadofaragene firadenovec-vncg (Adstiladrin), which has set the stage as the first gene therapy approved for bladder cancer, additional gene therapies with unique mechanisms of action are under development in high-risk, BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC).¹

The proposed mechanism of action of nadofaragene firadenovec is likely due to the pleiotropic nature of interferon-α2b (IFN-α2b) and its direct and indirect antitumor activities, according to investigators. Vikram M. Narayan, MD, explained that the agent “includes a nonreplicating adenovirus that delivers the payload of IFNα-2b. IFN is an immune-stimulatory agent, and [clinicians] have previously given IFN in the bladder with BCG or by itself but have found limited efficacy. Nadofaragene firadenovec uses the adenoviral vector to deliver IFN directly into urothelial cells to hijack the machinery of urothelial cells to produce the IFNα-2b protein. Then that goes on to have immunomodulatory effects that result in tumor and cell death—you can trigger apoptosis [and] antiangiogenesis; there are various pathways.”

He added, “We see cell death with TRAIL-mediated apoptosis, antiangiogenesis, and increased antitumor activity of natural killer cells, which preferentially target bladder cancer cells. All those things taken together result in cell death.”

Narayan practices at Emory University Hospital and serves as director of urological oncology at Grady Memorial Hospital, and is an assistant professor in the Department of Urology at Emory University School of Medicine and a member of the Winship Cancer Institute in Atlanta, Georgia. He highlighted that the polyamide surfactant and synthetic excipient Syn3 is a key component of the gene therapy (Figure 1).¹

Figure 1. Mechanism of Action of Nadofaragene Firadenovec¹

“Syn3 is a detergent that helps break down the glycosaminoglycan layer of the bladder, [which] was historically thought to be why giving IFN alone would not work. One of the reasons why we can do every-3-month dosing with nadofaragene firadenovec is because we’re creating a bit of a bioreactor in the bladder of the patient to produce this IFNα-2b protein,” he explained.

As approximately 60% to 70% of patients with high-risk NMIBC are likely to experience recurrence and 10% to 45% may have disease progression to muscle-invasive or metastatic bladder cancer within 5 years, gene therapies provide a potential way to improve outcomes for patients. When looking at the standard of care with BCG, approximately one-third of this patient population will not respond to BCG, and among those who do experience an initial response, approximately 50% will experience recurrence or progression.¹

“[Nadofaragene firadenovec] is a gene therapy drug, but it’s a nonreplicating adenoviral vector. It has local effects,” Narayan said. “In studies, there was not systemic absorption or systemic effects noted. Understanding the immune-modulating effects of the drug [is important].”

Examining the Data With Nadofaragene Firadenovec

In the phase 3, single-arm trial supporting nadofaragene firadenovec’s approval, Study CS-003 (NCT02773849), the complete response (CR) rate at 3 months for adult patients with BCG-unresponsive NMIBC enrolled in the carcinoma in situ (CIS) cohort (n = 103) was 53.4% (95% CI, 43.3%- 63.3%). In the high-grade Ta or T1 disease cohort (n = 48), 72.9% (95% CI, 58.2%-84.7%) of patients were free of highgrade recurrence at 3 months.

Referencing the CIS cohort, Narayan said, “There’s still more work to be done. We would like to see those numbers [improve], but one of the hopes we have is to stimulate interest and discussion in ways that nadofaragene firadenovec can be augmented, combined with other therapies potentially, or maybe even redosed to improve that long-term CR rate.”

The duration of CR or high-grade recurrence-free survival for patients treated with nadofaragene firadenovec was 9.69 months (95% CI, 9.17-not estimable [NE]) in the CIS cohort vs 12.35 months (95% CI, 6.67-NE) in the high-grade Ta or T1 cohort. At 12 months, 24.3% (95% CI, 16.4%-33.7%) of patients with CIS were free from high-grade recurrence compared with 43.8% (95% CI, 29.5%-58.8%) of those with high-grade Ta or T1 disease. Notably, 45.5% of patients who reached a CR at 3 months in the CIS cohort maintained this through 12 months.

In the trial, patients received 75 mL of the gene therapy via intravesical instillation—3 × 10¹¹ viral particles/ mL—once every 3 months for up to 12 months or until unacceptable toxicity or recurrent high-grade NMIBC.³ In the absence of high-grade recurrence, patients were allowed to continue nadofaragene firadenovec every 3 months. Notably, the median number of prior BCG instillations was 12 (range, 8-18), and the median number of nadofaragene firadenovec instillations was 2 (range, 1-5).⁴

“Clinicians will likely be very familiar with the handling and other operational pieces [of nadofaragene firadenovec],” Narayan noted. “The one thing that clinicians need to know is it’s shipped frozen on dry ice [and] does need to be thawed and then used within 24 hours, or it needs to be stored frozen until it’s used. In terms of handling, it’s very similar to BCG.”

Narayan also noted that nadofaragene firadenovec was well tolerated and that the safety profile of the agent observed in CS-003 was similar to that of BCG. In the safety population (n = 157), grade 1 or 2 adverse effects (AEs) included instillation site discharge (33%), fatigue (24%), bladder spasm (20%), micturition urgency (19%), hematuria (17%), dysuria (16%), chills (16%), and pyrexia (15%). No grade 4 or 5 AEs were observed and only 1.9% of patients discontinued treatment while on study (Figure 2).⁴

Figure 2. Adverse Effects Observed in Study CS-003

Data that supported the approval came from 98 patients in the BCG-unresponsive CIS cohort of CS-003; patients achieved a CR rate of 51% (95% CI, 41%-61%) with a median duration of response (DOR) of 9.7 months (range, 3 to 52+), and 46% of responding patients remained in CR for at least 1 year.³

“The American Urological Association [AUA] guidelines recently included nadofaragene firadenovec as an option for patients with BCG-unresponsive NMIBC. Patients are now coming to us in the clinic asking about this treatment, to know more about it and have access to it,” Narayan added.

The AUA guidelines include nadofaragene firadenovec under the “Intravesical Therapy; BCG/Maintenance; Chemotherapy/BCG Combinations” section. The section notes that a physician may recommend nadofaragene firadenovec as an alternative intravesical therapy for patients with persistent or recurrent high-grade NMIBC who are not candidates for or do not want cystectomy within 12 months of completion of adequate BCG therapy; BCG therapy includes 2 induction courses or 1 induction course plus 1 maintenance cycle. Alternatives to the gene therapy include clinical trials or intravesical chemotherapies such as gemcitabine or docetaxel.⁵

Furthermore, Narayan noted that “the question of whether redosing nadofaragene firadenovec [is ideal remains]. In the original trial, if therapy failed or patients had recurrence of high-grade disease, they would not get additional treatments; they would be switched to an alternative therapy because when we were designing [the CS-003] trial, the interest was to make sure that patients were safe and not given treatments that wouldn’t work. Now that we have data on efficacy, it’s reasonable to see whether a second treatment does offer benefit if a patient recurs initially. There’s justification for that [because] patients will often get repeat induction BCG, and some of the other drugs that are being developed in this space also have redosing regimens if they have failures.”

Further Novel Therapies Are Under Evaluation in BCG-Unresponsive Disease

The investigational engineered oncolytic immunotherapy cretostimogene grenadenorepvec (CG0070) received both fast track and breakthrough therapy designations from the FDA in December 2023 for the treatment of patients with high-risk BCG-unresponsive NMIBC with CIS with or without Ta or T1 tumors.⁶ Cretostimogene grenadenorepvec was designed to preferentially replicate in retinoblastoma gene pathway–defective cells that are present in most urothelial carcinomas and trigger an antitumor immune response. Modifications made for tumor selectivity and potency to the agent include the insertion of an E2F1 promoter and the insertion of the gene for the cytokine granulocyte-macrophage colony stimulation factor⁷ (Figure 3).⁸

Figure 3. Alternative Agents to BCG Therapy in NMIBC⁸

Findings from the phase 3 BOND-003 trial (NCT04452591) revealed that 75.7% of patients with high-risk BCG-unresponsive NMIBC treated with cretostimogene grenadenorepvec (n = 66) achieved a CR; the 3- and 6-month CR rates were 68.2% and 63.6%, respectively.⁹ Additionally, interim results from the phase 2 BOND-002 trial (NCT02365818) demonstrated this patient population (n = 45) experienced a 47% (95% CI, 32%-62%) CR rate at 6 months. Cretostimogene grenadenorepvec was well tolerated with no grade 4 or 5 AEs observed; grade 3 treatment-related effects included dysuria (3.0%) and hypotension (1.5%).¹⁰

The agent is currently under evaluation for NMIBC in the phase 3 PIVOT-006 trial (NCT06111235), which is currently recruiting patients in the US and Canada. It is also being examined in combination with pembrolizumab (Keytruda) in the active phase 2 CORE-001 trial (NCT04387461).¹¹

“Gene therapy is emerging as a [potential] significant option for patients who have BCG-unresponsive disease and bladder cancer in general,” Narayan said. “We’re likely going to see more of [these therapies], and we may even look at different payloads [of nadofaragene firadenovec in particular], but the bladder is a natural cavity for safe gene therapy treatment options because it’s easily accessible via catheter, you can provide contact-based delivery of the drugs that you’re using, and we know from preclinical data that for many agents, the absorption systemically is very low, assuming there isn’t a raw surface or something along those lines or active hematuria. For that reason, [in] bladder cancer at least in the antitumor space, there’s a lot of interest in gene therapy. With the approval of nadofaragene firadenovec, we’ll likely see other agents emerge as well in this space.”

Detalimogene voraplasmid (EG-70) has also emerged in the gene therapy space, receiving fast track designation from the FDA in 2020 for BCG-unresponsive NMIBC.¹² The nonviral gene therapy is a nanoparticle formulation of plasmids; the plasmid encodes IL-12 and activators of the innate immune receptor RIG-I. The agent elicited a 3-month CR rate of 71% in patients with CIS (n = 17), according to data presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium from the phase 1/2 LEGEND trial (NCT04752722).

What Remains in NMIBC?

“The biggest unmet need is having a durable treatment for BCG-unresponsive NMIBC. The concern that patients have [occurs] when we tell them they [did not respond to] BCG and all the other treatments we have are not as efficacious or they involve life-altering surgery in the form of removal of the bladder. When we compare this with pembrolizumab, which was also FDA approved, the big advantage that nadofaragene firadenovec offers is that it’s given in the bladder intravesically and dosed once every 3 months,” Narayan explained. “[This] is a much more favorable dosing regimen for patients than once a week for 6 weeks [with other treatment options].”

Pembrolizumab’s January 2020 approval for patients with BCG-unresponsive, highrisk NMIBC with CIS with or without papillary tumors was based on data from the phase 2 KEYNOTE-057 trial (NCT02625961). Patients in this population (n = 96) experienced a CR rate of 41% (95% CI, 31%-51%) with a median DOR of 16.2 months (range, 0.0+ to 30.4+).¹⁴

Although options for patients with high-risk, BCG-unresponsive NMIBC have expanded for patients who are ineligible for or decline cystectomy to include intravesical chemotherapy, pembrolizumab, and nadofaragene firadenovec, combination therapies may be on the horizon. Narayan noted that it is worthwhile to consider combination strategies with nadofaragene firadenovec to augment responses.

References

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