The standard of care for patients with high-grade (HG) non-muscle invasive bladder cancer (NMIBC) remains intravesical bacillus Calmette-Guérin (BCG) following transurethral resection. Unfortunately, up to 75% will develop tumor recurrence and 20% will progress within 5 years despite intravesical therapy.1-4 While current guidelines advise offering early radical cystectomy as an option for patients who have high-risk disease after BCG induction, there is a notable subset of patients who would like to preserve their bladders or are not suitable surgical candidates.5,6 Non-surgical options in this setting, however, remain limited. In fact, since 1959, the FDA has only approved 2 additional intravesical agents for bladder cancer: thiotepa and valrubicin, and neither of these has been found to be truly effective salvage options.7 As a result, there is a significant unmet need for efficacious second-line treatment options for patients who have failed BCG therapy for NMIBC.

Recent advances in our understanding of systemic immunotherapy, however, have transformed the management of urothelial carcinoma. Insight into T-cell biology related to checkpoint molecule inhibitors has resulted in the development of novel agents with applications in multiple malignancies, including advanced bladder cancer. With this insight, these agents are now also being investigated for use in NMIBC. In addition, multiple chemotherapeutic options recently have been evaluated as salvage intravesical options.   In this article, we evaluate recent developments in the management of BCG-unresponsive NMIBC.

Continue Reading

Defining risk

Defining what truly classifies BCG failure is essential to risk-stratify patients with tumor recurrence after BCG therapy. The prognosis of a patient who develops a new tumor after adequate BCG therapy is different from that of a patient who recurs after sub-optimal therapy.7 For patients with high-grade NMIBC, multiple studies support the use of 1 to 3 years of maintenance intravesical immunotherapy following a 6-week induction course to reduce the risk of recurrence and progression.1,8-10 Maintenance BCG therapy remains the most effective first-line therapy, significantly improving recurrence-free survival compared with induction BCG alone.1 Therefore, adequate BCG therapy is defined as at least 5 of 6 intended weekly induction treatments (1 induction course) followed by 2 or more additional weekly maintenance treatments (1 maintenance course), or a second re-induction instillation in a 6-month time period.11

For patients who have received adequate BCG therapy, different types of BCG failure are defined. “BCG intolerance” describes a scenario in which a patient cannot receive BCG due to treatment-related morbidity. “BCG refractory” disease indicates failure to achieve a disease-free state by 6 months after initial BCG therapy with either maintenance or retreatment at 3 months because of persistent or rapidly recurrent disease.7 “BCG relapse” indicates cancer recurrence after achieving a disease-free state for 6 months after treatment.11 Among relapsing patients, those whose tumor recurs within 6 months of the last BCG exposure seem to have as poor a prognosis as those who are BCG refractory.7 According to the latest definition by the FDA, “BCG unresponsive” disease is consequently defined as the combined group of patients with either BCG-relapse within 6 months of their last BCG exposure with HG Ta/T1 disease, BCG-refractory tumors with persistent or recurrent CIS +/- recurrent Ta/T1 disease within 12 months of completing BCG therapy, or those HG T1 disease found at the first evaluation following induction BCG.11,12

Prior to initiating intravesical therapy for high-risk Ta or T1 disease, patients should also undergo repeat transurethral resection of the primary tumor site within 6 weeks of the initial resection.5 Repeat transurethral resection for patients with these high-risk tumors achieves diagnostic and therapeutic benefits. Prior studies have demonstrated that residual tumor can be found at the time of repeat resection in up to 50% of patients with high-grade Ta disease and up to 15%–30% of patients are upstaged.13 Furthermore, repeat resection is associated with improved response rates to intravesical BCG therapy, specifically with a decreased risk of subsequent tumor recurrence and progression.4,5,14

For patients with NMIBC, current guidelines also recommend that clinicians offer blue light cystoscopy at the time of TURBT. 5 While cystoscopy and TURBT are conventionally performed using white light, this can lead to missing lesions that are present but not visible or indistinguishable from inflammation, such as carcinoma in situ (CIS), under white-light. Use of blue light cystoscopy, however, can help improve the detection of malignant tumors, particularly CIS, compared to conventional procedures; using this technology, both very small papillary lesions and almost one-third more cases of CIS that are overlooked by conventional cystoscopy can be identified.3,5, 15-17 A meta-analysis based on raw data of prospective trials also reported an increase in detection of malignant lesions in blue light cystoscopy arms and an absolute reduction of < 10% in recurrence rates within 1 year (35% vs 45%; RR 0.761; p = 0.006).18 Blue light cystoscopy may consequently also play an important role in the risk-stratification and treatment of patients with high-risk NMIBC.

The treatment options being discussed in this paper would ideally be developed who have undergone appropriate repeat resection for use in select patients with BCG-unresponsive disease as alternatives to radical cystectomy.


The goal of immunotherapy is to enhance the body’s ability to recognize and eradicate cancer. Applications in the use of immunotherapy include the use of exogenous cytokines to boost the immune response, vaccines to activate the immune system against specific tumor-associated antigens, agents that cause generalized local inflammation, and targeted antibodies against proteins on the surface of immune checkpoint molecules.19

The FDA has approved atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma. While the applicability of these agents has yet to be proven in NMIBC, insights regarding the immune system and tumor biology gained during the development of these medications are poised to potentially transform treatment options in NMIBC.

Intravesical immunotherapy

Enhancing BCG therapy. While Sanofi Pasteur has discontinued production of the Connaught strain of BCG as of November 2016, several trials are underway to evaluate the effectiveness of other strains of BCG.20 SWOG Trial S1602 is a randomized phase III trial currently underway and seeks to test the Tokyo strain of BCG against the currently-available Tice strain in patients with high-risk NMIBC. If the Tokyo strain proves non-inferior, this may facilitate entry of this strain into the US market. In addition to testing the 2 strains of BCG, a third arm of the S1602 trial is evaluating if vaccination of intradermal BCG prior to intravesical Tokyo BCG would enhance treatment efficacy.

A phase II trial (NCT02371447) is also underway to evaluate VPM1002BC, a Prague subtype of the Danish BCG strain, which has been genetically engineered to express the Listeria toxin listeriolysin. This pore-forming toxin enhances antigen presentation and stimulation of CD8 T-cells by inducing apoptosis of infected cells. This recombinant BCG has been tested intravesically in a dose escalation phase I trial that revealed no dose limiting toxicity.21 Further clinical results to evaluate its efficacy compared with traditional strains of BCG are pending. 

Novel intravesical agents. Interferon-α2b (rAd-IFN) is a recombinant adenovirus that can induce tumor cell death via multiple mechanisms. A phase I trial of an intravesical­ly delivered single dose rAd-IFN/Syn3 demonstrated an excellent safety profile and showed early signs of drug activity.22 The results of a phase II trial were recently presented and found that in 40 patients with BCG refractory or relapsed NMIBC, there was a 35% relapse-free survival at 12 months for HG tumors. Interestingly, there was a 50% recurrence-free survival at 12 months for patients with Ta/T1-only disease.23 As a result, intravesical rAd-IFNα/Syn3 shows promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy. A phase III trial is underway.

Another novel intravesical agent being evaluated is the CG0070 virus (Cold Genesys), an oncolytic adenovirus that selectively replicates in tumors that contain defects in the Rb pathway.20, 24 In a phase I study, 35 subjects underwent intravesical administration using varying doses and treatment schedules. A 49% complete response was noted at a median of 10.4 months, and responses were greater than 80% in a subset of patients with borderline or high RB status and 77% in those receiving 6 weekly doses.25 The agent is being studied as part of a phase II trial (NCT02365818) for patients who have failed BCG. The trial is also evaluating treatment-related changes in PDL-1 expression to establish the ratio­nale for possible combination therapy with a checkpoint inhibitor.

Mycobacterium phlei cell wall-nucleic acid complex (MCNA), an intravesical agent that contains mycobacte­rial cell wall fragments and nucleic acid derived from the nonpathogenic M. phlei, has also been recently evaluated for patients with NMIBC who have failed BCG. MCNA exerts an anticancer activity through a dual mode of action. It has an indirect immunotherapeutic effect (similar to BCG) that stimulates anticancer cytokine production by immune effector cells and has a direct chemotherapeutic effect (similar to cytotoxic agents).26, 27 A study of 129 patients with high-risk NMIBC, including 107 who were BCG refractory, demonstrated an overall disease-free survival rate was 25.0% at 1 year and 19.0% at 2 years.27 While trials evaluating MCNA have shown promise clinically, the FDA has not approved the agent at this time. 

Systemic immunotherapy

Checkpoint inhibitors have recently been FDA-approved as a second-line systemic therapy for patients with metastatic and locally-advanced bladder cancer and as a first-line therapy for cisplatin-ineligible patients. Based on our understanding of immune deficiency in bladder cancer and the proven efficacy of checkpoint inhibition in advanced disease, the use of PD-L1 and PD-1 inhibitors are now being investigated in the NMIBC domain.

There are multiple ongoing phase II monotherapy trials utilizing checkpoint inhibitors in BCG-unresponsive and relapsing NMIBC patients. Keynote-056 (NCT02625961) is currently an ongoing single-arm, open-label, phase II study evaluating the use of pembrolizumab, an anti-PD-1 humanized monoclonal antibody, in patients with high-risk NMIBC unresponsive to BCG. Patients in the study will receive pembrolizumab for 24 months or until disease recurrence, progression, or unacceptable toxicity, and they will be evaluated for complete response and disease-free survival rates. Similarly, atezolizumab (NCT02844816) and durvalumab (NCT02901548) are being investigated in phase II trials with NMIBC that has not responded to BCG. As prior studies have shown significant rates of PD-L1 expression in high-grade NMIBC,28 these trials may highlight the potentially important role of systemic checkpoint inhibitors in the management of BCG-refractory bladder cancer. Ongoing phase I/II studies are also currently evaluating combinations of BCG with either atezolizumab (NCT02792192) or pembrolizumab (NCT02808143) for patients with NMIBC, including those who are unresponsive to BCG.

Vaccine Therapy

In parallel to the developments of systemic immunotherapy and intravesical agents, there have been several noteworthy advancements in vaccine-based immunotherapy. PANVAC-VF is a cancer vaccine that uses recombinant vaccinia and fowlpox viruses engineered to contain genes for human CEA and MUC-1 (both known to be overexpressed in urothelial carcinoma), along with costimulatory molecules B7.1, ICAM-1 and LFA-3.29 It is currently being investigated in a phase II study in patients with NMIBC who have failed 1 course of BCG induction; patients will be randomized to PANVAC plus BCG versus BCG alone (NCT02015104).

Heat Biologics is developing HS-410 (Vesigenurtacel-L), an agent also designed to serve as an intradermal vaccine to enhance the effects of BCG.20 The cells have been engineered to express high levels of the heat shock protein gp96, which after secretion, delivers the tumor antigens to antigen presenting cells and stimulates activation of CD8+ cytotoxic T cells.  A phase I/II trial (NCT02010203) is evaluating a mixed population of BCG naïve and BCG recurrent patients with intermediate- or high-risk NMIBC undergoing 1:1:1 treatment with 1 of 2 doses of intradermal HS-410 (either 106 or 107cells/dose) or placebo in combination with 6 weeks of induction BCG, followed by 6 more weeks of HS-410 in the induction phase. Initial results from the trial have demonstrated that the intradermal vaccine is well-tolerated and that correlative biomarkers showed promising levels of immune response.30


Intravesical chemotherapy after BCG failure has been attempted with several agents, either alone or in combination with each other or with BCG. Valrubicin is currently an approved agent for intravesical use in BCG-refractory CIS when radical cystectomy is not an option.7 Evaluation of a single-arm study of patients with BCG-failure treated with intravesical valrubicin, however, have found a 12-month response rate of 16%, suggesting that it is a suboptimal salvage therapy following BCG failure.7, 31

Gemcitabine has also been evaluated as a chemotherapeutic option following BCG failure. A phase I study of 18 patients with NMIBC who had failed ≥1 BCG courses showed an early response rate of 39%, and a subsequent phase II trial demonstrated a disease-free response rate of 21% at 12 months in 30 patients.32, 33 A multicenter phase II study (SWOG S0353) similarly demonstrated a 12-month disease-free rate of 28%.34 While the efficiency of gemcitabine for patients who are truly BCG-unresponsive remains to be determined, additional trials are underway.7

Intravesical taxanes have also been evaluated for patients who have failed BCG. Barlow et al recently reported 1- and 3-year recurrence-free survival rates of 40% and 25%, respectively, in 54 patients who received salvage intravesical docetaxel.35 Similarly, a phase II trial evaluating nanoparticle albumin-bound paclitaxel demonstrated a disease-free response rate at 1 year of 36% in the 28 patients evaluated.36

Combination chemotherapy is also now being applied to patients who have failed BCG treatment. Using a protocol first established by Steinberg et al, studies are investigating the sequential use of intravesical gemcitabine followed by intravesical docetaxel.37, 38 Milbar et al recently reported a recurrence-free survival of 56% at 1 year and 42% at 2 years for patients with HG disease. 38 Among 25 patients who were BCG unresponsive/relapsing, 1- and 2-year recurrence-free survival rates were 49% and 34%, respectively. They found that gemcitabine/docetaxel was well-tolerated. Further studies are underway to determine if the combination therapy can serve as an alternative to immediate radical cystectomy.


BCG-unresponsive NMIBC is a potentially aggressive disease with a need for additional, effective non-surgical treatment options. Based on rapid advances in our understanding of the immune system and tumor biology, immunotherapy agents are being studied in the NMIBC setting. Similarly, intravesical chemotherapy options also hold potential as salvage agents. Together, these agents are poised to alter the therapeutic landscape for NMIBC as clinical trials are completed.

*Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Financial Disclosures/Funding Source: No financial disclosures.


1. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000; 163:1124-1129.

2. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49:466-465.

3. Jones JS. Non-muscle invasive bladder cancers (Ta, T1, and CIS). In: McDougal WS, Wein AJ, Kovoussi LR, et al. eds. Campbell-Walsh Urology. 11th ed. Philadelphia, PA: Elsevier; 2016. pp. 2205-2222.

4. Sfakianos JP, Kim PH, Hakimi AA, Herr HW. The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. J Urol. 2014;191:341-345.

5. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol. 2016;196:1021-1029.

6. Babjuk M, Bohle A, Burger M, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: Update 2016. Eur Urol. 2017;71:447-461.

7. Kamat AM, Colombel M, Sundi D, et al. BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG. Nat Rev Urol. 2017;14:244-255.

8. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63:462-472.

9. Hinotsu S, Akaza H, Naito S, et al. Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer. BJU Int. 2011;108:187-195.

10. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol. 2003;169:90-95.

11. Lerner SP, Dinney C, Kamat A, et al. Clarification of bladder cancer disease states following treatment of patients with intravesical BCG. Bladder Cancer. 2015;1:29-30.

12. BCG-unresponsive nonmuscle invasive bladder cancer: Developing drugs and biologics for treatment guidance for industry. US Department of Health and Human Services Food and Drug Administration. Feb 2018.> Accessed 29 Mar 2018.

13. Herr HW. Role of repeat resection in non-muscle-invasive bladder cancer. J Natl Compr Canc Netw. 2015;13:1041-1046.

14. Herr HW. Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy. J Urol. 2005;174:2134-2137.

15. Schmidbauer J, Witjes F, Schmeller N, et al. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol. 2004;171:135-138.

16. Rink M, Babjuk M, Catto JW, et al. Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: a critical review of the current literature. Eur Urol. 2013;64:624-638.

17. Witjes JA, Redorta JP, Jacqmin D, et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and recommendations. Eur Urol. 2010;57:607-614.

18. Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64:846-854.

19. Hurwitz ME, Sokhn J, Petrylak DP. Cancer immunotherapy: new applications in urologic oncology. Curr Opin Urol. 2016;26:535-542.

20. Black P. Intravesical Immunotherapy for Bladder Cancer. In: AUA News. American Urological Association; 2017.

21. Rentsch CA Mayor G, Rieken M, et al. Results  of the phase I open label clinical trial SAKK   06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium bacillus Calmette Guérin (BCG), in patients with non-muscle invasive bladder cancer and previous failure to conventional BCG therapy. In: International Bladder Cancer Network, Bochum, Germany: 2016.

22. Dinney CP, Fisher MB, O’Donnell MA, et al. Phase I Trial of Intravesical recombinant adenovirus-mediated interferon-α2b formulated in Syn3 for bacillus Calmette-Guérin failures in nonmuscle-invasive bladder cancer. J Urol. 2013;190:850-856.

23. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNalpha/Syn3 for patients with high-grade, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: A Phase II randomized study. J Clin Oncol. 2017;335:3410-3416.

24. Mitra AP, Birkhahn M, Cote RJ. p53 and retinoblastoma pathways in bladder cancer. World J Urol. 2007;25:563-571.

25. Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol. 2012;188:2391-2397.

26. Morales A, Cohen Z. Mycobacterium phlei cell wall-nucleic acid complex in the treatment of nonmuscle invasive bladder cancer unresponsive to bacillus Calmette-Guerin. Expert Opin Biol Ther. 2016;16:273-283.

27. Morales A, Herr H, Steinberg G, et al. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guérin. J Urol. 2015;193:1135-1143.

28. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer.2007;109:1499-1505.

29. Petrulio CA, Kaufman HL. Development of the PANVAC-VF vaccine for pancreatic cancer. Expert Rev Vaccines. 2006;5:9-19.

30. Steinberg GD, Shore N, Karsh L, et al. Immune response results of vesigenurtacel-l (HS-410) in combination with BCG from a randomized phase II trial in patients with non-muscle invasive bladder cancer (NMIBC). J Clin Oncol. 2017;35:319. 

31. Cookson MS, Chang SS, Lihou C, et al. Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder. Ther Adv Urol 2014;6:181-191.

32. Dalbagni G, Russo P, Sheinfeld J, et al. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guérin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol. 2002; 20:3193-3198.

33. Dalbagni G, Russo P, Bochner B, et al. Phase II trial of intravesical gemcitabine in bacille Calmette-Guérin-refractory transitional cell carcinoma of the bladder. J Clin Oncol. 2006;24:2729-2734.

34. Skinner EC, Goldman B, Sakr WA, et al. SWOG S0353: Phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin. J Urol. 2013;190:1200-1204.

35. Barlow LJ, McKiernan JM, Benson MC. Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy. J Urol. 2013;189:834-839.

36. McKiernan JM, Holder DD, Ghandour RA, et al. Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure. J Urol. 2014;192:1633-1638.

37. Valaer KN, Steinberg RL, Thomas LJ, et al. Experience with sequential intravesical gemcitabine and docetaxel as salvage therapy for non-muscle invasive bladder cancer. Curr Urol Rep. 2016;17:38.

38. Milbar N, Kates M, Chappidi MR, et al. Oncological outcomes of sequential intravesical gemcitabine and docetaxel in patients with non-muscle invasive bladder cancer. Bladder Cancer. 2017;3:293-303.