Transcript Bladder Cancer Incidence by Stage

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BCG Plus IFN-
Combination Therapy
Rationale
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Evidence of synergistic activity
– Accentuates the TH1 cytokine response
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
Reduced dose of BCG may reduce toxicity while
maintaining efficacy
BCG Plus IFN 
Mechanism of Action
IFN-
TH0
IL-12
(+)
(+)
IFN-g
Activated
Macrophage
TH1
IL-2
Bladder Tumor
Cell Expressing
Activation Markers
and BCG
(+)
Antigens
BCG
TNF-
IL 12
CTL
BCG Plus IFN -2b
Published Clinical Trials
No.
Tumor
Type
Stricker, 1996
7
CIS
pTCC
NED,
5
12
Bercovich, 1995
18
pTCC
Study
18
O’Donnell, 2001 40
Outcome
Median
F/U (Mo)
86% CR
12
10–100 MIU
1/2-dose BCG
60%
60 mg
40% PR
Full-dose BCG*
120 mg
RR = 28%
24
IFN -2b +
1/2-dose BCG
10 MIU
60 mg
RR = 22%
17
Regimen
Dose
IFN -2b +
10–100 MIU
1/2-dose BCG*
60 mg
IFN -2b +
Mixed,
IFN -2b +
high risk 1/3-dose BCG† +
maintenance
50 MIU
27 mg
63% NED @ 12 mo 30
53% NED @ 24 mo
*Pasteur strain; †Connaught strain
CR = complete response; NED = no evidence of disease; PR = partial response;
RR = recurrence rate.
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.
BCG Plus IFN -2b in
BCG Failures
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BCG failures (N = 40)
Median follow-up: 30 months; range, 15–52 months
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
– 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.
BCG Plus IFN -2b in BCG Failures
Disease-Free Survival
Fraction Free of Cancer
1.0
0.8
Median Follow-up = 30 Months
0.6
63%
53%
(Actual Disease Free = 55%)
0.4
0.2
No. Patients Available at Follow-up
40 40
40
39
37
31
25
15
10
8
4
12
16
20
24
28
32
36
40
4
2
0.0
0
8
44 48
Months After Treatment Initiation
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 -2b in BCG Failures
Recurrences
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45% (18/40) had recurrence following BCG + IFN -2b
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)
– 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
O’Donnell MA, et al. J Urol. 2001;166:1300.
BCG Plus IFN -2b in BCG Failures
Other Observations
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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
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 <6 months of BCG or disease
duration >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
O’Donnell MA, et al. J Urol. 2001;166:1300.
Disease Free at 2 Years (%)
BCG Plus IFN -2b in BCG Failures
Efficacy Comparison
With Historical Series
60
55
50
40
30
20
23
20
12
10
0
BCG1
8
IFN -2b2 Mitomycin C3 Valrubicin4
BCG +
IFN -2b5
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 -2b
in BCG-Naive Patients
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N = 22 BCG-naive patients
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Full-dose BCG + 50 MIU IFN -2b
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Disease free at 2 years: 68%
O’Donnell MA, unpublished data cited in O’Donnell MA, et al. J Urol.
2001;166:1300.
BCG Plus IFN  2b
Ongoing Randomized Trials
Study
No.
Tumor
Type
Esuvaranathan,
2000
80
pTCC
CIS
Lamm
100
TCC
CIS
Recurrence
Rate
Median
F/U (Mo)
19
Regimen
Dose
IFN -2b
+ 1/3 BCG*
vs
1/3 BCG
vs
full-dose
BCG
10 MIU/
27 mg
10%
27 mg
30%
81 mg
50%
IFN -2b
+ full-dose
BCG
vs
full-dose
BCG
50 MIU
Ongoing
*Connaught strain
Esuvaranathan K, et al. J Urol. 2000;163(suppl):152 [abstract 675].
Ongoing
BCG Plus IFN  2b Safety
National Multicenter Phase II Trial
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BCG/IFN has acceptable level of serious
toxicity in comparison with BCG
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%)
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
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BCG/IFN is considered investigational
Appropriate candidates may include:
1st-line
High-risk bladder cancer (T1,
grade 3 or multifocal CIS)
2nd-line (after CIS or multifocal stage Ta grade
BCG failure) 2–3
3rd-line
Any patient who has failed 2
BCG courses, if not candidate
for cystectomy
BCG + IFN -2b
Combination Therapy
Conclusions
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BCG + IFN -2b combination therapy has synergistic
immunomodulatory and antitumor activity (enhances
the TH1 response)
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
Combination therapy may be considered prior to radical
cystectomy in high-risk patients
Randomized controlled trials are under way