1. Oncologic Drugs Advisory Committee
Presented by
Susan Honig, M.D.
at the
Oncologic Drugs Advisory Committee
meeting on
June 7, 1999

2. NDA 21-010 (NDA 50-778) Epirubicin hydrochloride Pharmacia & Upjohn
As a component of adjuvant therapy in patients with node positive breast cancer
For therapy of patients with locally advanced or metastatic disease

3. Epirubicin review team

4. Administrative history
NDA first submitted 7/13/84 for advanced breast cancer
Incomplete application resulting in NA 7/10/85
Marketed in over 80 countries worldwide
Current NDA submitted 12/15/98
Current application includes new data and new indications

5. Phase I history 1979-1980: Original Phase I trials
Optimal Phase II dose was mg/m2 as a single agent
50-75 mg/m2 in combination
: Second set of Phase I trials
Evidence of a dose-response curve
Better understanding of patient management
Optimal dose redefined as mg/m2 as single agent OR in combination

6. Adjuvant breast cancer trials: MA-5 and GFEA-05
Common aspects of trial design:
Node positive breast cancer
T4 tumors excluded
6 cycles of chemotherapy
Post-lumpectomy RT delayed until chemo complete
Stratified by nodal groups
Endpoints: DFS, then OS
Follow-up approximately 5 years

7. Adjuvant breast cancer: Differences in study design
Patient population
Premenopausal women only on MA-5
Pre- and postmenopausal women on GFEA-05
Nodes
MA-5: > 1 (+) LN
GFEA-05 designed with higher risk group: > 4 (+) LN; 1-3 (+) LN and ER/PR(-) and grade 2-3

8. Adjuvant breast cancer: Differences in study design
Other therapy allowed on GFEA-05
Post-mastectomy chest wall RT (balanced between treatment arms)
Tamoxifen 30 mg daily for 3 years in postmenopausal women
Stratification
MA-5 also stratified by type of surgery and ER/PR results
GFEA-05 stratified by center

9. Trial Regimens: MA-5 (716 patients)
CEF (n=356)
CTX 75 mg/m2 PO D 1-14
Epirubicin 60 mg/m2 IV D 1, 8
5-FU 500 mg/m2 IV D 1, 8
CMF (n=360)
CTX 100 mg/m2 PO D 1-14
Methotrexate 40 mg/m2 IV D 1, 8
5-FU 600 mg/m2 IV D 1, 8
Cycles repeated q 28 D x 6

10. Trial Regimens: GFEA-05 (565)
FEC 100 (n=276)
CTX 500 mg/m2
Epirubicin 100 mg/m2
5-FU 500 mg/m2
FEC 50 (n=289)
Epirubicin 50 mg/m2
All IV D1 Q 21 days x 6

11. Adjuvant breast cancer: Differences in dose/schedule
Within each study:
The doses of CTX and 5-FU were higher on the CMF arm than on the CEF arm in MA-5
The dose of epirubicin was twice as high on FEC 100 compared to FEC 50 in GFEA-05; doses of 5-FU and CTX were constant
Between studies:
The dose of epirubicin was 120 mg/m2 on MA-5 and 100 mg/m2 on GFEA-05
MA-5 used a D 1, 8 q 28 day schedule; GFEA-05 used a D1 q 21 day schedule
Higher doses of C and F on MA-5 than on GFEA-05

12. Adjuvant breast cancer: Efficacy in MA-5
DFS (p=0.013) OS (p=0.13)
green=CEF; red=CMF

13. Adjuvant breast cancer: Efficacy in GFEA-05
DFS (p=0.007) OS (p=0.007)
red=FEC 100; green=FEC 50

14. Adjuvant breast cancer trials: Efficacy

15. Adjuvant breast cancer: Efficacy
Differences from the applicant’s analysis
FDA performed an unadjusted intent-to-treat analysis of DFS and OS for both studies
No difference from the results reported by the applicant
Efficacy seen in both pre- and postmenopausal women

16. Adjuvant breast cancer: Acute toxicity

17. Adjuvant breast cancer: Long-term toxicity (5-year F/U)

18. Adjuvant breast cancer: Secondary leukemias
Cumulative doses of 495 mg/m2 or higher in these trials
Short latency (9-36 months)
M4-M5 subtypes, some with characteristic translocations
Best assessment of the risk of secondary leukemia from the overall database:
0.24% at 3 years
0.77% at 5 years

19. Adjuvant breast cancer: Cardiac toxicity
MA-5: LVEF measurements at baseline, 6, 12, 36, and 60 months
5 patients on CEF and 1 on CMF developed CHF (MA-5)
7 on CEF and 3 on CMF experienced drops in LVEF without CHF
GFEA-05: Optional cardiac evaluation after treatment

20. Cardiac toxicity
Best assessment of cardiac risk from the overall database: 4% incidence of CHF at a cumulative dose of 900 mg/m2
Maximum epirubicin dose
720 mg/m2 on MA-5
600 mg/m2 on GFEA-05

21. Adjuvant breast cancer trials

22. Adjuvant breast cancer: Summary
Improvement in DFS and OS with epirubicin at the planned doses of 100 and 120 mg/m2
Delivered DI for C and F was higher on CMF than on CEF; outcome can be attributed to the effects of epirubicin

23. Advanced breast cancer trials: HEPI/013 and HEPI/010
Common design features:
Metastatic breast cancer patients with no prior chemotherapy for metastatic disease
Measurable or evaluable disease
DFI > 12 months
Stratified by number of sites and by presence of visceral disease
Incorporated 6 cycles of treatment followed by observation (2-3 consolidation cycles for responders)

24. Advanced breast cancer: Differences in study design
Prior adjuvant anthracyclines allowed in HEPI/010 (< 60 mg/m2)
Endpoints:
HEPI/013: TTP, then RR, then QOL, then OS
HEPI/010: OS, then RR, then TTP, then QOL

25. Trial regimens: HEPI/013 CEF CMF D 1 and 8 every 21 days
CTX 400 mg/m2 IV D1,8
Epirubicin 50 mg/m2 IV D1, 8
5-FU 500 mg/m2 IV D1, 8
CMF
CTX 500 mg/m2 IV D1, 8
Methotrexate 40 mg/m2 IV D1, 8
5-FU 600 mg/m2 IV D1, 8
D 1 and 8 every 21 days

26. Trial regimens: HEPI/010 FEC 100 FEC 50 D 1 Q 21 days
CTX 500 mg/m2 IV D1
Epirubicin 100 mg/m2 IV D1
5-FU 500 mg/m2 IV D1
FEC 50
Epirubicin 50 mg/m2 IV D1
D 1 Q 21 days

27. Advanced breast cancer: Differences in dose and schedule
Within each study:
HEPI/013: Doses of CTX and 5-FU were higher on CMF than on FEC
HEPI/010: For FEC 50 v. FEC 100, only the epirubicin dose differed
Between studies:
The high-dose epirubicin arms differed in schedule but not dose of epirubicin:
HEPI/013: D 1, 8 q 21 days
HEPI/010: D1 q 21 days
Higher doses of C and F (800 and 1000 mg/m2/cycle respectively) on HEPI/013 than on HEPI/010 (500 and 500 mg/m2/cycle)

28. Advanced breast cancer: Efficacy in HEPI/013
TTP (p=0.0002) OS (p=0.21)
green=FEC; red=CMF

29. Advanced breast cancer: Efficacy in study HEPI/013
Median TTP
8.75 mo FEC 100 v mo CMF; p=0.0002
Median OS
20.1 mo FEC 100 v mo CMF; p=0.21
44% of patients on CMF subsequently received anthracyclines
Survival benefit from second-line therapy may have confounded the analysis in this trial
FDA unadjusted ITT analysis gives the same results

30. Advanced breast cancer: Efficacy in study HEPI/010
No difference in OS, TTP
Response rates
49% on FEC 100 v. 36% on FEC 50
p=0.007
Verified by FDA

31. Advanced breast cancer: Toxicity

32. Deaths on study

33. Cardiac toxicity HEPI/013 HEPI/010
Evaluations: baseline, mg/m2, mg/m2, and at each cycle (71% on FEC were compliant)
Responders received up to 900 mg/m2 E
10 patients on FEC with CHF (4.5%)
HEPI/010
Evaluations: baseline, mg/m2, and after each subsequent cycle (poor compliance)
Patients in CR received up to 800 mg/m2 E
Patients with CHF: 0 on FEC 100, 2 (1%) on FEC 50

34. Advanced breast cancer trials

35. Literature comparison of epi to dox as first-line therapy of MBC
Doxorubicin generally considered to convey a 6-month survival benefit as first-line therapy
New drugs should demonstrate that this benefit is preserved
The overall odds ratio of D:E for survival calculated in the applicant’s mini-meta-analysis was 0.98 (95% CI 0.80, 1.20), suggesting that epi is comparable to dox

36. Regulatory Issues for metastatic breast cancer
HEPI/013: benefit as measured by TTP, but not survival
Survival potentially confounded by 44% crossover rate
HEPI/010: response rate the only endpoint that was significantly different between arms
Outcome may be sensitive to schedule
Threshold dose rather than dose-response

37. Regulatory issues in advanced breast cancer
Is TTP alone sufficient for demonstrating clinical benefit in first-line treatment of metastatic breast cancer?
Does the evidence of epirubicin activity and survival benefit in the adjuvant setting permit greater reliance on TTP in this setting?
Is a 2.5-month difference in TTP for FEC 100 compared to a dose-intense CMF regimen clinically meaningful in first-line treatment of metastatic breast cancer?