MoonRISe-1: TAR-210 for Intermediate-Risk NMIBC

Roger Li, MD, of the Moffitt Cancer Center, provides commentary on the rationale, design, and potential impact of the MoonRISe-1 study, which focuses on TAR-210—a drug-eluting stent that delivers erdafitinib directly to the bladder—for intermediate-risk non-muscle invasive bladder cancer (NMIBC).

Dr. Li covers eligibility criteria, using urinary circulating tumor DNA (ctDNA) to detect FGFR alterations, and the promise of TAR-210 to provide an effective, low-toxicity treatment option for these patients.

Could you explain the rationale behind the MoonRISe-1 study? Why was this study deemed necessary?

Dr. Li: There is still a critical need in the intermediate-risk NMIBC space. Despite the available treatment agents, the disease recurrence rate in this patient population remains high, underscoring the need to develop newer and more efficacious drugs.

This was the reason TAR-210 was tested, initially in a first-in-human trial where a marker lesion was left in situ in patients with intermediate-risk NMIBC to be treated with TAR-210. TAR-210 is a drug-eluting intravesical delivery system placed inside a patient’s bladder via an office-based procedure. It is unique in that it constantly emits erdafitinib, a tyrosine kinase inhibitor that targets tumors with FGFR gene alterations. Erdafitinib is approved in the United States for the treatment of metastatic and locally advanced urothelial carcinoma (UC) with FGFR3 alterations after 1 line of systemic treatment.

It has also been tested previously in intermediate- and high-risk NMIBC settings using an oral (PO) formulation. The problem with the PO formulation is that, despite showing efficacy in the THOR-2 trial, there was significant toxicity, similar to what was seen in the THOR-1 trial with patients having metastatic and locally advanced UC. In the intermediate-risk NMIBC setting, patients are less willing to tolerate these toxicities as their disease is much lower in risk and less likely to lead to progression and cancer-specific deaths.

The impetus behind TAR-210 is to utilize an intravesical delivery system to decrease the toxicity seen with PO erdafitinib. In the first-in-human study, we observed not only great efficacy with the drug but also a lack of toxicity, which is very promising.

What is the trial design, and what are the key eligibility criteria and stratification factors?

Dr. Li: MoonRISe-1 is a phase 3, randomized, controlled trial that will be conducted globally across multiple continents in 20 different countries. The study will enroll patients with intermediate-risk NMIBC who are low grade, but have at least 1 risk factor per the International Bladder Cancer Group risk criteria. These risk factors include tumors greater than 3 cm in diameter, recurrent tumors, tumors previously treated with intravesical agents, or multifocal tumors.

Patients will be randomized (1:1) to receive either TAR-210, which will be exchanged every 12 weeks for up to 1 year in the absence of disease recurrence, or intravesical chemotherapy (either mitomycin C or gemcitabine) scheduled with an induction course of 4 to 6 weekly doses followed by a 6- to 12-month maintenance course.

Patients will also need molecular screening to qualify for the trial. They must be found to have an FGFR2 or FGFR3 alteration, which can be determined using tumor tissue samples. Uniquely, this trial will also use urine samples collected at the start of the trial. If FGFR2 or FGFR3 alterations are found in the urine using a urinary ctDNA platform, the patient can be enrolled.

Additionally, patients will be stratified by whether the tumor is recurrent or primary, whether the tumor is diagnosed using white light cystoscopy or photodynamic cystoscopy, and the type of chemotherapy intended for treatment.

The primary end point for this study is disease-free survival, independent of grade or stage. Secondary end points include progression-free survival, cystectomy-free survival, cancer-specific survival, and others.

In summary, MoonRISe-1 will compare the efficacy of TAR-210 used in the adjuvant setting against the current standard of care, which is intravesical chemotherapy, in preventing disease recurrence in this patient population.

Why was urinary ctDNA chosen for this study to identify FGFR alterations?

Dr. Li: In this disease setting, many patients have very small tumor volume, which impairs the quality of next-generation sequencing (NGS) performed interrogate the relevant genomic alterations.

We published a study earlier this year that examined the complementarity between urinary-derived ctDNA and that from tissue samples. While each method alone yielded about 60% sufficiency for NGS, using both methods together provides up to 90% sufficiency for FGFR testing. This combinatory strategy significantly increases the number of patients who can enroll onto the study, which is why we are choosing to use both urine and tissue samples.

How far into the accrual process is MoonRISe-1?

Dr. Li: The study opened on April 10, 2024. It is going to be conducted in 20 countries across 4 different continents globally. As of a couple of weeks ago, when the data were originally presented at AUA2024, 8 sites in the United States were already open, plus an additional site in Israel. At that time, 10 patients were undergoing molecular screening.

These are exciting times. Even though we are in the beginning stages of the trial, we are all very enthusiastic about the possibilities given the preliminary results seen in the first-in-human study. We are hopeful that this study will potentially bring an efficacious, safe, and easy-to-deliver treatment option for patients with intermediate-risk NMIBC.

How do you believe TAR-210 will fare in this study and ultimately fit into the treatment paradigm for patients with FGFR-altered intermediate-risk NMIBC?

Dr. Li: I am very enthusiastic about this trial for several reasons. First, erdafitinib treatment for intermediate-risk NMIBC makes a lot of sense because up to 80% of tumors in this disease setting will harbor an FGFR alteration, compared with 15-30% in the metastatic setting. Moving this treatment into the intermediate-risk NMIBC space is logical, and having an agent that can deliver the treatment with minimal toxicity, as seen in the first-in-human study, is exciting.

Second, we see many patients in our clinics with intermediate-risk NMIBC, and we try various treatment modalities. However, these patients often experience disease recurrence, have multiple tumors in their bladder, requiring numerous surgeries, surveillance cystoscopies, and intravesical treatments, often with limited effectiveness. A platform that provides durable response and prevents disease recurrence while limiting the number of procedures needed to treat and diagnose the cancer is very promising.

Third, bladder cancer has lagged behind other cancer types in adopting targeted therapy due to its vast molecular heterogeneity. Introducing a targeted agent for such a large proportion of patients with bladder cancer is exciting.

Finally, the molecular detection of FGFR and other targets using urine samples sets the standard for future studies. Urine is a rich platform for diagnostic tests, enabling us to practice bona fide precision medicine. Coupled with the TARIS platform, we can deliver not only erdafitinib but also other small molecules, as seen in the SunRISe trials using TAR-200 to deliver gemcitabine, and potentially other agents in the future.

We are truly on the cusp of delivering precision medicine powered by diagnostics derived from easily accessible urine samples, with a treatment platform that can provide efficacy without significant toxicity. All these factors combined make me very excited about what the future holds.