1. Drug Treatment of Metastatic Breast Cancer
FDA Approval Overview
Patricia Cortazar, MD

2. Drugs approved for Metastatic Breast Cancer
Methotrexate
Cyclophosphamide 1959
Thiotepa
Vinblastine
5-Fluorouracil 1962
Doxorubicin

3. Drugs approved in 2nd-3rd line Metastatic Breast Cancer
Paclitaxel
Docetaxel
Trastuzumab
Capecitabine
Capecitabine + Docetaxel 2001
Abraxane
Lapatinib
Ixabepilone

4. Paclitaxel
TAXOL® is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated

5. Paclitaxel 135 mg/m2 3-hour infusion
TAXOL Study Design
Paclitaxel mg/m2 3-hour infusion
471
Patients who failed
one or two regimens
of chemotherapy
67% previous
anthracyclines
Paclitaxel mg/m hour infusion

6. TAXOL Efficacy Results Full Approval
Paclitaxel 175
235
Paclitaxel 135
236
Response (months)
28%
22%
P-value (log rank)
p=0.135
TTP median (months)
4.2
3.0
p=0.027
Survival (months)
11.7
10.5
p=0.321

7. Docetaxel
TAXOTERE® for Injection indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy

8. Docetaxel Accelerated Approval 1996
3 Phase II studies in total 134 patients
Dose 100 mg/m2 q 3 weeks
Endpoint: Overall RR
41% (95% CI: 33-49)
PMC: Submit data from controlled clinical studies (TAX311, TAX304)

9. TAX304 Study Design 392 Docetaxel 100 mg/m2 Q 3 weeks
Patients with
Prior anthracycline
regimens
Mytomicin 12 mg/m Q 6 weeks
Vinblastine mg/m2
Q 3 weeks

10. TAX304 Efficacy Results Full Approval
Docetaxel
203
Myt +Vinblastine
189
TTP (months)
4.3
2.5
Risk Ratio
95% CI (RR)
0.75
P-value (log rank)
p=0.01
Survival (months)
11.4
8.7
Risk Ratio*
0.73

11. Trastuzumab
Herceptin® is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease.

12. Herceptin MBC Study Design
Trastuzumab 4 mg/kg loading dose
2 mg/kg wkly maintenance
222
Patients with MBC
HER2 overexpression
2+3+
1 or 2 prior CT for MBC
Anthracycline and Taxane

13. Herceptin monotherapy Full Approval
Response Rate
14% CR 2% PR
12%
Response Duration median (months) 9
Survival median (months)
12.8

14. Capecitabine
Xeloda® is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy may be contraindicated, e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents.

15. Capecitabine monotherapy Accelerated Approval
Patients resistant to paclitaxel and anthracycline 43 CR PR 11
Response Rate
95% CI
25.6%
(13.5, 41.2)
Response Duration median (days)
Range
154
(63-233)

16. Capecitabine Xeloda® is indicated in combination
with Taxotere (docetaxel) for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.

17. Study Design 511 Capecitabine 1250 mg/m2 twice daily for 14 days
Docetaxel mg/m2
Q 3 weeks
511
metastatic
breast cancer
resistant to
Anthracycline
30% 1st line
Docetaxel mg/m2
Q 3 weeks

18. Capecitabine Efficacy Results Full Approval
Capeciabine + Docetaxel
Docetaxel
TTP (median days)
186
128
95% CI
( )
( )
Hazard Ratio
0.643
P-value (log rank)
p=0.01
Survival (median days)
442
352
( )
( )
0.775
0.0126

19. Overall Survival median days Docetaxel ---- 352
Capecitabine + Doc
Log rank p=0.0126

20. Lapatinib
TYKERB® in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors over-express HER2 (ErbB2) who have received prior therapy including an anthracycline, a taxane and trastuzumab.

21. Study Design 399 Lapatinib 1250 mg/m2 continuously
Capecitabine mg/m daily for 14 days
399
Locally advanced
or metastatic
breast cancer
HER2+ prior
anthracycline,
Taxane and
Herceptin.
Capecitabine mg/m daily for 14 days

22. Lapatinib Efficacy Results Full Approval
Independent radiology Review
Investigator
Lap +Cap
Cap
TTP # events 82
102
121
126
Median (weeks)
27.1
18.6
23.9
18.3
Hazard ratio
95% CI
0.57
(0.43, 0.77)
0.72
(0.56, 0.92)
P-value
ORR %
23.7
13.9
31.8
17.4

23. Efficacy of Combination Therapy: Kaplan-Meier Curves of TTP
Lapatinib + Capecitabine
Capecitabine p=

24. Ixabepilone Combination Therapy:
Ixempra is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant or for whom further anthracycline therapy is contraindicated.

25. Capecitabine 1250 mg/m2 BID Days 1 to 14 q 21 days
Study Design
Ixabepilone 40 mg/m2 Days 1 q 21 days
Capecitabine 1000 mg/m2
BID Days 1 to 14 q 21 days
752
Resistant to
Taxane and
anthracycline
Capecitabine mg/m BID Days 1 to 14 q 21 days

26. Ixabepilone Efficacy Results Full Approval
Ixa + Cape
375
Capecitabine
377
PFS (months)
5.7
4.1
Hazard Ratio
95% CI
0.69
P-value (log rank)
p <0.0001

27. Efficacy of Combination Therapy: Kaplan-Meier Curves of PFS
log rank p<

28. Ixabepilone Monotherapy:
Ixempra is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

29. Single-arm Monotherapy Studies (n=126)
Independent radiology Review
Investigator
ORR (%)
12.4
18.3
95% CI
6.9, 19.9
11.9, 26.1
Response Duration
Median (months)
6.0
5.0, 7.6

30. 1st line Metastatic Breast Cancer

31. Drugs approved in 1st line Metastatic Breast Cancer
Herceptin + Paclitaxel
Gemcitabine + Paclitaxel

32. Trastuzumab
Herceptin® in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress HER2 protein and who have not received chemotherapy for their metastatic disease.

33. Herceptin 1st line MBC Study Design
Chemotherapy (AC or Paclitaxel)
Herceptin loading: 4 mg/kg
weekly: 2 mg/kg
469
Patients with untreated
MBC
HER2 overexpression
2+3+
Chemotherapy Alone

34. Survival Time (months)
Survival ALL Patients
1.0
0.8
0.6
Proportion Alive
0.4
Herceptin 79%
Control 68%
0.2
P < 0.01
0.0 5 10 15 20 25 30
Survival Time (months)

35. Herceptin Full Approval
Survival All Patients

36. Time to Progression All Patients Time to Progression (Months)
1.0
0.8
p < 0.001
Herceptin
Proportion Progression-Free
0.6
Control
0.4
0.2
0.0 5 10 15 20 25
Time to Progression (Months)

37. Gemcitabine
Gemzar in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

38. Study Design 529 Gemcitabine 1250 mg/m2 Days 1 and 8 q 21 days
Paclitaxel 175 mg/m2
Days 1 and 8 q 21 days
529
Unresectable,
locally recurrent
or metastatic
breast cancer
Paclitaxel 175 mg/m2
Days 1 and 8 q 21 days

39. Survival Gemzar/Paclitaxel ---------- 18.6 months
Log rank p=0.0489

40. Time to Progression

41. Metastatic Breast Cancer
ENDPOINTS
Metastatic Breast Cancer

42. Survival: Basis of cytotoxic drug approval in 1st line MBC
Cytotoxic and biologic drugs are toxic
Survival is both a safety and an efficacy parameter
Deaths are caused by toxicity or
progressive disease or both

43. Efficacy Reasons for using Survival as basis of approval in 1st line MBC
Effective drugs prolong life:
Doxorubicin based regimens→ 6 months
Herceptin → 5 months
Docetaxel → 3 months
Capecitabine + Docetaxel → 3 months

44. Survival as a basis of approval: Examples
1st Line MBC:
Herceptin + Paclitaxel
Gemcitabine + Paclitaxel
2nd Line MBC
Docetaxel monoterapy
and
Capecitabine + Docetaxel after failure of prior chemotherapy

45. Cross-over therapy confounds survival effect: truth or myth?
According to ODAC 6/99: No
No literature to support this statement
A drug used after tumor progression should have the same effect in both arms, and should not obscure the effect of the drug tested. Examples:
Herceptin + chemo better than chemo, in spite of a 65% cross-over rate
Camptosar + 5-FU/leucovorin better than 5-FU/leucovorin, in spite of a 40% cross-over rate

46. SUMMARY

47. See ODAC transcript for Monday June 7, 1999, posted on the FDA website
TTP: Not acceptable for traditional approval in 1st line cytotoxic therapy for metastatic breast cancer

48. TTP as the basis of approval: Examples
2nd and 3rd Line MBC
Paclitaxel
Lapatinib

49. Progression Free Survival
Has not been used as basis for approval in 1st line MBC.
Has been used for basis of approval of Ixabepilone in 2nd-3rd line therapy.

50. Problems with PFS Needs blinded RCT
Blinded assessment by Independent Radiology Review
Problems with patients without measurable disease
Problems with missed assessments or incomplete assessments at baseline
Problems with infrequent assessments
Problems with uneven assessment in each arm

51. Is the use of PFS in the 1st line treatment of MBC appropriate, especially in a situation were there is no improvement in survival?

52. NDA submissions based on PFS will affect survival data
Premature stopping trial before accrual is complete or stop following patients for survival
Risk for not seeing survival data in future trials