Non-Muscle-Invasive Bladder Cancer -- Intravesical BCG and Beyond

— Treatment landscape for BCG-unresponsive bladder/urothelial cancer is expanding

Illustration of 5 circles with different treatment options over over a bladder with urothelial cancer
Key Points

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The goals of therapy for non-muscle-invasive bladder cancer (NMIBC) are to (1) prevent tumor progression and recurrence and increase the cure rate using appropriate, aggressive therapy for high-risk tumors, and (2) avoid overtreatment for low-risk tumors.

While the cure rate with cystectomy in this setting is almost 100%, "most patients mainly want to avoid cystectomy, so a substantial delay is important," noted Michiel Van der Heijden, MD, PhD, of the Netherlands Cancer Institute in Amsterdam. "Another important point is that the rate of progression to muscle-invasive disease should be low."

As such, following transurethral resection of the bladder tumor (TURBT), risk stratification guides the initial selection of therapy in patients with NMIBC. Risk according to updated guidelines from the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) is defined as the following:

  • Low-risk: A primary single Ta/T1 low-grade/G1 tumor ≤3 cm in diameter without carcinoma in situ (CIS) in a patient younger than age 70
  • Intermediate-risk: Recurrent low-grade Ta tumor within 1 year, a solitary low-grade Ta tumor >3 cm, multifocal low-grade Ta tumor, high-grade Ta tumor ≤3 cm, low-grade T1 tumor
  • High-risk: High-grade T1 tumor, any recurrent high-grade Ta tumor, high-grade Ta tumor >3 cm (or multifocal), any CIS, failure of Bacillus Calmette-Guérin (BCG) therapy in any patient with a high-grade tumor, tumor of any variant histology, any lymphovascular invasion, any high-grade tumor with prostatic urethral involvement

Risk Stratification

Risk stratification per the National Comprehensive Cancer Network and the European Association of Urology (EAU) is similar. The EAU adds a very high-risk category, based on tumor grade and the presence of additional risk factors (age >70 years, multiple papillary tumors, tumor diameter >3 cm), defined as:

  • Ta high-grade/G3 tumors and CIS with all three of the above risk factors
  • T1 grade 2 tumor and CIS with at least two risk factors
  • T1 high-grade/G3 tumor and CIS with at least one risk factor
  • T1 high-grade/G3 and no CIS with all three risk factors

BCG Therapy

Standard treatment after TURBT in an intermediate-risk patient is a 6-week course of induction intravesical chemotherapy or immunotherapy, followed by consideration of maintenance therapy in those with a complete response to induction therapy.

Intravesical BCG, a live attenuated vaccine form of Mycobacterium bovis used to prevent tuberculosis and other mycobacterial infections, is the most common intravesical immunotherapy for treating NMIBC, and remains the standard of care in the front-line setting; this is despite the shortage of BCG owing to a global demand that exceeds the supply.

"Don't cut the doses of BCG," cautioned Shilpa Gupta, MD, director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at Cleveland Clinic. "Don't be stingy with the dose. Use full-dose BCG whenever applicable."

She noted that the SWOG Cancer Research Network has competed a trial using a Tokyo-172 strain of BCG, comparing it with the TICE strain, and if this trial shows noninferiority, it will offer more options for alternate BCG strains.

In a high-risk patient with newly diagnosed CIS, high-grade T1, or high-risk Ta urothelial carcinoma, the guidelines advise a 6-week induction course of BCG.

Maintenance BCG therapy is recommended for patients at intermediate risk who have a complete response to induction BCG (1 year of maintenance), as well as for high-risk patients with a complete response to induction BCG (3 years of maintenance, as tolerated).

Induction intravesical therapy is not recommended for low-risk patients.

FDA defines "adequate" BCG as at least one of the following:

  • At least five of six doses of an initial induction course plus at least two of three doses of maintenance therapy
  • At least five of six doses of an initial induction course plus at least two of six doses of a second induction course

FDA defines BCG-unresponsive disease as being at least one of the following:

  • Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary disease/tumor invading the subepithelial connective tissue) disease within 12 months of completion of adequate BCG therapy
  • Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy
  • T1 high-grade disease at the first evaluation following an induction BCG course

Approximately 30-40% of patients are unresponsive to BCG, Gupta noted. For such patients, the gold standard has been radical cystectomy, but many patients are not candidates for the surgery or decline to have it, she added.

BCG-Unresponsive NMIBC

The treatment landscape for BCG-unresponsive NMIBC is expanding. In the single-arm multicohort phase II KEYNOTE-057 study, pembrolizumab (Keytruda) monotherapy showed encouraging antitumor activity in patients with papillary high-risk NMIBC that was unresponsive to treatment with BCG. Extended follow-up at 45 months showed an estimated 12-month disease-free survival (DFS) rate of 43.5% and a median DFS of 7.7 months.

"The initial results of KEYNOTE-057 were more promising than with longer-term follow-up, but pembrolizumab is an approved agent in this setting [BCG-unresponsive disease]," Gupta said.

Atezolizumab in the setting of BCG-unresponsive CIS showed efficacy similar to that of pembrolizumab, but did not receive FDA approval, she noted. "There are efforts to build onto pembrolizumab in ongoing studies by adding novel immunotherapies such as anti-TIGIT [T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains]/LAG-3 [lymphocyte activation gene-3] inhibitors."

In December 2022, the FDA approved the first gene therapy for the treatment of adult patients with high-risk BCG-unresponsive NMIBC -- nadofaragene firadenovec (Adstiladrin). The CS-003 study showed a complete response rate of 51% in patients evaluable for response, with a median duration of response of 9.7 months. All complete responses occurred within 3 months.

"This was really promising -- 46% of patients who are responding remained in complete remission for at least 1 year," Gupta said. "These data look better than what we know with pembrolizumab. Both of these therapies are not mutually exclusive. If somebody got this first, they could still get pembrolizumab after, and vice versa."

Van der Heijden compared the results of KEYNOTE-057 to other therapies in this setting. He said that in addition to the impressive data with nadofaragene firadenovec, studies evaluating intravesical chemotherapy produced higher rates of recurrence-free survival than pembrolizumab did in KEYNOTE-057, but were retrospective in nature, "and not in the context of a well-controlled clinical trial."

"Pembrolizumab mainly stands out for the robustness of the data, with 132 patients, which is the largest prospective clinical trial in this space," he added.

Pembrolizumab "probably has clinical activity in this space, although unless we have randomized trials in this space, the magnitude of this activity is still unknown," Van der Heijden continued. "These randomized trials are needed, but I acknowledge it will be difficult to find a comparator arm."

Several clinical trials with novel agents are ongoing in this space, Gupta noted. One is the QUILT-3 study of intravesical BCG in combination with ALT-803 (N-803) or N-803 monotherapy.

The 2020 AUA/SUO guideline recommends: "In a patient with persistent or recurrent intermediate- or high-risk NMIBC within 12 months of completion of adequate BCG therapy (two induction courses or one induction course plus one maintenance cycle) who is unwilling or unfit for cystectomy, a clinician may recommend clinical trial enrollment or offer alternate intravesical therapy (e.g., valrubicin, gemcitabine, docetaxel, combination chemotherapy) when clinical trials are unavailable. A clinician may also offer systemic immunotherapy with pembrolizumab to a patient with CIS within 12 months of completion of adequate BCG therapy."

Role of Cystectomy

Radical cystectomy is usually curative in NMIBC, with a 10-year overall survival rate of 92% in patients with pT1 tumors. Five-year survival is better with early cystectomy compared with delayed cystectomy.

AUA/SUO recommends that clinicians consider offering initial radical cystectomy for high-risk patients with persistent high-grade T1 disease on repeat resection, or T1 tumors with associated CIS, lymphovascular invasion, or variant histologies. Radical cystectomy should also be offered to high-risk patients with persistent or recurrent disease within 1 year following treatment with two induction cycles of BCG or BCG maintenance.

In a patient with Ta low- or intermediate-risk disease, radical cystectomy should not be performed until bladder-sparing modalities (staged TURBT, intravesical therapies) have failed, the guidelines state.

Read previous installments in this series:

Part 1: Urothelial Cancer: Diagnostic Evaluation

Part 2: Staging of Urothelial Cancer: Cystoscopy and CT Evaluation Remain Standard