Investigative Targeted Agents Are Set to Expand the BCG-Unresponsive NMIBC Treatment Paradigm

Yair Lotan, MD

Several notable agents are emerging for the treatment of patients with Bacillus Calmette–Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC), according to Yair Lotan, MD, a professor of urology and chief of Urologic Oncology, as well as the Jane and John Justin Distinguished Chair in Urology at UT Southwestern Medical Center in Dallas, Texas.

Notable agents that Lotan highlighted in an interview with OncLive^® include TAR-200 and cretostimogene grenadenorepvec (CG0070) from the phase 2b SunRISe-1 (NCT04640623) and phase 3 BOND-003 (NCT04452591) trials, respectively. Furthermore, he discussed the safety profiles of these therapies, as well as the importance of staying informed throughout the rapid evolution of the NMIBC treatment field to determine optimal treatments for patients.

Lotan, who also serves as the medical director of the Urology Clinic at UT Southwestern and Parkland Health and Hospital System, shared more about NMIBC management in another article.

OncLive: What investigational agents may influence the NMIBC treatment paradigm in the future?

Lotan: There are several promising agents that are in trials that have completed enrollment [of patients with BCG-unresponsive NMIBC]; [these agents] will likely be approved in the next 12 to 18 months. Firstly, the SunRISe-1 trial [is investigating] TAR-200, which uses a novel drug delivery system, resulting in sustained local release of gemcitabine in the bladder. The device is inserted cystoscopically, or with a catheter, and then cystoscopy is used to remove it, and every 3 weeks, it’s replaced, at least in the first 6 months. TAR-200 delivers gemcitabine, an active drug, over a long period of time. The results of this trial have been presented at various meetings. Most recently, investigators presented data showing a complete response [CR] rate of 83.5% with TAR-200 monotherapy. [The estimated duration of response (DOR) rate was] 65.7% at 12 months, which is favorable.

With pembrolizumab [(Keytruda) in the phase 2 KEYNOTE-057 trial (NCT02625961)], the CR rate was 41% at 3 months, with an approximate 60% [DOR rate; the DOR rate was] approximately 22% to 23% at 1 year.

[In a phase 3 trial (NCT02773849) of] nadofaragene firadenovec-vncg [Adstiladrin], which is the virus that encodes for interferon, the CR rate was 53.4% at 3 months, with an approximate 50% DOR rate; 24.3% of patients were still responding at 1 year.

[In the phase 2/3 QUILT-3.032 trial [NCT03022825] of nogapendekin alfa inbakicept-pmln [Anktiva; N-803], which is an interleukin-15 [IL-15] super agonist given in combination with BCG, the CR rate was 62% at 3 months, but this was the rate of CR at any time; some patients were allowed to get retreated. The durability of response was good, with 58% of patients maintaining a response at 1 year.

Another trial was the BOND-003 trial, which evaluated the oncolytic virus cretostimogene grenadenorepvec, which bonds to Coxsackie adenovirus receptor cells and then uses the E2F promoter to get activated. It works by 2 different mechanisms: killing cells directly and stimulating the immune system. In BOND-003, [this agent elicited] a 75.7% CR at any time and a good durability of response.

The phase 1/2 LEGEND trial [NCT04752722] is investigating EG-70, a plasmid that carries nucleic acids that encode for an IL-12 cytokine and a retinoic acid–inducible gene, which stimulate the adaptive and innate immune systems. The phase 1 investigation of this intravesical therapy is complete, [and the agent is] in the phase 2 portion now. Early data seemed to show responses that were promising. This is still an ongoing trial, and we await durability of responses to determine whether [EG-70] will get approved and how it will fit with the other drugs in our armamentarium.

What are the safety profiles of these agents?

Both cretostimogene grenadenorepvec and TAR-200 performed well from a toxicity standpoint, with small percentages of grade 3 treatment-related toxicities and no grade 4 or 5 treatment-related toxicities. Most of the patients [in these trials] completed the recommended therapies. Most of the intravesical agents tend to do well from a toxicity standpoint, with just some local adverse effects. [However], the checkpoint inhibitors, [such as] pembrolizumab, [though more effective than the intravesical agents, are associated] with approximately a 10% to 15% higher rate of more severe immune-related toxicities, such as colitis and pneumonitis. Therefore, the intravesical agents may be favored by urologists relative to systemic agents especially for noninvasive disease.

What would you like colleagues to understand about the evolving NMIBC treatment paradigm?

Patients with BCG-unresponsive disease want alternatives to bladder removal. Many of these patients are older and sicker and would do well with avoiding a major operation with a [high] morbidity [risk]. However, even younger, healthier patients would prefer to keep their bladder, which would preserve urinary and sexual function.

This is a rapidly evolving field. We’ve had a new drug approved [for patients with NMIBC in 2024], we will probably have 2 new drugs approved in 2025, and maybe another the following year. We still have a lot to learn. [NMIBC research has largely consisted of] single-arm trials, not head-to-head comparisons. The true efficacy [of these novel agents] has to be taken with a grain of salt. There’s heterogeneity between how the population is treated, where patients are treated, and detecting carcinoma in situ, which is the main disease state for which [these agents are] being approved. It’s good that we have these agents, though urologists need to be aware of what’s available. They should discuss these agents with patients, so the patients can try to make informed decisions.

The intravesical drugs are relatively familiar in terms of their mechanism of action. These are treatments we’ve given. The main issue is going to be learning whether there is an optimal sequence [for NMIBC treatment]. How long is it safe to avoid removing the bladder?

There’s a window of opportunity [for further research]. We don’t know exactly when that window will close, and it’s important to tell patients that removal of the bladder is still the most definitive therapy and may be necessary down the road. If they’re willing to try 1 or 2 treatments, they are taking a risk, and so it needs to be an informed risk. For most urologists, keeping track of the new drugs and being prepared to discuss them with patients is the most important aspect [of treatment].