Oncologic Drugs Advisory Committee Presented by Susan Honig, M.D. 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) Epirubicin 50 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 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

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

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 HEPI/010 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?