# Presentation: 771921

## Susan Honig, M.D.

- by
- at the
- Oncologic Drugs Advisory Committee
- meeting
- on
- June 7, 1999

## 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

## Epirubicin review team

## 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

## Phase I history

- 1979-1980: Original Phase I trials
- Optimal Phase II dose was 60-90 mg/m2 as a single agent
- 50-75 mg/m2 in combination
- 1983-1989: Second set of Phase I trials
- Evidence of a dose-response curve
- Better understanding of patient management
- Optimal dose redefined as 100-150 mg/m2 as single agent OR in combination

## 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

## 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

## 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

## 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

## 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)
- CTX 500 mg/m2
- Epirubicin 50 mg/m2
- 5-FU 500 mg/m2
- All IV D1 Q 21 days x 6

## 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

## Adjuvant breast cancer: Efficacy in MA-5

- DFS (p=0.013)			OS (p=0.13)
- green=CEF; red=CMF

## Adjuvant breast cancer: Efficacy in GFEA-05

- DFS (p=0.007)			OS (p=0.007)
- red=FEC 100; green=FEC 50

## Adjuvant breast cancer trials: Efficacy

## 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

## Adjuvant breast cancer: Acute toxicity

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

## 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

## 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

## 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

## Adjuvant breast cancer trials

## 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

## 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)

## 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

## Trial regimens: HEPI/013

- CEF
- 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

## Trial regimens: HEPI/010

- FEC 100
- CTX 500 mg/m2 IV D1
- Epirubicin 100 mg/m2 IV D1
- 5-FU 500 mg/m2 IV D1
- FEC 50
- CTX 500 mg/m2 IV D1
- Epirubicin 50 mg/m2 IV D1
- 5-FU 500 mg/m2 IV D1
- D 1 Q 21 days

## 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)

## Advanced breast cancer: Efficacy in HEPI/013

- TTP (p=0.0002)			OS (p=0.21)
- green=FEC; red=CMF

## Advanced breast cancer: Efficacy in study HEPI/013

- Median TTP
- 8.75 mo FEC 100 v. 6.25 mo CMF; p=0.0002
- Median OS
- 20.1 mo FEC 100 v. 18.2 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

## 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

## Advanced breast cancer: Toxicity

## Deaths on study

## Cardiac toxicity

- HEPI/013
- Evaluations: baseline, 400-500 mg/m2, 700-800 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, 350-400 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

## Advanced breast cancer trials

## 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

## 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

## 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?