# Presentation: 712511

## Avastin® (bevacizumab)

- United States Food and Drug AdministrationOncologic Drugs Advisory Committee
- December 5, 2007

## Overview

**David Schenkein, MD**
- Senior VP, Clinical Hematology/OncologyGenentech, Inc.

## Overview Topics

- Indication statement
- Avastin Overview
- E2100 Summary
- Today’s Agenda

## Indication Statement

- Avastin®, in combination with paclitaxel, for the treatment of patients who have not received chemotherapy for their locally recurrent or metastatic HER2-negative breast cancer.

## Avastin Overview

- Monoclonal antibody specific for VEGF ligand
- Validated antiangiogenesis in cancer therapy
- > 200,000 patients treated worldwide with Avastin
- Clinical validation in numerous settings
- Avastin approved
- Colorectal cancer and non-small cell lung cancer (worldwide)
- Progression-free and overall survival
- Metastatic breast cancer (ex-US)
- Progression-free survival (PFS)

## Avastin Milestone Developments in Metastatic Breast Cancer

**Avastin Milestone Developments in Metastatic Breast Cancer**

**E2100 **
**1st-line MBC**

**2002**

**2004**

**1989**

**1997**

**2000**

**2005**

**VEGF-A cloned**

**IND for Avastin**

**AVF0776 **
**Phase I/II MBC**

**AVF2119**
**2nd/3rd-line MBC**

**2001**

**GNE/NCI **
**Clinical Research Agreement**

**Avastin Approved Colorectal Cancer**

## ECOG Study E2100—Regulatory Milestones

- 2002

- 2005

- 2006

- 2007

- 2008

- E2100 BLA
- Supplement
- Submitted

## Key Agreements With FDA to Support Resubmission (1)

- Independent Review Facility (IRF) assessment of all 722 patients
- Primary endpoint PFS by IRF review
- Data cut-off in line with ECOG interim analysis applied to final clean database
- Mature survival data

## Key Agreements With FDA to Support Resubmission (2)

|  | Studies included in sBLA |  |  |
| --- | --- | --- | --- |
|  | Efficacy | Safety | Patient population |
| E2100 |  |  | 1st-line MBC |
| AVF2119 |  |  | Prior anthracycline and taxane treated |
| AVF0776 |  |  | Relapsed MBC |

## Study E2100 Summary

- Avastin + paclitaxel associated with compelling treatment effect
- PFS appropriately measured
- Consistency across subsets
- Sensitivity analyses retained benefit
- Objective Response Rate (ORR) improved
- Overall Survival (OS) improved
- Favorable benefit/risk ratio
- No new safety signals observed
- Important advance for women with breast cancer

## Avastin in Metastatic Breast Cancer

- E2100 demonstrates a robust and clinically meaningful PFS treatment effect
- A PFS effect of this magnitude represents clinical benefit
- Genentech has committed to a full understanding of Avastin’s role in breast cancer

## Today’s Agenda

| David Schenkein, MD
Genentech, Inc. | Overview |
| --- | --- |
| Kathy Miller, MD
Indiana University | Study E2100: Design, Efficacy |
| Barbara Klencke, MD
Genentech, Inc. | Study E2100: Safety |
| Eric Winer, MD
Dana-Farber Cancer Institute
Harvard Medical School | MBC and Bevacizumab:Placing ECOG Study 2100 in Context |
| Chris Bowden, MD
Genentech, Inc. | Concluding Remarks |

**Today’s Agenda**

## ECOG Study E2100:Avastin Added to Weekly Paclitaxel as Initial Chemotherapy for Patients With Metastatic Breast Cancer

**Kathy Miller, MD**
- Associate ProfessorIndiana University School of Medicine

## Topics

- Metastatic Breast Cancer Treatment Landscape
- E2100 Study Design Rationale
- E2100 Efficacy Data

## Metastatic Breast Cancer

- Overt metastatic disease is generally incurable
- Goal of therapy
- Live longer and prosper
- Chemotherapy
- Drug resistance is common
- Substantial toxicity

## Treatment Landscape 2001

- VATH/CMFVP1

- FEC2

- Paclitaxel3

- EM4

- Docetaxel5

- DV6

- Doxorubicin7

**1****Aisner. *****JCO*****. 1995; ****2****Brufman. *****Ann Oncol*****. 1997; ****3****Bishop. *****Sem Oncol*****. 1997; ****4****Pacini. *****Eur J Cancer*****. 2000; ****5****Chan. *****JCO*****. 1999; ****6****Norris. *****JCO*****. 2000; ****7****Parideans. *****JCO*****. 2000.**

## Treatment Landscape 2007—Little Progress With Chemotherapy

- AT1

- AT2

- GT3

- wkly Paclitaxel4

- Docetaxel5

- GET6

- GV7

**1****Jassem. *****JCO*****. 2001; ****2****Sledge. *****JCO*****. 2003; ****3****Albain. *****Proc ASCO*****. 2004; ****4****Seidman. *****Proc ASCO*****. 2004; ****5****Jones. *****JCO*****. 2005; ****6****Zielinski. *****JCO*****. 2005; ****7****Martin. *****Lancet Oncology*****. 2007.**

## Rationale for E2100

- Importance of angiogenesis
- Taxanes have antiangiogenic activity and are synergistic with Avastin

- AVF0776: Avastin activityas monotherapy
- AVF2119: Ongoing phase III trial in refractory disease
- Greater benefits expected earlier in natural history

**Pragmatic**

**Biologic**

**Clinical**

- Intravenous placebo considered barrier to accrual

## E2100—Study Design

**MBC not previously treated with chemotherapy**
**(N = 685)**
_**Stratification**_
- - Disease-free interval
- - Adjuvant therapy
- - ER+, ER–, unknown
- - Number of metastatic  sites

_**Paclitaxel**_**: **90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest
_**Avastin**_**: **10 mg/kg following paclitaxel treatment on Wk 1 and 3 of every cycle

**R**
**A**
**N**
**D**
**O**
**M**
**I**
**Z**
**E**
**D**

_**Paclitaxel**_**: **90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest

**E2100—Study ****Design**

## E2100—Endpoints

**E2100—Endpoints**

- Primary endpoint
- Progression-free survival (PFS)
- Secondary endpoints
- Objective response rate (ORR)
- Overall survival (OS)
- Quality of life (QoL)
- Safety

## Rationale for Progression-Free Survival as the Primary Endpoint for E2100

- Important endpoint in the first-line setting
- Clinical benefit from prolonging PFS
- Maintain disease control
- Prevent symptoms of disease progression
- Prevent toxicities, psychological burden, and uncertainty of disease progression
- PFS endpoint not obscured by subsequent therapy

## Statistical Considerations

- Primary endpoint: PFS
- N = 685
- 85% power to detect a 33% improvement
- 6 vs 8 mo
- Interim analyses after 50% and 78% events
- Final analysis after 546 events
- Secondary endpoint: OS
- 15% to 25% power to detect 2- to 3-mo improvement

## E2100—Key Eligibility Criteria

- Disease setting
- Locally recurrent or metastatic breast cancer (mBC)
- HER2+ only if pretreatment with Herceptin or unsuitable
- Measurable or non-measurable disease
- Prior therapy
- No prior chemotherapy for mBC
- Adjuvant taxanes if > 12 mo prior to randomization
- Baseline requirements
- No CNS metastases
- Performance status
- ECOG 0 or 1

## E2100—Assessments

| Assessment | Frequency (timing) |
| --- | --- |
| Clinical evaluation | Every cycle (every 4 wk) |
| Safety assessment | Every cycle (every 4 wk) |
| Tumor assessment
(scan or x-ray) | Every 3 cycles (every 12 wk)Balanced assessments on both arms |
| QoL (FACT-B) | Baseline, Wk 17, and Wk 33 |

**E2100—Assessments**

## Participating Centers

- 10 major cooperative groups participated
- 258 enrolling centers
- US, Canada, Peru, South Africa
- < 10% of patients enrolled ex-US

## ECOG Study E2100:Efficacy Results

## E2100 Baseline Characteristics—Balanced

|  | Paclitaxel(n = 354) | Paclitaxel + Avastin
(n = 368) |
| --- | --- | --- |
| Median age, years (range) | 55 (27 - 85) | 56 (29 - 84)  |
|   ≥ 65 years, % | 23 | 23 |
| Measurable disease at baseline, % | 77 | 68 |
| ER+ and/or PR+, % |  64 | 63 |
| HER2+, % | 1.7 | 2.7 |
| Disease-free interval ≤ 24 mo, % | 41 | 41 |
| ≥ 3 metastatic sites, % | 29 | 29 |
| Prior adjuvant chemotherapy, % | 65 | 66 |
|     Prior adjuvant anthracyclines, % | 51 | 50 |
|     Prior adjuvant taxane therapy, % | 19 | 20 |
| Metastatic hormonal therapy, % | 36 | 36 |

## E2100—PFS by Independent Radiology Facility (IRF)

|  | Paclitaxel(n = 354) | Paclitaxel + Avastin(n = 368) |
| --- | --- | --- |
| Patients with an event, n (%) | 184 (52) | 173 (47) |
| Stratified analysis |  |  |
|    HR | 0.483 |  |
|       95% CI | (0.385, 0.607) |  |
| p value |  |  |
|       Log-rank |  0.0001 |  |
| PFS, mo |  |  |
|       Median | 5.8 | 11.3 |
|       95% CI | (5.36, 8.15) | (10.45, 13.27) |

**E2100—****PFS by Independent Radiology Facility (IRF)**

## E2100—PFS by IRF (Kaplan-Meier)

- 0.8

- 0.6

- 0.4

- 0.2

- 0.0

- 1.0

- 36

- 30

- 24

- 12

- 6

- 0

- Proportion without event

- HR = 0.483 (0.385, 0.607)
- Log-rank test, *p* ≤ 0.0001

- Paclitaxel (n = 354)
- Paclitaxel + Avastin (n = 368)

- 18

- Time, mo

**E2100—****PFS by IRF (Kaplan-Meier)**

## Exploratory Analyses of PFS 

- PFS in key subsets
- IRF vs Investigator-assessed progression
- Sensitivity analyses

## E2100—PFS Consistent Across Subgroups

| All Patients |  |
| --- | --- |
|   Age < 40 yr |  |
|   Age 40 - 64 yr |  |
|   Age ≥ 65 yr |  |
|   < 3 Metastatic sites |  |
|   ≥ 3 Metastatic sites |  |
|   Measurable disease at baseline |  |
|   Non-measurable disease at baseline |  |
|   No prior adjuvant chemotherapy
  Prior adjuvant chemotherapy |  |
|       Prior adjuvant TAXANE therapy |  |
|   ER+ |  |
|   ER– |  |

**E2100—****PFS Consistent Across Subgroups**

- Paclitaxel better

- Paclitaxel + Avastin better

- 0.5

- 0.2

- 5

- 2

- 1

- Hazard ratio

## Exploratory Analyses of PFS

- PFS in key subsets
- IRF vs Investigator-assessed progression
- Sensitivity analyses

## E2100—PFS Consistent Between IRF and Investigator

**11.3**

- 18

- 36

- 30

- 24

- 12

- 6

- 0

- Proportion without event

**HR = 0.483**

**PAC**
**PAC + AVA**

**PFS by **_**IRF**_

**E2100—PFS Consistent Between ****IRF and Investigator**

**5.8**

- Months

## Exploratory Analyses of PFS

- PFS in key subsets
- IRF vs Investigator-assessed progression
- Sensitivity analyses

## Sensitivity Analyses—Significant Benefit Retained Even if Avastin Arm Penalized

|  | Median PFS |  |  |  |
| --- | --- | --- | --- | --- |
| PFS analysis variation | PAC (n = 354) | PAC + AVA(n = 368) | HR | p value |
| Primary analysis  | 5.8 | 11.3 | 0.48 | < 0.0001 |
| Investigator Progression not confirmed by IRF: 
 Paclitaxel alone: Censor
 Avastin arm: Assume progression  | 
5.8 |  
 9.2 | 
0.60 | 
< 0.0001 |

**Sensitivity Analyses—Significant Benefit Retained Even if Avastin Arm Penalized**

*CSR Table 15*

## Secondary Analyses

- Objective Response Rate
- Overall Survival
- Quality of Life

## Best Overall Response by IRFPatients With Measurable Disease at Baseline

- * Stratified analysis of CR + PR comparison, *p* < 0.0001

**0%**

**22%**

**50%***

**44%**

**34%**

**26%**

**12%**

- Best response, %

**Best Overall Response by IRF****Patients With Measurable Disease at Baseline**

**9%**

**5%**

## E2100—Objective Response by Investigators and IRFPatients With Measurable Disease at Baseline

- Best response, %

**E2100—Objective Response by Investigators and IRF****Patients With Measurable Disease at Baseline**

- Investigator assessment

- IRF assessment

- 50%

- 22%

- 23%

- 48%

- PAC

- PAC + AVA

## Overall Survival

|  | Paclitaxel(n = 354) | Paclitaxel + Avastin(n = 368) |
| --- | --- | --- |
| Patients who died, n (%) | 238 (67.2) | 243 (66) |
| Stratified analysis |  |  |
|    HR | 0.869 |  |
|       95% CI | (0.722, 1.046) |  |
| p value |  |  |
|       Log-rank | 0.1374 |  |
| Overall survival, mo |  |  |
|    Median | 24.8 | 26.5 |
|    95% CI | (21.39, 27.37) | (23.72, 29.21) |

- Note:  Data are based on a 21 October 2006 cutoff.

**Overall Survival**

## E2100—Overall Survival

- PAC+AVA

- 104

- 103

- 0

- 0

- 5

- 8

- 23

- 19

- 344

- 307

- PAC

- 48

- 48

- 193

- 165

- No. of patients at risk

- 249

- 215

- 368

- 354

- 297

- 258

**HR = 0.869 (0.722, 1.046)**
**Log-rank test, *****p***** = 0.1374**

**PAC (n = 354):        ****	**** ****Median OS 24.8 mo**
**PAC + AVA (n = 368):  ****Median OS 26.5 mo**

- 0.8

- 0.6

- 0.4

- 0.2

- 0.0

- 1.0

- 54

- 36

- 30

- 60

- 48

- 42

- 0

- Proportion surviving

- 18

- 24

- 12

- 6

- 0.8

- 0.6

- 0.4

- 0.2

- 0.0

- 1.0

- 54

- 36

- 30

- 60

- 48

- 42

- 0

- 18

- 24

- 12

- 6

- * Post-hoc

- Months

## E2100—Quality of Life: Primary Analysis Favors Avastin Therapy

- Decline

- Change from baseline for Trial Outcome Index-Breast

- _Patients with QoL data_
-  PAC  	N =
-  PAC + AVA 	N =

- 327
- 347

- 290
- 318

- 296
- 292

*p* = 0.0069

*p *= 0.0002

## E2100—Efficacy Conclusions for Avastin + Paclitaxel

- Clinically meaningful improvement in PFS
- Magnitude of PFS benefit consistent for all patient subgroups
- Similar PFS results based on IRF or investigator assessments validates ECOG review process
- Robust PFS result verified by sensitivity analyses
- Doubling of ORR, with improvement in 1-year survival and no additional QoL burden

## ECOG Study E2100:Safety

**Barbara Klencke, MD**
- Associate Group Medical DirectorGenentech, Inc

## E2100—Treatment Received 

|  | Paclitaxel(n = 342) | Paclitaxel + Avastin (n = 358) |
| --- | --- | --- |
| Cycles* received per patient |  |  |
|    Median | 6 | 10 |
|    Range | 1 - 26 | 1 - 38 |
|    25th - 75th percentile | 3 - 9 | 6 - 15 |

- *1 cycle = 4 weeks.

**E2100—Treatment Received **

## Reasons for Treatment Discontinuation

| Status and reason for discontinuation | Paclitaxel(n = 354)(%) | Paclitaxel + Avastin(n = 368)(%) | Total(N = 722)(%) |
| --- | --- | --- | --- |
| Not treated | 2.3 | 0.5 | 1.4 |
| Treatment ongoing  |   2 | 11 |   7 |
| Discontinued protocol therapy | 96 | 89 | 92 |
|       Disease progression | 55 | 45 | 50 |
|       Toxicity/side effects/complications | 19 | 20 | 20 |
|       Death | 1.4 | 1.6 | 1.5 |
|       Other  | 20 | 22 | 21 |

**Reasons for Treatment Discontinuation**

## E2100: Investigator-Reported Cause of Death in Safety Population

|  | Paclitaxel(n = 348)% | Paclitaxel +Avastin(n = 363)% |
| --- | --- | --- |
| Death events | 73.6 | 70.2 |
| Due to MBC | 69.3 | 66.9 |
| Due to protocol therapy |   0.3 |   0.0 |
| Due to other cause |   2.0 |   2.5 |
| Unknown |   2.0 |   0.8 |

**E2100: Investigator-Reported Cause of Death in Safety Population**

## E2100—Causes of Death:Comprehensive Genentech Clinical Review 

| Deaths | Paclitaxel(n = 348)n (%) | Paclitaxel +Avastin(n = 363)n (%) |
| --- | --- | --- |
| All deaths | 256 (73.6) | 255 (70.2) |
|     Due to protocol therapy |  Not assessable by Genentech | 6 (1.7) |

**E2100—Causes of Death:****Comprehensive Genentech Clinical Review **

## Most Frequent Grade 3-5 Adverse Events by Category and Preferred Term (≥ 5% Incidence)

| NCI-CTCAE Term 
Grade ≥ 3 | Paclitaxel 
(n = 348)(%) | Paclitaxel + Avastin(n = 363)(%) |
| --- | --- | --- |
| Patients with ≥ 1 event | 50.6 | 71.1 |
|   Neuropathy | 18.1 | 25.3 |
|   Hypertension |   1.4 | 16.0 |
|   Fatigue |   5.2 | 10.7 |
|   Infection without neutropenia |   4.6 |   9.1 |
|   Neutropenia (Grade 4) |   3.2 |   5.8 |
|   Vomiting |   2.3 |   5.5 |

**Grade 3-5 nonhematologic and Grade 4-5 hematologic events included.**

**Most Frequent Grade 3-5 Adverse Events by Category and Preferred Term (≥ 5% Incidence)**

## E2100—Grade 3-5 Adverse Events: Categories of Special Interest (%) by Grade

|  | Paclitaxel(n = 348) | Paclitaxel + Avastin(n = 363) |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  |  | Grade 3-5 |  |  |  |
|  | 1.4 | 16.0 |  |  |  |
|  | 0 | 3.6 |  |  |  |
|  | 0 | 3.0 |  |  |  |
|  | 0.3 | 2.2 |  |  |  |
|  | 0.3 | 2.2 |  |  |  |
|  | 0 | 0.6 |  |  |  |

|  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  |  |  | Gr 3 | Gr 4 | Gr 5 |
|  |  |  | 15.4 | 0.6 | 0 |
|  |  |  | 1.1 | 1.9 | 0.6 |
|  |  |  | 1.9 | 1.1 | 0 |
|  |  |  | 1.7 | 0.6 | 0 |
|  |  |  | 1.9 | 0.3 | 0 |
|  |  |  | 0 | 0 | 0.6 |

| Selected adverse events |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  |  |  |  |  |  |
| Hypertension  |  |  |  |  |  |
| Arterial thromboembolism |  |  |  |  |  |
| Proteinuria |  |  |  |  |  |
| Hemorrhage  |  |  |  |  |  |
| Left ventricular dysfunction  |  |  |  |  |  |
| GI perforations  |  |  |  |  |  |

**E2100—Grade 3-5 Adverse Events: ****Categories of Special Interest (%) by Grade**

## E2100—Safety Summary for Avastin + Paclitaxel

- Avastin + paclitaxel relatively well tolerated despite longer treatment
- Discontinuation for treatment toxicity equally balanced
- Safety profile consistent with known Avastin toxicity profile

## AVF2119—Study Design 

**AVF2119—Study Design **

- Metastatic breast cancer
- Measurable disease
- Prior anthracycline + taxane therapy required
- HER2+ or HER2–

- Primary endpoint
- PFS by IRF** **
- Stratification
- ECOG performance status
- Number of prior chemotherapy regimens

- Capecitabine
- 2500 mg/m2 q day × 14
- q 3 wk

- Capecitabine
- 2500 mg/m2 q day × 14
- Avastin 15 mg/kg
- q 3 wk

- N = 450

**R**
**A**
**N**
**D**
**O**
**M**
**I**
**Z**
**E**
**1:1**

## E2100 and AVF2119—Summary of Treatment

|  | E2100 |  | AVF2119 |  |
| --- | --- | --- | --- | --- |
|  | PAC
(n = 348) | PAC + AVA
(n = 363) | Cape
(n = 215) | Cape + AVA
(n = 229) |
| Median number of cycles administered | 6 | 10 | 4 | 6 |
|  | 4-wk cycles |  | 3-wk cycles |  |
| Discontinuation due to toxicity, % | 19 | 20 | 12 | 10 |
| Treatment-related deaths, % | Not assessable by Genentech | 1.7* | 0.9 | 0.4 |

***Comprehensive Genentech clinical review.**

## E2100 and AVF2119g—Grade 3-5 Adverse Events: Categories of Special Interest (%)

| AVF2119 |  |
| --- | --- |
| Cape(n = 215) | Cape + AVA(n = 229) |
| 0.5 | 20.0 |
| 0.5 | 0.4 |
| 0 | 1.3 |
| 0.5 | 0.4 |
| 1.0 | 3.5 |
| 0 | 0 |
| 0.9 | 0 |

**E2100 and AVF2119g—****Grade 3-5 Adverse Events: ****Categories of Special Interest (%)**

| Selected adverse events, Grade 3 - 5 | E2100 |  |
| --- | --- | --- |
|  | PAC(n = 348) | PAC + AVA(n = 363) |
| Hypertension | 1.4 | 16.0 |
| Arterial thromboembolic events | 0 | 3.6 |
| Proteinuria | 0 | 3.0 |
| Hemorrhage | 0.3 | 2.2 |
| Left ventricular dysfunction | 0.3 | 2.2 |
| GI perforations | 0 | 0.6 |
| Neuropathy | 18.1 | 25.3 |

## Avastin Safety Summary

- E2100 and AVF2119 report side effects consistent with current Avastin labeling
- Overall safety profile and QoL outcomes from E2100 support acceptability of the safety profile for Avastin + paclitaxel

## Metastatic Breast Cancer and Bevacizumab:Placing ECOG Study 2100 in Context

**Eric Winer, MD**
- Director, Breast Oncology CenterDana-Farber Cancer Institute
- Associate Professor of Medicine Harvard Medical School
- Chief Scientific AdvisorSusan G. Komen for the Cure

## Why Do We Develop New Therapies for Patients With Metastatic Breast Cancer?

- To improve treatment outcomes for women living with the disease today
- To identify promising new therapies that can be applied to the adjuvant setting

## How Do We Maximize Clinical Benefit forWomen With Metastatic Breast Cancer?

- Goals of treatment are to
- Maximize survival
- Median survival from initiation of first-line chemotherapy in HER2-negative disease is approximately 2 years
- Maintain disease control
- Minimize symptoms from disease
- Minimize toxicity from treatment

## Agents Approved for Metastatic Breast Cancer Since 2001

| Drug | Trial | Size |
| --- | --- | --- |
| Capecitabine
 | Docetaxel + Capecitabine
 vs
Docetaxel | N = 511 |
| Gemcitabine | Paclitaxel + Gemcitabine
vs
Paclitaxel | N = 529 |
| Lapatinib | Capecitabine + Lapatinib 
vs
Capecitabine | N = 324 |
| Ixabepilone | Capecitabine + Ixabepilone
vs
Ixabepilone | N = 752 |

**O’Shaughnessy. *****JCO*****. 2002; Melemed. ASCO Breast. 2007; Geyer. *****NEJM*****. 2006; Thomas. *****JCO*****. 2007.**

## MBC Tx—Recent Major Phase 3 Trials: Efficacy Results

**5 mo**

**MBC Tx—Recent Major Phase 3 Trials: Efficacy Results**

**20 mo**

**10 mo**

- PFS/TTP

- OS

**1****Miller. *****SABCS*****. 2005; ****2****O’Shaughnessy. *****JCO*****. 2002; ****3****Melemed. *****ASCO Breast*****. 2007; ****4****Geyer. *****NEJM*****. 2006; ****5****Thomas. *****JCO*****. 2007; NA: Not available.**

**Not reported yet**

**XD****2**

**GT****3**

**TyX****4**

**IxX****5**

**XD**
**D**

**GT**
**T**

**TvX**
**X**

**IxX**
**X**

**XD****2**

**GT****3**

**TyX****4**

**IxX****5**

**XD**
**D**

**GT**
**T**

**TvX**
**X**

**IxX**
**X**

## Phase III PFS/TTP Results in First-line Metastatic Breast Cancer Trials Utilizing Taxanes 

**Phase III PFS/TTP Results in First-line Metastatic Breast Cancer Trials Utilizing Taxanes**** **

**E2100**

**Paclitaxel + Bevacizumab**

- Pqw

- Experimental arm

- Control arm

## Is Prolonging Progression-Free Survival Meaningful for Patients? 

- Improvements in progression-free survival
- Delay the onset of disease-related symptoms and the side effects from a new therapy
- Avoid the psychological consequences associated with disease progression and changing therapy
- Eliminate the uncertainty as to whether new treatment will be effective

**Yes, prolonging progression-free survival**
** ****can be highly meaningful!**

## For Progression-Free Survival to Equal Patient Benefit, Then...

- The improvement in PFS must be
- Substantial in magnitude
- Established with confidence
- Supported by other measures of efficacy
- Survival
- QoL
- Objective response rate

## Applying These Criteria to the Combination of Paclitaxel + Bevacizumab

| Criteria | As demonstrated in ECOG 2100 |
| --- | --- |
| Substantial in magnitude | PFS hazard ratio: 0.48 (p < 0.0001) |
| Established with confidence | Agreement between investigator and independent review
Sensitivity analyses |
| Supported by other measures of efficacy 
 | OS hazard ratio: 0.87 (p = 0.14)
QoL favors bevacizumab
Doubling of response rate (p < 0.0001) |

## MBC Tx—Recent Major Phase 3 Trials: Efficacy Results

**5 mo**

**MBC Tx—Recent Major Phase 3 Trials: Efficacy Results**

**20 mo**

**10 mo**

- PFS/TTP

- OS

**1****Miller. *****SABCS*****. 2005; ****2****O’Shaughnessy. *****JCO*****. 2002; ****3****Melemed. *****ASCO Breast*****. 2007; ****4****Geyer. *****NEJM*****. 2006; ****5****Thomas. *****JCO*****. 2007; NA: Not available.**

**Not reported yet**

**XD****2**

**GT****3**

**TyX****4**

**IxX****5**

**E2100****1**

**TA**
**T**

**XD**
**D**

**GT**
**T**

**TvX**
**X**

**IxX**
**X**

**XD****2**

**GT****3**

**TyX****4**

**IxX****5**

**E2100****1**

**TA**
**T**

**XD**
**D**

**GT**
**T**

**TvX**
**X**

**IxX**
**X**

## The Trade-Off

**progression-free****survival**

**Side effects/risks**
** ****from treatment**

**Frequency**
**Severity**

**Extent of **
**improvement**

**The Trade-Off**

## What Side Effects and Risks Must Be Accepted With Paclitaxel and Bevacizumab?

- 20% increase in Grade 3-5 toxicity
- Asymptomatic Grade 3 hypertension and proteinuria were the most common adverse events
- Neuropathy increase due to duration of treatment
- Small increase in severe toxicity
- Arterial thrombotic events
- Congestive heart failure
- GI perforation
- Bleeding
- Added day-to-day toxicity quite limited

## In Summary

**In Summary**

- Progression-free survival is a meaningful endpoint
- The combination of bevacizumab and paclitaxel results in
- Substantial improvement in progression-free survival
- Modest additional toxicity for the majority of patients
- Bevacizumab in combination with paclitaxel is a valuable treatment option for women with metastatic breast cancer

## Concluding Remarks

**Chris Bowden, MD**
- Senior Group Medical DirectorGenentech, Inc.

## E2100 Summary

- Benefit
- Clinically meaningful treatment effect on progression-free survival
- PFS supported by all secondary endpoints
- Risk
- Safety profile familiar to prescribing oncologists
- Confidence
- Independent cooperative group study
- Consistency across subsets, IRF vs investigator, multiple sensitivity analyses

## Indication Statement

- 	Avastin® in combination with paclitaxel is indicated for the treatment of patients who have not received chemotherapy for their locally recurrent or metastatic HER2-negative breast cancer.

## Avastin®Supportive Slides

## Duration of Objective Response Patients with Measurable Disease at Baseline and an Objective Response

|  | TAX(n54) | TAX/AV(n114) |
| --- | --- | --- |
| No. of patients with an objective response | 54 | 112 a |
|    No. of patients with an event | 22 (40.7%) | 56 (50.0%) |
| Duration of objective response (months) |  |  |
|    Median | 9.7 | 9.4 |
|    95% CI | (7.43, 12.62) | (8.38, 13.31) |
| Unstratified Hazard Ratio (Relative to TAX) | 0.838 (0.508, 1.382) |  |

- a Two patients (21061 and 29004) have negative durations of objective response because a PD was recorded prior to a PR.  For Patient 21061, the PD was retracted in the reader comments; for Patient 29004, the PD date was kept and allowed to be followed by a best response of PR since PD was not assessed as a best response.

**Duration of Objective Response ****Patients with Measurable Disease at Baseline and an Objective Response**

## Subgroup Analysis of PFS (1)

| Baseline Risk Factor |  | Total n | n | Median (mo) | n | Median (mo) | Hazard Ratio | (95% Cl) |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All Patients |  | 722 | 354 | 5.8 | 368 | 11.3 | 0.54 | (0.44-0.67) |  |
| Age (yrs) |  |  |  |  |  |  |  |  |  |
|  | <40 | 59 | 32 | 4.8 | 27 | 8.3 | 0.54 | (0.26-1.09) |  |
|  | 40-64 | 496 | 239 | 6.1 | 257 | 12.1 | 0.51 | (0.39-0.66) |  |
|  | ≥65 | 167 | 83 | 6.1 | 84 | 10.4 | 0.67 | (0.42-1.05) |  |
| Race |  |  |  |  |  |  |  |  |  |
|  | White | 550 | 266 | 6.0 | 284 | 12.0 | 0.54 | (0.42-0.69) |  |
|  | Non-White | 172 | 88 | 5.6 | 84 | 10.9 | 0.55 | (0.36-0.86) |  |
| Region |  |  |  |  |  |  |  |  |  |
|  | North America | 663 | 324 | 5.8 | 339 | 11.2 | 0.55 | (0.44-0.68) |  |
|  | Rest of the World | 59 | 30 | 6.5 | 29 | 12.5 | 0.43 | (0.19-0.94) |  |
| Disease Status |  |  |  |  |  |  |  |  |  |
|  | Locally recurrent | 12 | 4 | - | 8 | 10.9 | 0.83 | (0.09-8.04) |  |
|  | Metastatic | 709 | 349 | 5.8 | 360 | 11.4 | 0.54 | (0.44-0.67) |  |

- TAX better

- TAX/AV better

- 0.5

- 0.2

- 5

- 2

- 1

## Subgroup Analysis of PFS (2)

| Baseline Risk Factor |  | Total n | n | Median (mo) | n | Median (mo) | Hazard Ratio | (95% Cl) |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All Patients |  | 722 | 354 | 5.8 | 368 | 11.3 | 0.54 | (0.44-0.67) |  |
| Disease-free intervals (months) |  |  |  |  |  |  |  |  |  |
|  | ≤24 months | 296 | 146 | 4.9 | 150 | 10.6 | 0.58 | (0.42-0.79) |  |
|  | >24 months | 426 | 208 | 8.3 | 218 | 12.1 | 0.50 | (0.38-0.67) |  |
| ER status |  |  |  |  |  |  |  |  |  |
|  | Positive | 446 | 223 | 7.7 | 223 | 11.9 | 0.59 | (0.44-0.78) |  |
|  | Negative | 265 | 127 | 4.9 | 138 | 11.1 | 0.44 | (0.31-0.61) |  |
|  | Unknown | 11 | 4 | 21.3 | 7 |  | 1.70 | (0.15-19.07) |  |
| ER/PR/HER2 combined |  |  |  |  |  |  |  |  |  |
|  | Negative | 232 | 110 | 5.3 | 122 | 10.6 | 0.49 | (0.34-0.70) |  |
|  | All others | 490 | 224 | 7.4 | 246 | 12.5 | 0.57 | (0.44-0.75) |  |
| HER2 status |  |  |  |  |  |  |  |  |  |
|  | Positive | 15 | 6 | 2.4 | 9 | 11.3 | 0.00 | (0.00- ) |  |
|  | Negative | 650 | 316 | 6.1 | 334 | 11.1 | 0.57 | (0.45-0.71) |  |
|  | Unknown | 57 | 32 | 7.7 | 25 | 12.5 | 0.42 | (0.19-0.93) |  |

- TAX better

- TAX/AV better

- 0.5

- 0.2

- 5

- 2

- 1

## Subgroup Analysis of PFS (3)

| Baseline Risk Factor |  | Total n | n | Median (mo) | n | Median (mo) | Hazard Ratio | (95% Cl) |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All Patients |  | 722 | 354 | 5.8 | 368 | 11.3 | 0.54 | (0.44-0.67) |  |
| Number of metastatic sites |  |  |  |  |  |  |  |  |  |
|  | <3 | 514 | 252 | 6.6 | 262 | 13.3 | 0.53 | (0.41-0.69) |  |
|  | ≥3 | 208 | 102 | 4.8 | 106 | 8.3 | 0.56 | (0.38-0.81) |  |
| Measurable Disease at baseline |  |  |  |  |  |  |  |  |  |
|  | No | 250 | 111 | 4.1 | 139 | 16.6 | 0.37 | (0.25-0.54) |  |
|  | Yes | 472 | 243 | 6.7 | 229 | 10.7 | 0.66 | (0.51-0.85) |  |
| SLD of target lessions (mm) |  |  |  |  |  |  |  |  |  |
|  | ≤Median (76.00) | 238 | 116 | 8.6 | 122 | 11.1 | 0.72 | (0.50-1.03) |  |
|  | >Median | 234 | 127 | 5.8 | 107 | 8.6 | 0.63 | (0.44-0.91) |  |
| Prior adjuvant hormone therapy |  |  |  |  |  |  |  |  |  |
|  | Yes | 343 | 175 | 6.1 | 168 | 12.4 | 0.56 | (0.41-0.77) |  |
|  | No | 379 | 179 | 5.5 | 200 | 11.1 | 0.52 | (0.39-0.70) |  |
| Metastatic / Recurrence hormone therapy |  |  |  |  |  |  |  |  |  |
|  | Yes | 262 | 128 | 6.0 | 134 | 11.9 | 0.53 | (0.37-0.77) |  |
|  | No | 460 | 226 | 5.8 | 234 | 11.1 | 0.55 | (0.43-0.72) |  |

- TAX better

- TAX/AV better

- 0.5

- 0.2

- 5

- 2

- 1

## Reasons for PFS censoring: Patients censored more than 90 days from data cutoff (%)

|   | TAX(n=354)   | TAX/AV 
(n=368)   | Total (n=722) |
| --- | --- | --- | --- |
| Patients censored more than 90 days prior to data cutoff | 40 | 35 | 37  |
|      No scans or pertinent clinical    
     information submitted to IRF
 | 6 | 6 | 6 |
| 
     Non-protocol Therapy
 | 15 | 13 | 14 |
|      Investigator PD not confirmed 
     by IRF | 15 | 9 | 12 |
|      Data cutoff | 3 | 9 | 5 |