Intravesical Therapy for NMIBC/BCG Refractory. Gary D Steinberg, M.D. Chief of Urologic Oncology Section of Urology University of Chicago Medicine

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1 Intravesical Therapy for NMIBC/BCG Refractory Gary D Steinberg, M.D. Chief of Urologic Oncology Section of Urology University of Chicago Medicine

2 Intravesical Therapy for BCG Refractory NMIBC Disclosures: Consultant for Endo Pharmaceuticals, Taris Biomedical, PhotoCure, Predictive BioSciences, Abbott Molecular.

3 BCG Immunotherapy 6 weekly induction treatments starting 4 weeks after endoscopic resection Optimization strategies Repeat 3-week course for non-progressing or non T1 patients with first failure 1 year of maintenance therapy

4 The BCG Treatment Failure Problem Intravesical therapy with BCG is used as the predominant agent in N. America by >2:1 majority vs. chemotherapy even in low-intermediate grade bladder cancer Despite superior BCG efficacy, over 50% of patients have BCG Treatment failure incidence of ~15,000/yr or ~50,000 total in US There is wide heterogeneity among Rx failures: Papillary vs CIS, low-grade vs. high grade, number of courses, time of Rx failure, recurrence during maintenance Even the term BCG refractory has different meanings to different people For Consultant Use Only.

5 NCCN Guidelines Treatment of non-muscle -invasive bladder cancer NCCN Bladder Cancer 2007 For Consultant Use Only.

6 Radical Cystectomy After BCG: Are we waiting too long? Michael Simon, MD Alan Nieder, MD Murugesan Manoharan, MD Sandy Kim Mark Soloway, MD

7 Results: Soloway et al 5 Year Estimated Overall Survival: 65% 5 Year Estimated Disease-Specific Survival: 69% 11 Patients (12%) had Metastatic Disease to the Pelvic Lymph Nodes, all were Stage T2 or Higher. 17 Patients (19%) Died of Bladder Ca Disease-Specific Survival for Patients with Non-Muscle Invasive vs Muscle-Invasive Dz (87% vs. 74%, p = 0.01). Death from Bladder Cancer for Patients w/pathological Upstage was 82% vs. 50%, Respectively (p = 0.03).

8 Treatment Options for BCG-refractory CIS of the Bladder: Intravesical Agents FDA-APPROVED AGENTS VALSTAR (valrubicin) Semisynthetic analogue of doxorubicin indicated for intravesical therapy of BCGrefractory CIS of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality NON FDA-APPROVED AGENTS Doxorubicin Gemcitabine Interferon alpha-2b Mitomycin Thiotepa Absorption and systemic toxicity rare due to high molecular weight Dosing and instillation schedules vary Broad-spectrum antitumor activity Limited patient population evaluated for non muscle-invasive bladder cancer The most commonly used interferon to treat non muscle-invasive urothelial carcinoma Commonly used in a perioperative fashion immediately after TURBT Should not be administered to patients with a known or suspected bladder perforation The oldest and one of the least-expensive intravesical drugs Myelosuppression is a risk at higher doses Bladder Cancer Clinical Guideline Update Panel. Linthicum, MD: American Urological Association Education and Research, Inc; 2007.

9 Indication for VALSTAR (valrubicin) Treatment for patients who have BCG Rx failure with CIS of the urinary bladder in patients in whom immediate cystectomy would be associated with unacceptable morbidity or mortality Only FDA approved drug for BCG-refractory CIS For Consultant Use Only.

10 Patient Demographics N=90 Median age: 69.5 years (range: 31 to 85) Male: 88%; White: 98% 100% had at least one TURB 82% had 4+ TURBs 40% had 5-17 TURBs 70% had undergone 2 or more courses of IVe BCG therapy 28% had between 3 and 5 courses of BCG Mean duration of disease 5 years (range: 1-27 years) Median duration of Tis: 25 months Data on file, Indevus Pharmaceuticals, Inc. For Consultant Use Only.

11 Efficacy Results Primary Efficacy Results 19 of 90 (21%) had a complete response; 7 were disease-free at last evaluation (21+ months) Median duration of response was 18 months for complete responders 10 patients who were non-responders had disease regression from CIS to lowgrade papillary tumors Therefore, 29/90 (32%) of patients had a clinical benefit from VALSTAR Other Efficacy Results Median time to cystectomy was 24 mo in nonresponders (40) and has not been reached in responders (4) Of the 4 patients who died from bladder cancer, none was a complete responder or underwent cystectomy Steinberg G, Bahnson R, Brosman S et al. J Urol 2000;163: For Consultant Use Only.

12 Intravesical Treatment Failures Chemotherapy Rx failures - BCG BCG Rx failures controversial 2 nd course of BCG more than 2 with very low success rates Early cystectomy high-risk patient (multifocal T1HG, CIS, Lymphatic/vascular invasion, Micropapillary) Intravesical chemotherapy poor results Salvage intravesical therapy

13 Salvage Intravesical Therapy IFN well tolerated, dose-dependent with 12-20% response rates BCG + IFN 1-2 year success rates of 40-45%, improved with 2 nd course and maintenance No difference BCG vs. BCG/IFN in BCG naïve patients Intravesical chemotherapeutics Valrubicin 8% durable response, 90% side effects Gemcitabine promising data, not FDA approved Taxanes (Paclitaxel and Docetaxel)

14 Emerging Intravesical Therapies ChemoThermotherapy Mitomycin C with local hyperthermia using micowave antennae on Foley catheter Electromotive Mitomycin C with 20 ma of electric current Photodynamic therapy using 5-aminoleulinic acid or the newer hypericin Taris Biomedical New Delivery System for Intravesical Therapy

15 Phase III Study to Evaluate the Efficacy and Safety of Mycobacterial Cell Wall DNA Complex in the Treatment of Patients With Non Muscle Invasive Bladder Cancer at High Risk of Progression and Who Are Refractory to BCG Alvaro Morales, 1 Harry Herr, 2 Ashish Kamat, 3 Gary Steinberg, 4 Robert Given, 5 Christine Lihou, 6 Zvi Cohen 7 1 Queen s University, Kingston, ON; 2 Memorial Sloan-Kettering Cancer Center, New York, NY; 3 The University of Texas M.D. Anderson Cancer Center, Houston, TX; 4 University of Chicago Medical Center, Chicago, IL; 5 Urology of Virginia, Norfolk, VA; 6 Endo Pharmaceuticals Inc., Chadds Ford, PA; 7 Bioniche Life Sciences Inc., Belleville, ON Research was supported by Bioniche Life Sciences Inc. and Endo Pharmaceuticals Inc. The information concerns an investigational use of a drug that has not been approved by the US Food and Drug Administration

16 MCC Dual Mechanism of Action NK = natural killer Figure kindly provided by Nigel C. Phillips of Bioniche Life Sciences Inc. and reprinted with permission NC Phillips, NC Phillips, Filion et al. Cancer Immunol Immunother. 2000;49: ; Filion MC, et al. Br J Cancer. 1999;79:

17 Patient Baseline Characteristics 129 patients were enrolled at 25 study sites in the United States and Canada Elderly population Mean age [range] 69 [41 90] years Over 2/3 of patients had CIS (primary or concomitant with papillary tumors), according to central pathologist 42% CIS only 25% CIS + papillary 26% papillary only 7% missing/no tumor Most patients had previously received 7 BCG instillations 24% received 1 induction course with no maintenance 21% received 21 instillations

18 Overall 1-Year DFS From First Dose Overall 1-year DFS rate was 25.0% and median DFS of 177 days DFS=disease-free survival; MCC=mycobacterial cell wall DNA complex. DFS in the overall intent-to-treat populations was determined from the central pathology results.

19 1-Year DFS by Tumor Type at Study Entry CIS vs Papillary Disease When subdivided by tumor type at study entry 35% for patients with only papillary tumors 21% for patients with CIS (primary or concomitant with papillary) CIS=carcinoma in situ; DFS=disease-free survival; MCC=mycobacterial cell wall DNA complex. DFS was determined from the central pathology results.

20 Conclusion Preliminary results indicate that MCC has activity in patients with BCG-refractory NMIBC and may provide an alternative to cystectomy for this patient population An additional phase III clinical trial of MCC vs Mitomycin C for BCG Refractory High Risk NMIBC is currently enrolling patients Research was supported by Bioniche Life Sciences Inc. and Endo Pharmaceuticals Inc. The information concerns an investigational use of a drug that has not been approved by the US Food and Drug Administration

21 Conclusions Significant Heterogenity of High Risk NMIBC Biomarkers needed to Predict Tumor Aggressiveness as well as Response to Therapy Newer Methods Required to Deliver Therapy Significant Patient and Surgery Comorbidities Make Cystectomy more Difficult.