X Treatment Patterns in High-Risk, Bacille Calmette-Guérin Unresponsive Non- Muscle Invasive Bladder Cancer Patients: A Systematic Literature Review

Broughton E1, Chun D1,2, Gooden K1, Hofer K3, Fazeli MS3,4 1Bristol-Myers Squibb, Princeton, NJ, USA, 2Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA, 3Evidinno Outcomes Research Inc., Vancouver, BC, Canada, 4Doctor Evidence LLC., Santa Monica, CA, USA

Table 1. Interventions classified by type of treatment proportion of patients having disease-free survival ranged Background from 0% (n=1 [5-aminolevulinic acid + whole bladder wall Treatment Type Included Interventions Studies, n irradiation at 33 months]) to 91.18% (n=1 [radachlorin + •Approximately 50% of non-muscle invasive bladder cancer photodynamic therapy at 12 months]), and proportion of (NMIBC) patients fail standard Bacille Calmette–Guérin (BCG) BCG 15 patients with progression-free survival was reported as 89% therapy, putting them at high-risk of disease progression and as reported by one study (n=1 [docetaxel at 48.3 months]). 1 BCG + Interferon 5 mortality. •Proportion of patients undergoing cystectomy after failure to •Current American Urological Association and European Bropirimine 3 respond to treatment ranged from 0% (n=1 [mitomycin c at 9- Association of Urology guidelines recommend radical 12 months]) to 100% (n=2 [5.0 mg/kg chlorin e6- cystectomy for high-risk, BCG-unresponsive NMIBC patients CG0070 1 polyvinylpyrrolidone + light irradiation at 16 months; and local 2,3However, radical cystectomy has previously been treatment in a BCG treatment failure subgroup]). Immunotherapy associated with a 90-day major complication rate of 17% and Interferon 2 90-day mortality rate of 2-10%.4 (n = 31) Table 2. Number of studies reporting efficacy outcomes and •For bladder cancer patients not eligible for radical cystectomy Mycobacterial Cell Wall Extract 1 ranges of occurrence by treatment type or for whom bladder preservation is desired, bladder sparing Mycobacterial Cell Wall DNA Complex 2 Chemotherapy therapies may be an effective alternative to radical Radiation/ Immunotherap + 5 Chemotherapy Photodynamic cystectomy. Thus, there is substantial need for guidelines and Mycobacterium Phlei Cell Wall Nucleic y Immunotherap 1 (n = 23) Approaches recommended treatment plans that include bladder sparing (n = 31) y Acid Complex (n = 7) therapeutic options for high-risk NMIBC patients who have (n = 5) Vicinium 1 Efficacy either not responded to, or have disease recurrence following n Range n Range n Range n Range prior intravesical BCG treatment. Outcome Bladder Wall Hyperthermia + Mitomycin C 1 Overall 47.6 to 1 4 54 to 100 2 70.8 to 94.7 1 53 to 100 Survival, % 100 Objective Docetaxel 2 Overall 28.5 to 79.7 Survival, 1 54 1 61.4 2 1 58 To describe the landscape of evidence for bladder sparing (median) Everolimus + Gemcitabine 2 Months, Mean treatment options and their associated clinical outcomes in Progression- patients with high-risk NMIBC who have either not responded Gemcitabine 7 Free Survival, 0 NR 1 89 0 NR 0 NR to, or have disease recurrence, following prior intravesical BCG % Progression- treatment. Gemcitabine + Cisplatin + Cabazitaxel 1 Free Survival, 1 18 1 8.7 0 NR 1 52 (mean) Months, Chemotherapy Gemcitabine + Docetaxel 1 Median (n = 23) Methods Disease-Free 8 5.9 to 71.4 5 13 to 73.1 4 0 to 91.2 2 6.7 to 30 Mitomycin C 3 Survival, % •A systematic search was performed in MEDLINE®, Embase, Disease-Free Mitomycin C + Radiofrequency Induced Survival, 1 and CENTRAL (inception to December 17, 2018) using the 1 7 3 to 80 16 to 100 4 33.8 to 90.9 2 6.1 to 100 following key search terms and their synonyms: Urinary Thermochemotherapy Kaplan Meier, 0 % Bladder Cancer, BCG Vaccine, and Treatment Failure. Paclitaxel 2 13.3 Disease-Free 175 days months to 12.1 •Searches were supplemented by a grey literature search Survival, 2 to 10 2 1 1 23 months 17.7 months conducted on December 17, 2018 (2016 to 2018) in US and Paclitaxel-Hyaluronic Acid 1 Median months months EU clinical trials registries and American Society of Clinical Complete 1 1 Valrubicin 2 0 to 80 0 to 100 6 31 to 100 1 33.33 Oncology (ASCO), European Society for Medical Oncology Response, % 8 3 (ESMO), and American Urology Association (AUA) 5-Aminolevulinic Acid + Whole Bladder 1 Duration of conferences. Wall Irradiation Complete 0 NR 0 NR 0 NR 0 NR •Population of interest was high-risk NMIBC patients (≥18 Chlorin E6-Polyvinylpyrrolidone + Light Response 1 years of age) who have either not responded to, or have Irradiation Duration of Disease 0 NR 0 NR 0 NR 0 NR Radiation/ disease recurrence, following prior intravesical BCG treatment. Mitomycin + Direct Nonionizing Irradiation 2 Response Photodynamic •Randomized controlled trials (RCTs), non-randomized and/or 8.5 months Approaches Gemcitabine + Paclitaxel + Doxorubicin + Time to non-controlled clinical trials, and observational studies 1 Disease (mean) to Pegfilgrastim + Radiotherapy 1 461 days 2 0 NR 0 NR investigating the effect of any approved, late-phase (n = 7) Progression, 12.5 Median months investigational, or ongoing clinical trial treatments on clinical Radachlorin + Photodynamic Therapy 1 outcomes of interest were eligible. 1 1 Whole Bladder Laser Light + Porfimer Recurrence, % 0 to 87.5 4.7 to 87.8 4 0 to 40 0 NR 1 8 3 •Study baseline characteristics (such as age, gender Sodium distribution, geography), treatment characteristics, Time to BCG + Epirubicin 2 Recurrence, 3.1 (mean) 3.5 (mean) 4 6 0 NR 0 NR efficacy/effectiveness and safety outcomes were extracted Months, to 24 to 37.3 from studies meeting the pre-defined population, intervention, Median Chemotherapy + BCG + Interferon + Gemcitabine 1 6 comparator and outcome (PICO) criteria. 1 Immunotherapy Cystectomy, % 8 9.8 to 85.7 0 to 61.5 3 5.6 to 100 1 33 6 •Risk of bias associated with each study was evaluated by two (n = 5) BCG + Interferon + Valrubicin 1 reviewers using the Cochrane Collaborations tool for Time to Cystectomy, 1 10 2 4 to 16.1 1 8 0 NR assessing risk of bias in randomized clinical trials, and the Cetuximab + 366–821 MBq 1 Months, Methodological Index for Non-randomized Studies (MINORS) Median for both comparative and non-comparative non-randomized Figure 3. Distribution of post-BCG treatment interventions n = number of studies; No. = number; NR = not reported. studies. across included studies Safety Outcomes Results 35 31 •Safety outcomes by type of treatment are summarized in 30 Table 3. •Sixty-nine publications pertaining to 60 studies were eligible 25 23 •Hematuria was the most commonly reported AE (n=19; (Figure 1), representing non-controlled clinical trials (n=32), 20 proportion range: 0% to 100%), followed by fever or pyrexia non-comparative observational studies (n=11), non- 15 (n=7; 0% to 100%), and diarrhea (n=4; 0% to 14.3%). Less randomized controlled trials (n=7), randomized controlled trials 10 7 commonly reported safety outcomes included proportions of (n=6), retrospective cohort studies (n=3), and a prospective Studies Reporting, n 5 5 drug discontinuation (n=9), all-cause mortality (n=8), and cohort study (n=1) (Figure 2). 0 study withdrawal (n=3). •Study sample size ranged from 5 to 334, the proportion of Immunotherapy Chemotherapy Radiation/ Chemotherapy + female ranged from 4.9% to 60.0% and mean age ranged Photodynamic Immunotherapy Table 3. Number of studies reporting safety outcomes and Approaches from 58 to 80 years. Thirty-two of the studies were conducted ranges of occurrence by treatment type in the US. Figure 4. Definitions of BCG-related NMIBC disease states by the Figure 1. PRISMA diagram Radiation/ number and timing of BCG cycles across studies reporting Chemotherapy + Immunotherapy Chemotherapy Photodynamic Immunotherapy (n = 31) (n = 23) Approaches (n = 5) Records Records Records Records Records Records (n = 7) identified identified identified identified identified identified through through through through US through EU through MEDLINE® Embase Cochrane clinical trial clinical trial manual search (n = 3,096) (n = 2,794) (n = 3) (n = 118) (n = 35) (n = 12) Identification Safety Outcome n Range, % n Range, % n Range, % n Range, %

Records after duplicates removed (n = 3,911)

Treatment-Related AE 5 0 to 85.7 3 0 to 69 0 NR 0 NR

Records screened based on References excluded title/abstract (n = 3,911) (n = 2,907) Screening Arthralgia 2 0 to 10.5 0 NR 0 NR 0 NR

Full-text articles excluded Full-text articles assessed for (n = 938): Arthritis 0 NR 0 NR 0 NR 0 NR eligibility (n = 1,004) Study design: n = 87

Eligibility Population: n = 735 Cystitis 1 0 to 5.3 0 NR 1 0 to 97 0 NR Intervention: n = 20 Outcomes: n = 78 Outcome stratification: n = 7 Publications included in qualitative Diarrhea 3 0 to 14.3 2 4.4 to 7.1 0 NR 0 NR Not English: n = 3 synthesis (n = 69), Duplicate publication: n =7 pertaining to 60 studies Animal study: n = 1

Included Epididymo-orchitis 0 NR 0 NR 0 NR 0 NR

Fever 3 0 to 100 4 2.5 to 11.1 1 12 0 NR

Figure 2. Distribution of study designs across included studies Haematuria 9 0 to 100 10 0 to 50 2 0 to 68 0 NR

Reporting Studies, n (%) Prostatitis 0 NR 0 NR 0 NR 0 NR

Rash 2 0 to 13 1 7 0 NR 0 NR 3 (5%) 1 (2%) Sepsis 2 0 to 4.8 1 2.22 0 NR 0 NR Non-Controlled Clinical 6 (10%) Trials Mortality, All-Cause 3 0 to 47 5 0 to 50 1 100 1 20

Non-Comparative Drug Discont. due to 6 0 to 16.7 3 0 to 11.5 0 NR 0 NR Observational Studies AE Non-Randomized 7 (12%) Study Withdrawal due Controlled Trials 2 5.8 to 14.3 1 15.8 0 NR 0 NR to AE Randomized Controlled 32 (53%) Trials AE = adverse event; Drug Discont. = drug discontinuation; n = number of studies; No. = Number; NR = not reported. Retrospective Cohort Studies Prospective Cohort Conclusions Studies 11 (18%) • Among therapeutic options for patients with high-risk NMIBC who fail BCG treatment, both chemotherapy and immunotherapy are most frequently researched, while combination therapy with chemotherapy + immunotherapy, •Studies were mixed in terms of risk of bias: RCTs were and radiation/photodynamic approaches are less-thoroughly generally at high-risk of performance bias, detection bias, and investigated. reporting bias, but at low or unclear risk of selection bias, • Observed heterogeneity across studies in definitions of high- attrition bias, and other sources of bias; comparative and non- risk populations or BCG-unresponsiveness negatively impacts comparative observational studies were generally at risk of the ability to quantitatively compare data across studies and to inappropriate reporting of outcomes according to study aims draw comprehensive clinical recommendations from the and did not clearly state unbiased assessment of endpoints, existing evidence base. but were deemed at low or unclear risk in all other domains. BCG-refractory = patients described as not responding to initial treatment with BCG; BCG-relapsed = patients who had a Additionally, non-randomized comparative studies generally documented complete response, but later relapsed; BCG-unresponsive = a mix of patients described as refractory, recurrent, relapsed or intolerant; PC = pathologically confirmed. Green bars capped with arrow tips indicate that the provided adequate information regarding control and treatment duration continues beyond 48 weeks. contemporary groups, as well as having assured the groups References were equivalent at baseline; although half the studies did not Efficacy Outcomes •Please see online version for full reference list provide details on statistical analyses. •Efficacy outcomes by type of treatment are summarized in •Post-BCG treatment interventions (Table 1 and Figure 3) Table 2. Acknowledgments consisted of immunotherapy (n=31), chemotherapy (n=23), •Complete response was the most frequently reported efficacy radiation/photodynamic approaches (n=7), and chemotherapy outcome (n=36), with proportions of complete responders •This study was sponsored by Bristol-Myers Squibb. + immunotherapy (n=5); where some studies reported multiple ranging from 0% (n=4 [BCG; gemcitabine; paclitaxel- interventions. hyaluronic acid; CG0070]) to 100% (n=3 [gemcitabine + Disclosure •Substantial heterogeneity was observed between studies in paclitaxel + doxorubicin + pegfilgrastim + radiotherapy; •E. Broughton, D. Chun, and K. Gooden report employment by terms of definitions of both high-risk populations and BCG- paclitaxel-hyaluronic acid; 5-aminolevulinic acid]). Bristol-Myers Squibb. K. Hofer and M.S. Fazeli report unresponsiveness and/or refractory/recurrent, as well as •Overall survival ranged from 47.6% (n=1 [mycobacterial cell employment by Evidinno Outcomes Research Inc., contracted follow-up period (Figure 4). As such, it was not feasible to pool wall DNA complex; follow-up: 64.8 months] to 100% (n=2 by Doctor Evidence, who in turn was contracted by Bristol- the results of the studies identified via the SLR, and an [gemcitabine at 18.4 months; mycobacterial cell wall DNA Myers Squibb to conduct this work. Authors report no other unbiased quantitative comparisons of treatment strategies complex at 12 months; and BCG + interferon + gemcitabine at conflicts of interest. could not be made. 24 months]),

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