1. NDA 50-772 TLC D-99 Doxorubicin HCL Liposome The Liposome Company, Inc. Proposed Indication: “First line treatment of metastatic breast cancer in combination with cyclophosphamide”

2. TLC D-99 Review Team

3. Administrative History 11/24/87IND # 30,894 submitted 2/4/94End of Phase II meeting 2/4/94End of Phase II meeting 6/30/98Guidance meeting (Study 2 closed) 6/30/98Guidance meeting (Study 2 closed) 11/3/98Study 3 included as a supportive trial 11/3/98Study 3 included as a supportive trial 12/14/98NDA submitted

4. In 1994 the Agency agreed to: n Utilize response rate as the primary basis of efficacy comparison. n Utilize proportional analyses rather than absolute increments (15%). n Evaluate response rates using 95% C.I. of the odds ratio. n Utilize 1-sided C.I. for this response comparison. n Utilize a lower bound of this C.I. (R = 0.75)

5. Administrative History n June 30,1998Guidance meeting (Study 2 closed) n Nov 3, 1998Study 3 included as a supportive trial n Dec 14, 1998NDA submitted

6. Study Design and Endpoints

7. The dose of epirubicin used in study 3 has not been established equivalent to doxorubicin for the following reasons: n Doses of 100 to 120 mg/m 2 have been used in combination therapy and were more effective than the lower doses. n Epirubicin may be not equivalent to doxorubicin on a mg per mg basis. n Epirubicin at 75 mg/m 2 has not been demonstrated to be a standard treatment for first line metastatic breast cancer.

8. Survival Curve Epirubicin Study

9. Efficacy Results Studies 1 and 2

10. Survival Studies 1 and 2

11. Study 1 Survival

12. Study 2 Survival

13. Study 2 Multivariate analysis n n Prognostic factors for covariate adjustment : (J Clin Oncol 16:2401-2408, 1998) – –Disease Free Interval – –AST level – –Liver metastases – –Previous adjuvant chemotherapy n n Treatment effect with covariates: Risk Ratio: 0.70 p-value :0.034 n n Covariates adjustment for progesterone and estrogen receptors: p-value 0.05

14. Time to Progression Studies 1 and 2

15. Efficacy Results Study 3

16. Survival Study 3

17. Time to Progression Study 3

18. Summary Study 3 n Similar response rates and survival n Trend toward longer TTP for TLC arm n Relatively low dose of Epirubicin n Small study stopped prematurely

19. Cardiotoxicity

20. Summary of Toxicities

21. Regulatory issues n Studies 1 and 2 showed less cardiotoxicity TLC arm n Non-inferiority (Ratio of Response Rates): –Study 1: 0.78 –Study 2: 0.62

22. Regulatory issues Overall survival: Study 1: HR: 1.01 95% CI: 0.71 Study 2: p= 0.07 HR: 0.75 95% CI: 0.54 The comparator arm on Study 3 is not adequate

23. Reviewer Conclusions n Insufficient evidence to support TLC D-99 for first line treatment of metastatic breast cancer –Non-inferior R.R in Study 1 –Negative Survival trend Study 2 –Study 3 inadequate comparator n TLC D-99 less cardiotoxic, but this endpoint alone does not support the proposed indication