Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "Presented by Susan Honig, M.D. at the Oncologic Drugs Advisory Committee meeting on June 7, 1999."— Presentation transcript:

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

2 NDA (NDA ) 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 : Original Phase I trials –Optimal Phase II dose was mg/m 2 as a single agent –50-75 mg/m 2 in combination : Second set of Phase I trials –Evidence of a dose-response curve –Better understanding of patient management –Optimal dose redefined as mg/m 2 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/m 2 PO D 1-14 –Epirubicin 60 mg/m 2 IV D 1, 8 –5-FU 500 mg/m 2 IV D 1, 8 CMF (n=360) –CTX 100 mg/m 2 PO D 1-14 –Methotrexate 40 mg/m 2 IV D 1, 8 –5-FU 600 mg/m 2 IV D 1, 8 Cycles repeated q 28 D x 6

10 Trial Regimens: GFEA-05 (565) FEC 100 (n=276) –CTX 500 mg/m 2 –Epirubicin 100 mg/m 2 –5-FU 500 mg/m 2 FEC 50 (n=289) –CTX 500 mg/m 2 –Epirubicin 50 mg/m 2 –5-FU 500 mg/m 2 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/m 2 on MA-5 and 100 mg/m 2 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/m 2 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/m 2 Maximum epirubicin dose –720 mg/m 2 on MA-5 –600 mg/m 2 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/m 2 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/m 2 ) 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 –CTX 400 mg/m 2 IV D1,8 –Epirubicin 50 mg/m 2 IV D1, 8 –5-FU 500 mg/m 2 IV D1, 8 CMF –CTX 500 mg/m 2 IV D1, 8 –Methotrexate 40 mg/m 2 IV D1, 8 –5-FU 600 mg/m 2 IV D1, 8 D 1 and 8 every 21 days

26 Trial regimens: HEPI/010 FEC 100 –CTX 500 mg/m 2 IV D1 –Epirubicin 100 mg/m 2 IV D1 –5-FU 500 mg/m 2 IV D1 FEC 50 –CTX 500 mg/m 2 IV D1 –Epirubicin 50 mg/m 2 IV D1 –5-FU 500 mg/m 2 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/m 2 /cycle respectively) on HEPI/013 than on HEPI/010 (500 and 500 mg/m 2 /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= 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 –Evaluations: baseline, mg/m 2, mg/m 2, and at each cycle (71% on FEC were compliant) –Responders received up to 900 mg/m 2 E –10 patients on FEC with CHF (4.5%) HEPI/010 –Evaluations: baseline, mg/m 2, and after each subsequent cycle (poor compliance) –Patients in CR received up to 800 mg/m 2 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?


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

Similar presentations


Ads by Google