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BCG Plus IFN-BCG Plus IFN- Combination TherapyCombination Therapy

RationaleRationale Evidence of synergistic activityEvidence of synergistic activity

– Accentuates the TAccentuates the THH1 cytokine response1 cytokine response Recombinant interferon alfa and BCG have complementary Recombinant interferon alfa and BCG have complementary

biologic activitiesbiologic activities– Infiltration of lymphocytes and NK cells to bladder (BCG)Infiltration of lymphocytes and NK cells to bladder (BCG)– Increased HLA expression on TCC cells (IFN-Increased HLA expression on TCC cells (IFN-))– Increased cytolytic activity of cytotoxic T cells (IFN-Increased cytolytic activity of cytotoxic T cells (IFN-))

Recombinant interferon alfa and BCG are biocompatibleRecombinant interferon alfa and BCG are biocompatible Reduced dose of BCG may reduce toxicity while Reduced dose of BCG may reduce toxicity while

maintaining efficacymaintaining efficacy

BCG Plus IFN BCG Plus IFN Mechanism of ActionMechanism of Action

Bladder Tumor Bladder Tumor Cell ExpressingCell Expressing

Activation Markers Activation Markers and BCG and BCG AntigensAntigens

TTHH11 IL-2IL-2

IFN-IFN-

TTHH00 IL-12IL-12

TNF-TNF-

IL 12IL 12

(+)(+)

(+)(+)

ActivatedActivatedMacrophageMacrophage

IFN-IFN-

(+)(+)

BCG

CTLCTL

BCG Plus IFN BCG Plus IFN -2b-2bPublished Clinical TrialsPublished Clinical Trials

TumorTumorMedianMedian

StudyStudy No.No. TypeType RegimenRegimen DoseDose OutcomeOutcome F/U (Mo)F/U (Mo)

Stricker, 1996Stricker, 1996 77 CISCIS IFN IFN -2b +-2b + 10–100 MIU10–100 MIU 86% CR86% CR 1212

1/2-dose BCG* 1/2-dose BCG* 60 mg60 mg

55 pTCC pTCC IFN IFN -2b +-2b + 10–100 MIU10–100 MIU 60% NED,60% NED, 12121/2-dose BCG1/2-dose BCG 60 mg60 mg 40% PR40% PR

Bercovich, 1995Bercovich, 1995 1818 pTCCpTCC Full-dose BCG*Full-dose BCG* 120 mg120 mg RR = 28%RR = 28% 2424

1818 IFN IFN -2b +-2b + 10 MIU10 MIU RR = 22%RR = 22% 17171/2-dose BCG1/2-dose BCG 60 mg60 mg

O’Donnell,  2001O’Donnell,  2001 4040 Mixed,Mixed, IFN IFN -2b +-2b + 50 MIU50 MIU 63% NED @ 12 mo63% NED @ 12 mo 3030high riskhigh risk 1/3-dose BCG1/3-dose BCG†† + + 27 mg27 mg 53% NED @ 24 mo53% NED @ 24 mo

maintenancemaintenance

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 BCG Plus IFN -2b in -2b in BCG FailuresBCG Failures

BCG failures (N = 40)BCG failures (N = 40) Median follow-up: 30 months; range, 15–52 monthsMedian follow-up: 30 months; range, 15–52 months High-risk population High-risk population

– 98% multifocal disease 98% multifocal disease

– 85% failed BCG within 6 months 85% failed BCG within 6 months

– 78% aggressive histology (CIS or grade 3, T1)78% aggressive histology (CIS or grade 3, T1)

– 63% multirecurrent disease (>2) 63% multirecurrent disease (>2) 52% failed >1 course of BCG; 48% failed 152% failed >1 course of BCG; 48% failed 1

– 33% had long duration of bladder cancer (>4 years)33% had long duration of bladder cancer (>4 years)

– Cystectomy had already been offered to 22Cystectomy had already been offered to 22

O’Donnell MA, et al. J Urol. 2001;166:1300.

0 4 8 12 16 20 24 28 32 36 40 440.0

0.2

0.4

0.6

0.8

1.0

63%63%53%

Median Follow-up = 30 MonthsMedian Follow-up = 30 Months

40 40 40 39 37 31 25 15 10 8 4 2

No. Patients Available at Follow-upNo. Patients Available at Follow-up

Months After Treatment InitiationMonths After Treatment Initiation

(Actual Disease Free = 55%)(Actual Disease Free = 55%)

BCG Plus IFN BCG Plus IFN -2b in BCG Failures -2b in BCG Failures Disease-Free SurvivalDisease-Free SurvivalF

ract

ion

Fre

e o

f C

an

cer

Fra

ctio

n F

ree

of

Ca

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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;166:1300-1305.

BCG Plus IFN BCG Plus IFN -2b in BCG Failures-2b in BCG Failures RecurrencesRecurrences

45% (18/40) had recurrence following BCG + IFN 45% (18/40) had recurrence following BCG + IFN -2b-2b 78% (14/18) recurrences were detected at 1st cystoscopy78% (14/18) recurrences were detected at 1st cystoscopy

– 5 cases of muscle invasion, referred for cystectomy 5 cases of muscle invasion, referred for cystectomy and/or chemotherapy + radiationand/or chemotherapy + radiation

– No early failures had metastasis or died of No early failures had metastasis or died of bladder cancerbladder cancer

4 late recurrences (8, 21, 22, 24 months)4 late recurrences (8, 21, 22, 24 months)– 2 low-grade, low-stage treated with TUR2 low-grade, low-stage treated with TUR– 2 with disease outside bladder 2 with disease outside bladder

No recurrences after 24 months or in the 46% who No recurrences after 24 months or in the 46% who completed all 3 planned maintenance cyclescompleted all 3 planned maintenance cycles

O’Donnell MA, et al. J Urol. 2001;166:1300.

BCG Plus IFN BCG Plus IFN -2b in BCG Failures -2b in BCG Failures Other ObservationsOther Observations

42% (5/12) of those who required 2 induction regimens 42% (5/12) of those who required 2 induction regimens were long-term responderswere long-term responders

Number of previous recurrences and tumor Number of previous recurrences and tumor aggressiveness did not predict responseaggressiveness did not predict response

Patients who failed BCG twice did about as well as Patients who failed BCG twice did about as well as those who had failed BCG only oncethose who had failed BCG only once

Trend toward lower response rates in patients with Trend toward lower response rates in patients with previous relapse at <6 months of BCG or disease previous relapse at <6 months of BCG or disease duration >4 years duration >4 years

Of 22 patients for whom cystectomy had already been Of 22 patients for whom cystectomy had already been recommended, 12 (55%) were disease free with recommended, 12 (55%) were disease free with normally functioning bladder at end of studynormally functioning bladder at end of study

O’Donnell MA, et al. J Urol. 2001;166:1300.

BCG Plus IFN BCG Plus IFN -2b in BCG Failures -2b in BCG Failures Efficacy Comparison Efficacy Comparison With Historical SeriesWith Historical Series

Dis

ease

Fre

e at

2 Y

ears

(%

)D

isea

se F

ree

at 2

Yea

rs (

%)

0

10

20

30

40

50

60

BCGBCG11 IFN IFN -2b-2b22 Mitomycin CMitomycin C33 ValrubicinValrubicin44 BCG + BCG + IFN IFN -2b-2b55

20

12

23

8

55

1. Catalona WJ, et al. J Urol. 1987;137:220. 2. Williams RD, et al. J Urol. 1996;155(suppl):494A [abstract 735]. 3. Malmstrom PU, et al. J Urol. 1999;161:1124. 4. Steinberg G, et al. J Urol. 2000;163:761. 5. O’Donnell MA, et al. J Urol. 2001;166:1300.

BCG Plus IFN BCG Plus IFN -2b -2b in BCG-Naive Patientsin BCG-Naive Patients

N = 22 BCG-naive patientsN = 22 BCG-naive patients Full-dose BCG + 50 MIU IFN Full-dose BCG + 50 MIU IFN -2b-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.

TumorTumor RecurrenceRecurrence MedianMedianStudyStudy No.No. TypeType RegimenRegimen DoseDose RateRate F/U (Mo)F/U (Mo)

Esuvaranathan, Esuvaranathan, 8080 pTCCpTCC IFN IFN -2b -2b 10 MIU/10 MIU/ 10%10% 1919 2000 2000 + 1/3 BCG* + 1/3 BCG* 27 mg 27 mg

CIS CIS vsvs1/3 BCG 1/3 BCG 27 mg27 mg 30%30%

vsvsfull-dosefull-dose 81 mg81 mg 50%50%

BCG BCG

LammLamm 100100 TCCTCC IFN IFN -2b -2b 50 MIU50 MIU OngoingOngoing Ongoing OngoingCISCIS + full-dose + full-dose

BCGBCG vsvs

full-dosefull-dose BCG BCG

*Connaught strain

Esuvaranathan K, et al. J Urol. 2000;163(suppl):152 [abstract 675].

BCG Plus IFN BCG Plus IFN 2b 2b Ongoing Randomized TrialsOngoing Randomized Trials

BCG Plus IFN BCG Plus IFN 2b Safety2b SafetyNational Multicenter Phase II TrialNational Multicenter Phase II Trial

BCG/IFN has acceptable level of serious BCG/IFN has acceptable level of serious toxicity in comparison with BCGtoxicity in comparison with BCG

Additional serious AEs with BCG/IFNAdditional serious AEs with BCG/IFN– 10 cardiac events (8 not drug related)10 cardiac events (8 not drug related)– 6 reversible neurologic events6 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 Patients with previous BCG failure not at

increased risk for toxicityincreased risk for toxicity

O’Donnell MA, et al. Abstract 760. AUA 9th Annual Meeting; May 25–30, 2002; Orlando, Fla.

BCG Plus IFN BCG Plus IFN 2b Candidates2b Candidates

BCG/IFN is considered investigationalBCG/IFN is considered investigational Appropriate candidates may include:Appropriate candidates may include:

1st-line1st-line High-risk bladder cancer (T1, High-risk bladder cancer (T1, grade 3 or multifocal CIS)grade 3 or multifocal CIS)

2nd-line (after 2nd-line (after BCG failure)BCG failure)

CIS or multifocal stage Ta grade CIS or multifocal stage Ta grade 2–32–3

3rd-line3rd-line Any patient who has failed 2 Any patient who has failed 2 BCG courses, if not candidate BCG courses, if not candidate for cystectomyfor cystectomy

BCG + IFN BCG + IFN -2b -2b Combination TherapyCombination Therapy

ConclusionsConclusions BCG + IFN BCG + IFN -2b combination therapy has synergistic -2b combination therapy has synergistic

immunomodulatory and antitumor activity (enhances the immunomodulatory and antitumor activity (enhances the TTHH1 response)1 response)

In open-label trials, BCG + IFN In open-label trials, BCG + IFN -2b combination -2b combination therapy was well tolerated and allowed BCG dose therapy was well tolerated and allowed BCG dose reductions without compromising efficacy reductions without compromising efficacy

BCG + IFN BCG + IFN -2b combination therapy is effective in -2b combination therapy is effective in patients who have failed ≥1 previous course(s) of BCGpatients who have failed ≥1 previous course(s) of BCG

Combination therapy may be considered prior to radical Combination therapy may be considered prior to radical cystectomy in high-risk patientscystectomy in high-risk patients

Randomized controlled trials are under wayRandomized controlled trials are under way