2022 - Lesson 14 (Treatment of Bacillus Calmette-Guérin Unresponsive Nonmuscle-Invasive Bladder Cancer

Question 1

Adequate BCG

Answer 1

At least 5 of 6 instillations of induction as well as at least 2 of 3 maintenance doses, or
Two induction courses of BCG

Question 2

BCG intolerant

Answer 2

Disease persistence due to inability to receive adequate BCG due to poor tolerability or toxicity

Question 3

BCG refractory

Answer 3

Persistent high-grade NMIBC at 6 months after adequate BCG
Any progression at 3 months after induction BCG

Question 4

BCG relapsing

Answer 4

Recurrence of high-grade disease after achieving a complete response at 6 months after adequate BCG

Question 5

BCG unresponsive

Answer 5

BCG refractory and BCG relapsing within 6 months of last BCG
New or persistent high-grade disease at 6 months (12 months if CIS recurrence) after adequate BCG
High-grade T1 3 months after induction BCG

Question 6

What is GemRIS™, and how does it contribute to intravesical chemotherapy for bladder cancer?

Answer 6

GemRIS™ is an implantable drug delivery system designed to increase the bladder’s exposure time to intravesical chemotherapy, such as gemcitabine. It’s implanted via cystoscopy and actively evaluated to improve absorption and allow for longer dwell times in the bladder, potentially evaluating other intravesical therapies.

Question 7

Explain the concept of Vakzine Projekt Management GmbH (VPM1002) and its application in NMIBC.

Answer 7

VPM1002 is a recombinant BCG modified with the insertion of the listeriolysin gene, enhancing immunogenicity and cellular toxicity. It’s being evaluated in a phase I/II clinical trial (NCT02371447) for intravesical use against standard BCG in recurrent NMIBC.

Question 8

Describe Cavatak, its origin, and results from the phase I/II CANON trial.

Answer 8

Cavatak is a recombinant form of the enterovirus Coxsackievirus A21 (CVA21), used as an oncolytic agent. The phase I/II CANON trial (NCT02316171) indicated it was well tolerated and showed good clinical activity, including complete tumor response.

Question 9

What is PANVAC, and how does it interact with BCG in high-grade NMIBC treatment?

Answer 9

PANVAC is a pox viral vaccine targeting tumor-associated antigens and oncoproteins. A phase II study is comparing BCG plus PANVAC vs. BCG alone in high-grade NMIBC patients who failed at least one BCG course. Preliminary results showed an impactful immunological response with BCG + PANVAC compared to BCG alone.

Question 10

Explain the concept of phototherapy using TLD-1433 for treating BCG intolerant/refractory patients.

Answer 10

Phototherapy involves the photodynamic compound TLD-1433, which has preferential uptake by bladder cells. When activated by green light, it can cause free radical release and tumor cell lethality. A phase II clinical trial (NCT03945162) is ongoing to evaluate its efficacy in BCG intolerant/refractory patients.

Question 11

What is Erdafitinib, and how is it being studied for BCG unresponsive NMIBC?

Answer 11

Erdafitinib is a tyrosine kinase inhibitor of FGFR1-4, FDA-approved for metastatic urothelial carcinoma. It is currently being studied in a randomized phase II clinical trial to assess recurrence-free survival compared to intravesical chemotherapy in high-risk BCG unresponsive NMIBC patients with FGFR mutation/fusion.

Question 12

Explain the role of the fusion protein ALT-803 in the treatment of BCG refractory NMIBC. Provide the results of the preliminary phase II data.

Answer 12

ALT-803 is a fusion protein with enhanced activity for cytokine IL-15, crucial for the development of natural killer cells and CD8 T-cells. In preliminary phase II data, BCG-naïve patients treated with BCG and ALT-803 showed that 78% of CIS patients had complete response at 6 months, and 77% of BCG unresponsive high-grade Ta/T1 were disease-free at 3 months.

Question 13

What is CG0070, and how does it work? Share the results of the phase II data for BCG unresponsive NMIBC patients.

Answer 13

CG0070 is an oncolytic adenovirus that selectively replicates in bladder cancer cells through their defective retinoblastoma pathway, leading to immunogenic cell death. Phase II data shows a 47% complete response rate at 6 months in BCG unresponsive NMIBC patients, with an 18-month complete response of 21%.

Question 14

Describe Nadofaragene firadenovec (INSTILADRIN®) and its phase III study results for treating BCG unresponsive NMIBC.

Answer 14

Nadofaragene firadenovec (INSTILADRIN®) is a recombinant replication-deficient adenovirus that encodes the human interferon α-2b gene, enhancing drug delivery into the urothelium. In a phase III study of 157 BCG unresponsive NMIBC patients, 53.4% had a complete response by 3 months, and 24% did not have high-grade recurrence by 1 year. The therapy was generally well-tolerated, with irritative voiding symptoms as the most common adverse event.

Question 15

Describe the ongoing research and trials combining PD-1/PD-L1 inhibitors with other therapies in the treatment of BCG unresponsive NMIBC.

Answer 15

Several trials are exploring combinations of PD-1/PD-L1 inhibitors with BCG, external beam radiation therapy, enzymatic inhibitors, and fusion proteins like Vicinium. Examples include KEYNOTE-676 (BCG plus pembrolizumab), ADAPT-BLADDER (durvalumab combinations), and CheckMate 9UT (nivolumab combinations). These combinations aim to enhance efficacy and explore novel synergistic effects.

Question 16

Explain the concept of intravesical administration of checkpoint inhibitors and its potential advantages.

Answer 16

Intravesical administration of checkpoint inhibitors, such as pembrolizumab and durvalumab, is being explored in clinical trials. This method may spare patients the systemic adverse effects associated with systemic delivery. If beneficial, intravesical administration may allow urologists to direct care using an administration technique within their comfort zone.

Question 17

Describe the notable toxicities of pembrolizumab and the recommended handling for adverse reactions.

Answer 17

Pembrolizumab’s toxicities include immune-mediated reactions like pneumonitis, colitis, endocrinopathies, nephritis, and infusion-related reactions. Common adverse events include fatigue, musculoskeletal pain, and nausea. Infusion should be slowed or interrupted for grade 1 or 2 reactions and permanently discontinued for grade 3 or 4 reactions. Dose reduction is not recommended.

Question 18

Summarize the KEYNOTE-057 trial and its outcomes that led to the FDA approval of pembrolizumab for BCG unresponsive NMIBC.

Answer 18

KEYNOTE-057 was a multicenter, open-label, phase II trial of pembrolizumab in BCG unresponsive NMIBC. Administered via IV every 3 weeks for up to 24 weeks, it showed a complete response rate of 40.6% with a median duration of 16.2 months in responders. Progression-free survival and overall survival at 12 months were 82.7% and 97.9%, respectively, leading to FDA approval on January 8, 2020.

Question 19

What is the role of checkpoint inhibition in the treatment of metastatic and muscle-invasive urothelial cancer, and which agents are FDA approved?

Answer 19

Checkpoint inhibition, via the PD-1/PD-L1/PD-L2 pathways, has revolutionized the care of patients with metastatic and muscle-invasive urothelial cancer. FDA-approved agents include atezolizumab, avelumab, durvalumab (all anti-PD-L1), nivolumab, and pembrolizumab (both anti-PD-1). Pembrolizumab is specifically approved for BCG unresponsive high-risk NMIBC (CIS).

Question 20

Describe the FDA-approved intravesical chemotherapy for patients who fail BCG and the outcomes from the study cohort.

Answer 20

Valrubicin is the only FDA-approved intravesical chemotherapy for patients who fail BCG, specifically in patients with CIS. In the study cohort, 18% of treated patients had a complete response at 6 months, while 2-year efficacy was roughly 8%.

Question 21

Discuss the phase I trial of sequential intravesical treatment with cabazitaxel, gemcitabine, and cisplatin, including the reported outcomes.

Answer 21

The phase I trial of sequential intravesical treatment with cabazitaxel, gemcitabine, and cisplatin demonstrated excellent tolerability, with the majority of patients remaining recurrence-free at 12 months. Despite only 18 enrolled patients, robust complete response (89%) and partial response (94%) rates were reported, with a recurrence-free survival of 83% at 1 year. The regimen was logistically challenging, requiring instillations 2 to 3 times weekly during the 6-week induction period.

Question 22

What novel delivery mechanisms have been utilized to deliver intravesical chemotherapy, and what are the outcomes?

Answer 22

Novel delivery mechanisms include chemohyperthermia (CHT) and nanoparticle-encapsulated chemotherapeutics. CHT delivers heat to enhance penetration of the agent, with devices like Synergo® and COMBAT®. It has shown improved disease-free survival with CHT and MMC versus MMC alone at 10 years (53% vs 15%). Nanoparticle-encapsulated agents have demonstrated increased drug accumulation in the urothelium, with trials involving docetaxel-loaded polymeric micelles and nanoparticle albumin-bound (nab)–paclitaxel.

Question 23

Describe the sequential chemotherapy strategy using gemcitabine and docetaxel, including its administration protocol and outcomes.

Answer 23

Sequential chemotherapy with gemcitabine and docetaxel aims to increase treatment effect by utilizing multiple agents. Gemcitabine inhibits DNA synthesis, resulting in cell apoptosis, and docetaxel inhibits tubulin disassembly. The administration protocol includes 1,300 mg of oral sodium bicarbonate, 1 gm of gemcitabine instilled and retained for 90 minutes, followed by 37.5 mg of docetaxel retained for 120 minutes. In a multi-institutional analysis, high-grade recurrence-free survival was 65% at 1 year and 52% at 2 years for all patients, and 81% and 59% disease-free survival at 1 and 2 years for BCG unresponsive patients with a complete response to induction therapy.

Question 24

What is the current first-line treatment for BCG-naïve patients when BCG is not available, and what are its associated risks?

Answer 24

Mitomycin-C (MMC) is currently utilized as a first-line treatment for BCG-naïve patients when BCG is not available. It is primarily associated with local toxicity, including bladder irritability and local skin reactions, and studies have suggested a higher risk of recurrence when compared with BCG.

Question 25

Why must the morbidity and mortality of radical cystectomy be considered when counseling high-risk patients?

Answer 25

The significant morbidity and mortality associated with radical cystectomy must be considered when counseling high-risk patients to ensure that they are fully informed of the risks and that the management options are tailored to the individual patient’s situation.

Question 26

What are the morbidity and mortality associated with radical cystectomy, even when performed at centers of excellence?

Answer 26

Radical cystectomy is associated with significant morbidity and mortality. Perioperative mortality was 2.1%–3.2% at 30 days and 3.4%–8.4% at 90 days, while morbidity and mortality outcomes tended to be worse at low volume hospitals. Even in a large single-center series of over 1,000 cases, a major complication rate of 40.8% was reported.

Question 27

How is delayed cystectomy associated with outcomes in patients with T1 high-grade NMIBC, including BCG unresponsive disease?

Answer 27

Delayed cystectomy has been associated with worse outcomes. In patients with high-grade superficial bladder tumors, 5-year disease-specific survival was superior for those undergoing cystectomy <2 years post-BCG induction compared to those waiting >2 years. Early cystectomy had improved 5- to 10-year cancer-specific survival compared to deferred cystectomy.

Question 28

What are the advantages of early cystectomy in patients with BCG unresponsive NMIBC?

Answer 28

Early cystectomy offers several advantages, including disease-free survival rates of 80%–90%, appropriate treatment for the 25%–50% of patients who may be understaged, and diagnostic and therapeutic benefits in patients with occult lymph node metastasis, allowing for appropriate staging and management.

Question 29

What is the preferred treatment for BCG unresponsive NMIBC patients, and how is the timing of cystectomy defined?

Answer 29

The preferred treatment for BCG unresponsive NMIBC patients is radical cystectomy with urinary diversion. Timing of cystectomy can be defined as immediate (at initial transurethral resection of bladder tumor), early (immediately following BCG failure), and delayed (after attempting other bladder-sparing therapies following BCG unresponsiveness).

Question 30

What is the preferred option for BCG unresponsive disease, and what are the considerations for patients who may be poor surgical candidates or prefer bladder sparing options?

Answer 30

The preferred option for BCG unresponsive disease is early radical cystectomy. However, a proportion of patients may be poor surgical candidates or strongly prefer bladder sparing options, making them eligible for bladder-sparing clinical trials. The U.S. FDA has been supportive of single-arm registration trials.

Question 31

What are the treatment options suggested by the National Comprehensive Cancer Network® and European Association of Urology for BCG unresponsive disease?

Answer 31

The treatment options include radical cystectomy, another intravesical immunotherapy, intravesical chemotherapy, device-assisted therapy, combination chemoimmunotherapy, gene therapy, and participation in a clinical trial. Further investigation is warranted for these alternative therapies.

Question 32

How is “adequate BCG” defined, and what constitutes BCG unresponsive patients?

Answer 32

Adequate BCG is defined as 2 courses of BCG: at least 5 of 6 instillations of induction and at least 2 of 3 maintenance doses or 2 induction courses. BCG unresponsive patients are those who did not respond to BCG treatment and have a new or persistent high-grade papillary recurrence at 6 months after BCG was initiated (12 months if CIS recurrence), or those who relapse with high-grade NMIBC within 6 months of their last intravesical treatment with BCG despite an initial complete response.

Question 33

List the four categories of BCG-treated patients described by bladder experts.

Answer 33

The four categories of BCG-treated patients are BCG refractory, BCG relapsing, BCG intolerance, and BCG unresponsive.

Question 34

Before 2015, why was there significant heterogeneity in defining “BCG failure” patients?

Answer 34

Before 2015, BCG unresponsive disease was not clearly defined, and variation in practitioner use of BCG induction and maintenance protocols led to heterogeneity in defining “BCG failure” patients.

Question 35

What are the financial aspects and gender predominance of bladder cancer?

Answer 35

Bladder cancer is the fourth most common cancer diagnosed in men, with an approximately 3:1 male predominance. It remains one of the most costly cancers to treat, especially in the first year after diagnosis, with the annual cost of treatment in the U.S. rising to $5 billion in 2020.

Question 36

What is the relapse and progression rate for high-risk cases treated with BCG within 5 years? What is the next step for patients with recurrence after adequate BCG therapy?

Answer 36

Up to 40% of high-risk cases treated with BCG will relapse, and 20% will progress to muscle-invasive disease within 5 years. Patients with recurrence after adequate BCG therapy will not achieve any additional benefit to further BCG treatment, and radical cystectomy is indicated.

Question 37

What is the standard of care for high-grade NMIBC, and what challenges have been faced in its treatment?

Answer 37

The standard of care for high-grade NMIBC is complete transurethral resection of the bladder tumor followed by intravesical immunotherapy with BCG. Challenges include patients developing recurrences and BCG marketplace scarcity, limiting the number of patients able to receive treatment.

Question 38

What percentage of all newly diagnosed cases of bladder cancer does NMIBC represent? What portion of those is high grade?

Answer 38

NMIBC represents 75% of all newly diagnosed cases of bladder cancer, with 50% of those being high grade.

Question 39

What is the most common malignancy of the urinary tract, and what were the estimated cases and deaths in the U.S. in 2020?

Answer 39

Bladder cancer is the most common malignancy of the urinary tract, with an estimated 81,400 cases diagnosed in the U.S. in 2020 and an estimated 17,980 deaths.