# Presentation: 678618

## 	Drug Treatment of 	Metastatic Breast Cancer

- FDA Approval Overview
- Patricia Cortazar, MD

## Drugs approved for Metastatic Breast Cancer

- Methotrexate			1953
- Cyclophosphamide	1959
- Thiotepa			1959
- Vinblastine			1961
- 5-Fluorouracil		1962
- Doxorubicin			1974

## 
Paclitaxel					1994
Docetaxel				1996
Trastuzumab 				1998
Capecitabine				1998
Capecitabine + Docetaxel		2001
Abraxane					2005
Lapatinib					2006
Ixabepilone				2007

- Paclitaxel					1994
- Docetaxel				1996
- Trastuzumab 				1998
- Capecitabine				1998
- Capecitabine + Docetaxel		2001
- Abraxane					2005
- Lapatinib					2006
- Ixabepilone				2007

**Drugs approved in ****2****nd****-3****rd**** line**** Metastatic Breast Cancer**

## 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

## TAXOL Study Design

-  Paclitaxel	          135 mg/m2		   3-hour infusion

**TAXOL Study Design**

-   Paclitaxel 	  175 mg/m2	3-hour infusion

**471**

**Patients who failed **
**one or two regimens**
**of chemotherapy**
**67% previous **
**anthracyclines**

## 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-value (log rank) | p=0.027 |  |
| Survival (months) | 11.7 | 10.5 |
|       P-value (log rank) | p=0.321 |  |

## Docetaxel

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

## 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)

## TAX304 Study Design

-     Mytomicin 	 12 mg/m2			  Q 6 weeks
-   Vinblastine	        6 mg/m2
- 	                      Q 3 weeks

**TAX304 Study Design**

-      Docetaxel 	  100 mg/m2	Q 3 weeks

**392**

**Patients with **
**Prior anthracycline**
**regimens**

## TAX304 Efficacy ResultsFull Approval

|  | Docetaxel
203 | Myt +Vinblastine
189 |
| --- | --- | --- |
| TTP (months) | 4.3 | 2.5 |
|       Risk Ratio
      95% CI (RR) | 0.75
0.61-0.94 |  |
|       P-value (log rank) | p=0.01 |  |
| Survival (months) | 11.4 | 8.7 |
|       Risk Ratio*
      95% CI (RR) | 0.73
0.58-0.93 |  |
|       P-value (log rank) | p=0.01 |  |

## 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.

## Herceptin MBC 

- Trastuzumab 4 mg/kg loading dose
- 2 mg/kg wkly maintenance

**Herceptin MBC **
**Study Design**

**222**

- Patients with MBC
- HER2 overexpression
- 2+3+
- 1 or 2 prior CT for MBC
- Anthracycline and Taxane

## Herceptin monotherapy Full Approval

| Response Rate				 | 14% |
| --- | --- |
| CR | 2% |
| PR | 12% |
| Response Duration  median (months)				 | 9 |
| Survival  median (months) | 12.8 |

## 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.

## Capecitabine monotherapy Accelerated Approval

| Patients resistant to paclitaxel and anthracycline | 43 |
| --- | --- |
| CR | 0 |
| PR | 11 |
| Response Rate
				95% CI | 25.6%
(13.5, 41.2) |
| Response Duration  median (days)
				Range | 154
(63-233) |

## 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.

## Study Design

- Docetaxel 	       100 mg/m2
- Q 3 weeks

**Study Design**

-    Capecitabine 	1250 mg/m2	    twice daily for 14 days
-    Docetaxel           75 mg/m2
-              Q 3 weeks

**511**

**metastatic**
**breast cancer **
**resistant  to **
**Anthracycline**
**30% 1****st**** line**

## Capecitabine Efficacy ResultsFull Approval

|  | Capeciabine + Docetaxel | Docetaxel |
| --- | --- | --- |
| TTP (median days) | 186 | 128 |
|       95% CI | (165-198) | (105-136) |
|       Hazard Ratio | 0.643 |  |
|       P-value (log rank) | p=0.01 |  |
| Survival (median days) | 442 | 352 |
|       95% CI | (375-497) | (298-387) |
|       Hazard Ratio | 0.775 |  |
|       P-value (log rank) | 0.0126 |  |

## Overall Survival

**Overall Survival**

**	****	****	****median days**
**Docetaxel                 ----    ****	****352**
**Capecitabine + Doc ****---- ****   ****	****442****  **

**Log rank p=0.0126**

## 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.

## Study Design

-      Capecitabine 	   2500 mg/m2	                 daily for 14 days

**Study Design**

- Lapatinib              1250 mg/m2
-                      continuously
- Capecitabine 	2000 mg/m2	    daily for 14 days

**399**

**Locally advanced**
**or metastatic**
**breast cancer**
**HER2+ prior **
**anthracycline,**
**Taxane and**
**Herceptin.**

## Lapatinib Efficacy ResultsFull Approval

|  | Independent radiology Review |  | Investigator
 |  |
| --- | --- | --- | --- | --- |
|  | Lap +Cap | Cap | 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 | 0.00013 |  | 0.00762 |  |
| ORR % | 23.7 | 13.9 | 31.8 | 17.4 |

## Efficacy of Combination Therapy:Kaplan-Meier Curves of TTP

- Lapatinib + Capecitabine     -----------
- Capecitabine                      ---------

**p= 0.00013**

## 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.

## Study Design

-       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**

## Ixabepilone Efficacy ResultsFull Approval

|  | Ixa + Cape
375 | Capecitabine
377 |
| --- | --- | --- |
| PFS (months) | 5.7 | 4.1 |
|       Hazard Ratio
      95% CI  | 0.69
0.58-0.83 |  |
|       P-value (log rank) | p <0.0001 |  |

## Efficacy of Combination Therapy:Kaplan-Meier Curves of PFS

**Efficacy of Combination Therapy:****Kaplan-Meier Curves of PFS**

**log rank p< 0.0001**

## 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.

##  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 |  |
|        95% CI | 5.0, 7.6 |  |

## 1st line Metastatic Breast Cancer

## Drugs approved in 1st line Metastatic Breast Cancer

- Herceptin + Paclitaxel 			1998
- Gemcitabine + Paclitaxel  		2004

## 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.

## Herceptin 1st line MBC 

- Chemotherapy Alone

**Herceptin 1****st**** 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+**

## Survival ALL Patients

**Survival Time (months)**

**Proportion Alive**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**Survival ALL Patients**

**Herceptin 79%**

**Control 68%**

- P < 0.01

## Herceptin Full Approval

**Herceptin Full Approval**
**Survival All Patients**

## Time to Progression All Patients

**Time to Progression (Months)**

**Proportion Progression-Free**

**0**

**5**

**10**

**15**

**20**

**25**

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**Time to Progression All Patients**

**Herceptin**

**Control**

**p < 0.001**

## 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.

## Study Design

- Paclitaxel	175 mg/m2
- 	  Days 1 and 8 q 21 days

**Study Design**

-    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**

## Survival

- Gemzar/Paclitaxel ----------  18.6 months
- Paclitaxel               ----------  15.8 months

**Log rank p=0.0489**

- 	         **SURVIVAL**

## Time to Progression

**Time to Progression**

## ENDPOINTS 

- Metastatic Breast Cancer

## 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

## 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

## 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

## 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

## SUMMARY

## See ODAC transcript for Monday June 7, 1999, posted on the FDA website

**TTP: Not acceptable for traditional approval in 1****st**** line cytotoxic therapy for metastatic breast cancer**

## TTP as the basis of approval: Examples

- 2nd and 3rd Line MBC
- Paclitaxel
- Lapatinib

## 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.

## 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

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

## 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