Introduction

Bacillus Calmette-Guérin (BCG) has long remained the standard of care for patients with high-risk nonmuscle-invasive bladder cancer (NMIBC). Unfortunately, the failure rate of BCG ranges between 30% and 50%, and historically there has been a paucity of second-line therapies. Until recently, limited treatment options were available for high-risk, BCG-unresponsive NMIBC aside from early cystectomy. Fortunately, there has been tremendous effort and resources focused on expanding treatment options.

Food and Drug Administration–Approved Therapies

In 2020, pembrolizumab, an antiprogrammed cell death protein 1 antibody, was approved by the Food and Drug Administration (FDA) for the treatment of BCG-unresponsive, high-risk NMIBC. In KEYNOTE-057, a single-arm, phase 2 study evaluated pembrolizumab in patients with carcinoma in situ (CIS) ± high-grade Ta or T1 tumors (cohort A) and patients with only papillary tumors (cohort B), who were ineligible or unwilling to undergo radical cystectomy.¹ Pembrolizumab was given every 3 weeks for up to 24 months or until disease recurrence, progression, or unacceptable toxicity. In cohort A, 41.7% of patients achieved clinical complete response (CR) at 3 months; however, the 12-month CR rate was 19%. In patients with papillary-only disease, the 12-month disease-free survival was 43.5%. About 14% of patients suffered grade 3 or 4 adverse effects between the cohorts. Due to the relatively low durability of response and the burden of serious systemic treatment-related adverse events (TRAEs), pembrolizumab has not gained widespread use among urologists.

Nadofaragene firadenovec is the first FDA-approved intravesical gene therapy for the treatment of BCG-unresponsive NMIBC. Nadofaragene firadenovec is a nonreplicating adenoviral vector-based gene therapy administered into the bladder once every 3 months for up to 12 months. In a multicenter, single-arm trial, 157 patients with high-risk NMIBC (CIS ± high-grade Ta or T1 tumor) were enrolled with repeat dosing every 3 months in the absence of high-grade recurrence or unacceptable toxicity.² Of the patients, 53.4% had a CR within 3 months of the first dose with a 12-month CR rate of 24.3%. Cystectomy-free survival at 60 months was 49% in the CIS ± papillary tumor cohort and 43% in the papillary tumor–only cohort. Only 5 patients experienced clinical progression to muscle-invasive disease at 60 months. Urinary symptoms were the most common TRAEs, and only 4% of patients developed grade 3 or higher TRAEs. Importantly, the dosing schedule is convenient for patients, especially those traveling long distances.

The QUILT trial evaluated the addition of interleukin-15 receptor agonist, nogapendekin alfa inbakicept (NAI), to BCG reinduction.³ NAI activates the body’s natural killer and killer T-cell immune system to attack tumor cells. Patients with CIS ± high-grade Ta or T1 tumor (cohort A) or high-grade papillary tumors only (cohort B) were treated with NAI plus BCG once a week for 6 weeks with an option for reinduction if there was persistent disease without progression and maintenance therapy every 3 months after. In cohort A, CR rate was 55% at 3 months and the 12-month CR rate was 45%. The median duration of response was 26.6 months. In cohort B, the disease-free survival was 19.3 months with 55% of patients remaining disease free at 12 months. The cystectomy rate was 16% in cohort A and 7% in cohort B. There were no grade 4 or 5 TRAEs. This treatment option is promising; however, there may be limited access due to the BCG shortage.

Ongoing Trials

The SUNRISE-1 trial is a phase 2b study evaluating TAR-200 monotherapy in patients with BCG-unresponsive high-risk NMIBC with CIS ± high-grade Ta or T1 tumors who are ineligible for or decline radical cystectomy.⁴ TAR-200 is a novel targeted releasing system designed to provide extended release of gemcitabine directly into the bladder. A silicone device, frequently referred to as a “pretzel,” is administered into the bladder with a quick 3- to 5-minute procedure in the office every 3 weeks for 12 weeks and every 12 weeks thereafter. The study began with a cetrelimab-only arm as well as a cetrelimab with TAR-200 combination arm. Both of these arms were closed early due to the high response rates achieved with TAR-200 monotherapy in cohort 2. Eighty-five patients received TAR-200 monotherapy with a CR rate of 82.8%. TRAEs were present in 71.8% of patients and included predominantly urinary symptoms, such as pollakiuria, dysuria, urgency, and UTIs. Grade 3 or higher TRAEs were present in 8.2% of the patients. These promising results led to the FDA granting breakthrough therapy designation for TAR-200.

Cretostimogene grenadenorepvec is a novel recombinant oncolytic adenovirus that selectively infects and replicates in tumor cells and leads to tumor cell lysis. One hundred twelve patients with high-risk BCG-unresponsive NMIBC (CIS ± high-grade Ta or T1 tumor) enrolled in the phase 3 BOND-003 trial.⁵ Patients received an induction course at enrollment, followed by maintenance every 12 weeks if there was no disease recurrence, or repeat induction if there was disease present. The overall CR rate at any time point for all patients was 75.2%. Early results demonstrated a 6-month CR of 63.6%, with durability data still pending. There were no grade 3 or greater TRAEs, and the most common adverse events were related to urinary symptoms. This led to the FDA granting cretostimogene a fast track and breakthrough therapy designation.

Retrospective Data

Sequential intravesical gemcitabine and docetaxel therapy has for many years been the preferred rescue therapy for BCG-unresponsive NMIBC. A multi-institutional retrospective study evaluated patients with BCG-unresponsive NMIBC, given as a 6-week induction course, followed by maintenance therapy.⁶ The 12-month recurrence-free survival rate was 60%, with 15.6% of patients undergoing cystectomy. In this retrospectively selected patient population, sequential intravesical gemcitabine and docetaxel therapy offered patients an alternative therapy for BCG-unresponsive NMIBC.

Conclusion

The treatment landscape for BCG-unresponsive NMIBC is rapidly changing. In the last 5 years, 3 drugs have gained FDA approval with more upcoming approvals likely. Patients now have more bladder preservation options with higher response rates. Patients will likely continue to benefit from the continued progress ongoing in this space with additional treatment options on the horizon.