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BCG Plus IFN-  Combination Therapy Rationale Evidence of synergistic activity Evidence of synergistic activity –Accentuates the T H 1 cytokine response Recombinant interferon alfa and BCG have complementary biologic activities Recombinant interferon alfa and BCG have complementary biologic activities –Infiltration of lymphocytes and NK cells to bladder (BCG) –Increased HLA expression on TCC cells (IFN-  ) –Increased cytolytic activity of cytotoxic T cells (IFN-  ) Recombinant interferon alfa and BCG are biocompatible Recombinant interferon alfa and BCG are biocompatible Reduced dose of BCG may reduce toxicity while maintaining efficacy Reduced dose of BCG may reduce toxicity while maintaining efficacy

BCG Plus IFN    Mechanism of Action Bladder Tumor Cell Expressing Activation Markers and BCG Antigens TH1TH1TH1TH1 IL-2 IFN-  TH0TH0TH0TH0 IL-12 TNF-  IL 12 (+) (+) Activated Macrophage IFN-  (+) BCG CTL

BCG Plus IFN  -2b Published Clinical Trials TumorMedian TumorMedian StudyNo.TypeRegimenDoseOutcomeF/U (Mo) Stricker, 19967CISIFN  -2b +10–100 MIU86% CR 12 1/2-dose BCG* 60 mg 5 pTCC IFN  -2b +10–100 MIU60% NED,121/2-dose BCG60 mg40% PR Bercovich, pTCCFull-dose BCG*120 mgRR = 28%24 18 IFN  -2b +10 MIURR = 22%17 1/2-dose BCG60 mg O’Donnell, Mixed, IFN  -2b +50 MIU63% 12 mo30 O’Donnell, Mixed, IFN  -2b +50 MIU63% 12 mo30 high risk1/3-dose BCG † +27 mg53% 24 mo maintenance Stricker P, et al. Urology. 1996;48:957. Bercovich E, et al. Arch Ital Urol Androl. 1995;67:257. O’Donnell MA, et al. J Urol. 2001;166:1300. *Pasteur strain; † Connaught strain CR = complete response; NED = no evidence of disease; PR = partial response; RR = recurrence rate.

BCG Plus IFN  -2b in BCG Failures BCG failures (N = 40) BCG failures (N = 40) Median follow-up: 30 months; range, 15–52 months Median follow-up: 30 months; range, 15–52 months High-risk population High-risk population –98% multifocal disease –85% failed BCG within 6 months –78% aggressive histology (CIS or grade 3, T1) –63% multirecurrent disease (>2) 52% failed >1 course of BCG; 48% failed 1 52% failed >1 course of BCG; 48% failed 1 –33% had long duration of bladder cancer (>4 years) –Cystectomy had already been offered to 22 O’Donnell MA, et al. J Urol. 2001;166:1300.

% 53% Median Follow-up = 30 Months No. Patients Available at Follow-up Months After Treatment Initiation (Actual Disease Free = 55%) BCG Plus IFN  -2b in BCG Failures Disease-Free Survival Fraction Free of Cancer 48 Reprinted by permission of Lippincott Williams and Wilkins from O’Donnell MA, Krohn J, DeWolf WC. Salvage intravesical therapy with superficial bladder cancer in whom bacillus Calmette-Guerin alone previously failed. J Urol. 2001;166:

BCG Plus IFN  -2b in BCG Failures Recurrences 45% (18/40) had recurrence following BCG + IFN  -2b 45% (18/40) had recurrence following BCG + IFN  -2b 78% (14/18) recurrences were detected at 1st cystoscopy 78% (14/18) recurrences were detected at 1st cystoscopy –5 cases of muscle invasion, referred for cystectomy and/or chemotherapy + radiation –No early failures had metastasis or died of bladder cancer 4 late recurrences (8, 21, 22, 24 months) 4 late recurrences (8, 21, 22, 24 months) –2 low-grade, low-stage treated with TUR –2 with disease outside bladder No recurrences after 24 months or in the 46% who completed all 3 planned maintenance cycles No recurrences after 24 months or in the 46% who completed all 3 planned maintenance cycles O’Donnell MA, et al. J Urol. 2001;166:1300.

BCG Plus IFN  -2b in BCG Failures Other Observations 42% (5/12) of those who required 2 induction regimens were long-term responders 42% (5/12) of those who required 2 induction regimens were long-term responders Number of previous recurrences and tumor aggressiveness did not predict response Number of previous recurrences and tumor aggressiveness did not predict response Patients who failed BCG twice did about as well as those who had failed BCG only once Patients who failed BCG twice did about as well as those who had failed BCG only once Trend toward lower response rates in patients with previous relapse at 4 years Trend toward lower response rates in patients with previous relapse at 4 years Of 22 patients for whom cystectomy had already been recommended, 12 (55%) were disease free with normally functioning bladder at end of study Of 22 patients for whom cystectomy had already been recommended, 12 (55%) were disease free with normally functioning bladder at end of study O’Donnell MA, et al. J Urol. 2001;166:1300.

BCG Plus IFN  -2b in BCG Failures Efficacy Comparison With Historical Series Disease Free at 2 Years (%) BCG 1 IFN  -2b 2 Mitomycin C 3 Valrubicin 4 BCG + IFN  -2b Catalona WJ, et al. J Urol. 1987;137: Williams RD, et al. J Urol. 1996;155(suppl):494A [abstract 735]. 3. Malmstrom PU, et al. J Urol. 1999;161: Steinberg G, et al. J Urol. 2000;163: O’Donnell MA, et al. J Urol. 2001;166:1300.

BCG Plus IFN  -2b in BCG-Naive Patients N = 22 BCG-naive patients N = 22 BCG-naive patients Full-dose BCG + 50 MIU IFN  -2b Full-dose BCG + 50 MIU IFN  -2b Disease free at 2 years: 68% Disease free at 2 years: 68% O’Donnell MA, unpublished data cited in O’Donnell MA, et al. J Urol. 2001;166:1300.

TumorRecurrenceMedian StudyNo.TypeRegimenDoseRateF/U (Mo) Esuvaranathan, 80pTCC IFN  -2b 10 MIU/10% /3 BCG* 27 mg CIS vs 1/3 BCG 27 mg30% vs full-dose81 mg50% BCG Lamm100TCCIFN  -2b 50 MIUOngoing Ongoing CIS + full-dose BCG vs full-dose BCG *Connaught strain Esuvaranathan K, et al. J Urol. 2000;163(suppl):152 [abstract 675]. BCG Plus IFN  2b Ongoing Randomized Trials

BCG Plus IFN  2b Safety National Multicenter Phase II Trial BCG/IFN has acceptable level of serious toxicity in comparison with BCG BCG/IFN has acceptable level of serious toxicity in comparison with BCG Additional serious AEs with BCG/IFN Additional serious AEs with BCG/IFN –10 cardiac events (8 not drug related) –6 reversible neurologic events Less risk of BCG sepsis (0.1% vs 0.4%) Less risk of BCG sepsis (0.1% vs 0.4%) Patients with previous BCG failure not at increased risk for toxicity Patients with previous BCG failure not at increased risk for toxicity O’Donnell MA, et al. Abstract 760. AUA 9th Annual Meeting; May 25–30, 2002; Orlando, Fla.

BCG Plus IFN  2b Candidates BCG/IFN is considered investigational BCG/IFN is considered investigational Appropriate candidates may include: Appropriate candidates may include: 1st-line High-risk bladder cancer (T1, grade 3 or multifocal CIS) 2nd-line (after BCG failure) CIS or multifocal stage Ta grade 2–3 3rd-line Any patient who has failed 2 BCG courses, if not candidate for cystectomy

BCG + IFN  -2b Combination Therapy Conclusions BCG + IFN  -2b combination therapy has synergistic immunomodulatory and antitumor activity (enhances the T H 1 response) BCG + IFN  -2b combination therapy has synergistic immunomodulatory and antitumor activity (enhances the T H 1 response) In open-label trials, BCG + IFN  -2b combination therapy was well tolerated and allowed BCG dose reductions without compromising efficacy In open-label trials, BCG + IFN  -2b combination therapy was well tolerated and allowed BCG dose reductions without compromising efficacy BCG + IFN  -2b combination therapy is effective in patients who have failed ≥1 previous course(s) of BCG BCG + IFN  -2b combination therapy is effective in patients who have failed ≥1 previous course(s) of BCG Combination therapy may be considered prior to radical cystectomy in high-risk patients Combination therapy may be considered prior to radical cystectomy in high-risk patients Randomized controlled trials are under way Randomized controlled trials are under way