Pivotal Study Data Support Further Research in BCG-Unresponsive, High-Risk NMIBC

Reviewing clinical trial data with approved intravesical and systemic therapy approaches for patients with BCG-unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) reinforces the clinical rationale for the use of agents beyond the historical standard of BCG in this population, according to Alberto Martini, MD.

Key studies in this population, including the phase 3 CS-003 trial (NCT02773849) of nadofaragene firadenovec-vncg (Adstiladrin), the phase 2/3 QUILT 3.032 trial (NCT03022825) of nogapendekin alfa inbakicept-pmln (Anktiva), and the phase 2 KEYNOTE-057 trial (NCT02625961) of pembrolizumab (Keytruda), have defined the current paradigm. In addition, the off-patent combination of gemcitabine and docetaxel continues to offer a low-cost alternative supported by multi-institutional analyses.

“A few years ago, we did not have many options for our patients with BCG-unresponsive disease. Now we have quite a few, and there will likely be even more available in the next 5 to 10 years. It would be useful to see a head-to-head comparison [between available options], possibly in the form of a multi-arm prospective trial,” Martini explained in an interview with OncLive®.

In the interview, Martini discussed how nadofaragene firadenovec, pembrolizumab, and nogapendekin alfa inbakicept each fit into the NMIBC treatment paradigm, highlighted the role of intravesical vs systemic approaches, and addressed safety and cost considerations that guide clinical decision-making.

OncLive: What does the current treatment arena look like for urothelial carcinoma? How do intravesical therapies fit into that paradigm?

Martini: We have many options for patients with localized urothelial carcinoma, and those options are dependent on the patient’s stage and risk category. For example, for patients with high-risk bladder cancer—specifically high-risk NMIBC—the first-line treatment should be a course of BCG followed by maintenance in the absence of recurrence. In the case of recurrence, we can consider alternative options.

[Today, we have] therapies and treatment approaches for patients who progress on first-line treatment, which is generally BCG. An alternative to BCG could be a combination of 2 chemotherapeutic medications: gemcitabine and docetaxel, which are administered with BCG. In the case of [treatment] progression, we have different options available for our patients.

What significant data have emerged from the key trials evaluating updates to the NMIBC treatment paradigm?

Over the past few years, we’ve seen several trials published in this domain. One of the main ones that led to the approval of a novel medication is the CS-003 study on the first gene therapy approved by the FDA for patients with BCG-unresponsive NMIBC: nadofaragene firadenovec. Findings from that single-arm trial were published in 2021. [This trial included] 151 patients in the per-protocol analysis.¹ [53.4]% of [evaluable] patients were disease free at 3 months, and [45.5%] of [evaluable] patients maintained a complete response [CR] at 12 months. In this pragmatic study, all patients underwent biopsy at 12 months. Approximately 10% of [evaluable] patients without apparent disease at 12 months were found to have occult disease on biopsy. This was a peculiarity of this trial.

In the [QUILT 3.032] trial that led to the approval of nogapendekin alfa inbakicept— a superagonist of interleukin-15 that is administered with BCG—we found similar efficacy data, with 62% of patients having a CR at 3 months and a CR rate of 58% at 12 months.² However, in this trial, patients were allowed to receive a second induction in case of progression at 3 months, and they also did not undergo a biopsy at the end of the study, at 12 months. [It is] likely that this higher [response] rate could be ascribed to higher efficacy of [nogapendekin alfa vs nadofaragene firadenovec] but also could be due to the different trial designs.

Another trial that led to the approval of systemic therapy [for this population] in the form of pembrolizumab is KEYNOTE-057. In the KEYNOTE-057 study, we observed a lower response rate relative to nadofaragene firadenovec [in CS-003], with a 41% CR rate at 3 months, and 46% of patients maintaining a CR at 12 months.³

In KEYNOTE-057, an end-of-study biopsy at 12 months was not mandated, [so the design differences [between all 3 of these trials need to be kept in mind]. When we compare the results of the different studies, the results we see at 12 months seem a little different, but they can also be due to the different study designs across the trials.

What is the enduring role of chemotherapy in the management of BCG-unresponsive NMIBC?

Another alternative to those medications, which are expensive, is the combination of gemcitabine and docetaxel. These are 2 medications for which the patents expired several years ago, making the regimen inexpensive. We have seen good results [with this combination] at 3 months and 6 months, so this is the cheapest option with encouraging results. The issue with the gemcitabine/docetaxel data is that they were mostly collected through multi-institutional analyses and not in a prospective trial. There may be some heterogeneity in the data, but despite that, the results that have been reported in the literature are good and encouraging.

References

1. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4
2. FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. FDA. April 22, 2024. Accessed August 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle-invasive-bladder-cancer
3. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. FDA. January 8, 2020. Accessed August 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer