Single-Arm Pivotal Studies in Bacillus Calmette-Guérin–Unresponsive Non–Muscle-Invasive Bladder Cancer

In 2025, approximately 85,000 patients will be diagnosed with bladder cancer.¹ Of these, approximately 80% are non–muscle-invasive bladder cancer (NMIBC). Risk categorizations in NMIBC are designated according to progression risk, and the high/very high-risk population includes Bacillus Calmette-Guérin (BCG)–unresponsive carcinoma in situ with or without papillary (CIS ± Ta/T1) disease. Classical management of BCG-unresponsive CIS ± Ta/T1 is radical cystectomy with pelvic lymphadenectomy, resulting in a high unmet need for bladder-sparing approaches.

THE TAKEAWAY

• In the article that accompanies this editorial, the SunRISe-1² investigators evaluated the TAR-200 drug-releasing system in Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer. It is a pivotal study in BCG-unresponsive carcinoma in situ with or without papillary disease. TAR-200 is a first-in-class intravesical drug-releasing system intended to provide sustained delivery of gemcitabine into the bladder, whose major advantages include robust activity, acceptable safety, and dosing simplicity.

In the article that accompanies this editorial, the SunRISe-1² investigators evaluated the TAR-200 drug-releasing system as a bladder-sparing approach in BCG-unresponsive NMIBC. It is a pivotal study in BCG-unresponsive CIS ± Ta/T1 disease. TAR-200 is a first-in-class intravesical drug-releasing system intended to provide sustained delivery of gemcitabine into the bladder, whose major advantages include robust activity, acceptable safety, and dosing simplicity. SunRISe-1 was a noncomparative 3-arm study: cohort C1 (TAR-200 + cetrelimab [anti-PD1]), cohort C2 (TAR-200 monotherapy), and cohort C3 (cetrelimab monotherapy). Counterintuitively, TAR-200 monotherapy cohort C2 demonstrated the highest preliminary activity and was expanded to provide the basis for US Food and Drug Administration (FDA) approval. This cohort produced a clinically meaningful complete response (CR) rate of 82.4%, median duration of response (DOR) of 25.8 months, and 52.9% of patients having DOR ≥ 12 months. Classically, a CR rate whose 95% CI lower bound exceeds a 20% futility threshold with a median DOR of >12 months is considered clinically meaningful.³ In this editorial, we will detail the regulatory history behind the precedent for single-arm registrational studies, highlight controversies surrounding its assumptions, and provide context for careful interpretation of single-arm NMIBC studies.

Regulatory History of Single-Arm Pivotal Studies

For over 20 years after valrubicin's approval in 1998,⁴ no therapies were approved in BCG-unresponsive NMIBC. In response to this unmet need, the FDA held a public workshop in 2013 to align with stakeholders on end points and study design, which ultimately led to the 2018 and 2024 guidance statements.^5,6 Although randomized trials are required for papillary disease because of its surgical responsiveness to transurethral resection of bladder tumor (TURBT), single-arm studies were deemed acceptable for approval in BCG-unresponsive CIS ± Ta/T1 under the assumptions that (1) carcinoma in situ (CIS) is not resectable by TURBT; (2) the natural history of CIS is well understood to persist and progress; and (3) random assignment is either unethical or not feasible. These efforts proved largely successful, and since the guidelines were published, pembrolizumab,³ nadofaragene firadenovec,⁷ and BCG + nogapendekin alfa inbakicept-pmln⁸ have been approved. On the horizon, the accompanying article's TAR-200² and cretostimogene grenadenorepvec⁹ show promising clinically meaningful activity and tolerability profiles. Additionally, although not conducted under FDA standards with the majority of evidence retrospective in nature, gemcitabine/docetaxel combination is an available generic option.¹⁰ Given the rapid development of the field, cystectomy is no longer standard of care at our site and has been replaced with gemcitabine/docetaxel, the FDA-approved novel agents, and clinical trial enrollment.

Single-arm studies as the basis for FDA approval in CIS is not without controversy. For example, although CIS is classically considered unresectable by TURBT and understood to persist, there are some reports of cystectomy performed for CIS with no cancer identified on the final specimen, suggesting responsiveness to initial TURBT.¹¹ For such tumors, a time-to-event end point would be required in a randomized setting, similar to that in papillary disease. Additionally, responses to continuation of treatment at the first observation of nonresponse (so-called reinduction) would be upwardly biased by surgical response because continued treatment is immediately preceded by surgical resection. Furthermore, FDA stated in its 2018 guidance that if effective therapies become available in BCG-unresponsive NMIBC, a randomized trial may be appropriate and reiterated its preference for random assignment in the 2024 guidance.⁶ We agree that random assignment is not feasible in a paradigm where cystectomy is standard of care, but opine that someday it may be when nonsurgical therapies are more commonplace.

Difficulties Interpreting Single-Arm Studies

Assuming CIS is not resectable by TURBT, the natural history of CIS is well understood to persist and progress, and random assignment is either unethical or not feasible, then single-arm studies are certainly interpretable. However, no matter how well-conducted the study may be, the end points are still prone to biases that should be carefully considered. CRs are identified by the absence of disease, which is a composite of cytology and cystoscopic evaluation (with subsequent tissue sampling). Although all cytologic specimens can be centrally verified, cystoscopic visualization is not. Under for-cause tissue sampling, the subjective interpretation of the cystoscopy determines whether to proceed to biopsy/TURBT. This directionally biases the CR rates upward because some CIS will be visually missed. Even when sampling is performed, the selection of which and how much tissue to biopsy is prone to bias. This bias is partly mitigated by mandatory biopsy with standardized template,¹² which in SunRISe-1 was performed at 24 and 48 weeks. It is important to note that most patients reported in the primary CR rate of 82.4% were not under conditions of mandatory biopsy, and some of the nondurable responders who were identified 3 months after CR (ie, week-24/month-6 tumor evaluation) may have had occult disease at the primary end point which were missed because of lack of mandatory biopsy. Thus, we agree with the FDA's view that the primary end point, CR rate, cannot be viewed in isolation, and clinical meaningfulness can only be established in the context of durability.

We applaud the SunRISe-1 study for performing two mandatory biopsies at 24 and 48 weeks, which provides additional robustness to the durability end point and is beyond typical FDA standards. Under rigorous sampling conditions, the median DOR is 25.8 months with 52.9% of patients demonstrating DOR ≥ 12 months. For these patients, there is little debate as to the clinical meaningfulness of response. The risk/benefit analysis is further reinforced by acceptable tolerability: only 12.9% grade 3 or greater TEAEs, and although 31.8% of patients interrupted TAR-200, only 3.5% discontinued treatment entirely. Given these data, counseling may be required to encourage patients to continue treatment after interruption; otherwise the full benefit of durability may be compromised.

If TAR-200 is FDA approved, it will be the fourth novel agent approved since the publication of FDA's 2018 guidance. Because all therapies were developed on a noncomparative basis, clinicians will need to rely on careful interpretation of each single-arm cohort and take into consideration efficacy, safety, simplicity of dose/dose regimen, patient access/affordability, mechanism of action, and a patient's prior exposure to other therapies. For example, there are limited data on administering TAR-200 before or after gemcitabine/docetaxel, and it is unclear whether sequencing two gemcitabine-based therapies would produce adequate cancer control. On the basis of mechanism of action, one may opt to avoid sequencing gemcitabine-based regimens. Because all of the novel agents were developed in the second-line setting after BCG, future studies need to be performed in third- and later line settings to identify the optimal sequence before cystectomy.

Discussion

In conclusion, we congratulate the study team for SunRISe-1, their patients, regulators, and sponsors for this collaborative and successful trial. We have participated in several NMIBC studies over the past decades and have observed major advances in the quality of studies supporting substantial evidence of safety and efficacy. We emphasize that there is still more to progress to be made and are looking forward to future study designs in this space.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Single-Arm Pivotal Studies in Bacillus Calmette-Guérin–Unresponsive Non–Muscle-Invasive Bladder Cancer

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