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STN 125085/91Bevacizumab (Avastin®) plus Paclitaxel

for 1st line Metastatic Breast Cancer

ODAC MeetingDecember 5th, 2007

Clinical Review - Lee Pai-Scherf, M.D.Statistical Review - Hong Lu, Ph.D.

CDER/FDA

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Proposed Indication

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

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Overview

• Regulatory Background

• Clinical studies

– Pivotal study E2100 (Phase 3)

– AVF2119g (Phase 3)

• Summary of Findings

• Questions to ODAC

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Regulatory Background

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Regulatory Background

Bevacizumab is approved by FDA for:

• 1st (2004) and 2nd line (2006) metastatic colorectal cancer in combination with 5-FU–based chemotherapy. Approval endpoint: OS

• 1st line unresectable, or metastatic non-squamous non-SCLC in combination with carboplatin and paclitaxel (2006) . Approval endpoint: OS

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Regulatory Background – AVF2119g

• July, 2000

Genentech and FDA discussed study AVF2119g design [RCT of capecitabine +/- bevacizumab for 2nd and 3rd line therapy of MBC] intended to support Avastin approval

• November, 2000 – March 2002

Accrual period

• March, 2002

Genentech and FDA discussed BLA based on this trial

• September, 2002

AVF2119g failed to meet primary endpoint of PFS

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Regulatory Background – E2100• October, 2001

– NCI submitted protocol E2100 [RCT of paclitaxel +/- bevacizumab for 1st line therapy of MBC]. Study not identified by NCI as intended to support drug approval.*

– Study opened for accrual December 2001

• May, 2002– Genentech identified E2100 as additional study to

support drug approval– FDA provided comments to NCI; noted that SAP was

extremely deficient– Key issues:

• SAP did not clearly identify primary & important secondary efficacy endpoints

• Primary analysis methods for primary & important secondary endpoints not described

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Regulatory Background – E2100

October, 2002 (2nd letter to NCI re: E2100)– FDA reiterated that study identified by Genentech as

to support Avastin approval – NCI did not request meeting to discuss adequacy of

the trial design and analysis plan

– FDA asked NCI for additional clarification regarding SAP

– FDA stated it was crucial that primary endpoint and statistical plan be adequate if study to serve as basis for drug approval

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Regulatory Background – E2100

• May 2004– E2100 completed patient accrual

• October 2004 – Genentech submitted SAP addressing FDA’s letters

to NCI and request for meeting re: adequacy of E2100 to support Avastin label expansion

– FDA noted E2100 may not be adequate to support licensure due to 1) non-blinded nature of study and 2) lack of pre-specified, detailed and objective radiological and clinical parameters for determination of disease progression

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Regulatory Background – E2100

October 2004 (cont.)– FDA noted Genentech must provide overall

survival data for regular approval of the proposed indication. In reviewing the results of E2100, FDA will consider data from AVF2119g (negative phase 3 study)

– Genentech asked if PFS would be an adequate endpoint for full approval. FDA replied it depends on the overall robustness and magnitude of PFS and results of survival data at time of PFS analysis

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Regulatory Background – E2100• April, 2005

– 1st interim efficacy analysis by ECOG DMC: Improved PFS (6.1 vs. 10.9 mos) in favor of the bevacizumab/paclitaxel arm (HR 0.49, log rank p < 0.001). Unplanned survival analysis reported HR 0.67, log rank test p=0.01

– Trial “stopped” based on these findings

– Genentech made results public April 14, 2005 and ASCO (May 2005) meeting

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Regulatory Background

• September 2005 (pre-sBLA meeting)

– FDA agreed E2100 could form basis of sBLA

– FDA stated PFS would support accelerated approval and final overall survival necessary for regular approval

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Regulatory Background

May, 2006– Genentech submitted sBLA for labeling

expansion of Avastin

September 8, 2006– FDA issued a Complete Review Letter

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Complete Review Letter – Key issues

1. Data set incomplete, without data cut-off date for efficacy and safety. Per Genentech, data collection and clean-up was still ongoing

Why do we need a clean data set with clear data cut-off date?

Data “cut-off”

date

No. of PFS events per ECOG

ECOG 1st interim analysis (4/05) 2/9/05 260

Data presented at ASCO (5/05) 2/9/05 355

1st sBLA submission (5/06) 4/14/05 395

2nd sBLA submission (8/07) 2/9/05 445

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Complete Review Letter – Key issues

2. FDA reiterated need for independent radiology review of progression events in at least a subset of patients, given subjective nature of PFS endpoint and open-label design of E2100

3. Submission incomplete in regards to documentation of eligibility, baseline tumor description, study violations, drug exposure, and treatment delays/discontinuation due to toxicity

Data submitted did not allow full evaluation of efficacy and safety

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Regulatory Background

• November 2006 – March 2007

– Agreement reached regarding the data cut off dates for efficacy and safety

– Genentech to submit a “cleaned” dataset– Genentech to conduct independent, blinded review of

all patients enrolled in E2100 study to verify efficacy results

– The primary regulatory endpoint to be PFS adjudicated by independent review facility (IRF)

– Genentech to submit updated survival data

• August 2007– sBLA resubmitted for labeling expansion of Avastin

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E2100

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E2100 Study Design

• Recurrent or metastatic adenocarcinoma of the breast • No prior chemo for recurrent or metastatic disease• HER2 neu negative

Arm A

Paclitaxel 90mg/m2 q wk x 3 Bevacizumab 10mg/kg wks 1 and 3

4 week cycles

Arm B

Paclitaxel 90mg/m2 q wk x 3

4 week cycles

Stratificationdisease-free interval (≤ 24, > 24 months), number of metastatic sites (<3, ≥ 3), prior adjuvant chemotherapy (yes, no) and ER status (positive, negative, and unknown)

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Study Plan

• Treatment continued until disease progression or unacceptable toxicity

• Crossover not allowed

• Tumor assessment every 12 weeks– Protocol required “x-rays and scans”

• Follow up every 3 months if < 2 years and every 6 months (2-5 years)

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Efficacy Endpoints

Primary• PFS adjudicated by blinded independent

radiographic facility (IRF)

Secondary • Survival• RR and duration • QOL (FACT-B questionnaire)

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E2100 Enrollment

• December 21, 2001 – May 26, 2004

• N = 722 (368/354)

• 258 centers from ECOG, CALGB, SWOG, NSABP, NCCTG, RTOG, GOG and EPP (NCI’s Expanded Participation Project)

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Patient and Disease Characteristics

Demographic/Tumor Characteristics Total (N=722)

Female 99.2

Age 55 (27-85)

Post Menopausal 55.3

Metastatic disease 98.3

No. of involved sites < 3 ≥ 3

54.345.7

Common sites of involvement Bone Liver Lung

54.541.741.5

ER status Negative 61.8

No measurable disease at baseline 27.3 (23% vs. 32%)

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Prior Cancer Therapy

Prior Cancer Therapy Total N= 722)

Hormonal therapy Adjuvant or Metastatic setting 61%

Adjuvant Chemo 66%

Prior taxane 20%

Prior anthracycline 50%

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E2100 Protocol Deviation

Protocol DeviationTotal N=722

Treated beyond progression6 %

(4 vs. 7)

Stratification error* (ER status, adj. chemo) 7%

Initiation of Non-Protocol anti-cancer therapy (NPT) prior to documented PD

16%

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E2100 Efficacy Results

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PFS as the Primary Efficacy Endpoint

• Application rests solely on evidence of an improvement on PFS in a single study

• A 5.5 month improvement in PFS is claimed by Genentech.

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PFS as the Primary Efficacy Endpoint

In considering Genentech’s claim, the

FDA needs to verify:

1. Robustness (i.e., is there an effect?)

2. Magnitude (i.e., is the 5.5 month

improvement in PFS reliable ?)

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Outline

• Summary of issues

• Results in PFS

• Confidence in PFS measurement– IRF radiologist results – IRF vs. ECOG results– Sensitivity analyses for PFS

• Results in OS

• Results in Objective Response

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Summary of Issues

• Confidence in PFS results– Incomplete data– Loss-to-follow-up– Lack of consistent scan readings

• No effect on overall survival

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E2100: Results in PFS

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PFS Results based on IRF Assessments (data cutoff date 2/9/2005)

PAC PAC/BV

No. of patients 354 368

No. of patients with an event (%)

184 (52%) 173 (47%)

Median (month) 5.8 11.3

HR (relative to PAC) 0.48

p-valued < 0.0001

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Type of Progression by IRF

PFS eventsPAC

N=184

PAC/BEV

N=173

Radiologic Progression 79% 76%

Clinical Progression 11% 15%

Death 10% 9%

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Cumulative Incidence

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

PFS Ti me ( mont hs ) ( I RF)

0 6 12 18 24 30 36

PAC:

PAC/ BEV:

# at r i sk

Progression-Free Survival (IRF)

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IRF vs. ECOG in PFS Results(data cutoff date 2/9/2005)

PAC (N=354)PAC/BV

(N=368)

No. of patients with an event (IRF/ECOG)

184/244 173/201

Median (IRF/ECOG) 5.8/5.8 11.3/11.4

HR (IRF/ECOG) 0.48/0.42

p-value (IRF/ECOG)<0.0001/<0.0001

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Confidence in PFS Results

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Completeness of Tumor assessment

• Missing Radiographic Information: In retrospective collection, Genentech unable to obtain scans in 73 (10%) patients

• Loss-to-follow up: 247 (34%) patients not

followed until IRF-PFS event or end of study

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• Two radiologists assigned to read all films for each patient

• Readings to be performed independently

• If readings are discordant, 3rd radiologist performed adjudication of radiology results

• An oncologist reviewed all pertinent clinical information

IRF assessment procedure

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Lack of consistency between the IRF Radiologists in Scan Reading

N No. Patients Adjudicated for Discordant Response or PD Status/Date

Patients with Scan 649 328 (50.5%)

PAC 319 158 (49.5%)

PAC/BEV 330 170 (51.5%)

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Lack of Consistency between IRF Radiologists for PD Status or Date

NNo. of Patients with Discordant

PD Status or Date (%)

Patients with Scan 649 222 (34.2%)

Radiographic PD 278 131 (47.1%)

No Radiographic PD 371 91 (24.5%)

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Lack of Consistency between IRF and ECOG for PFS Event Status or Date

 

Discordance in PFS status (%)Discordance in PFS date when PFS status are agreed upon (%)

IRF PDECOG no PD

IRF no PDECOG PD

Total N =722

43 (6%) 131 (18%) 194 (27%)

51%

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Lack of consistency between IRF and ECOG

for PFS Event Status

Treatment

No. of discordance (%)

IRF PDECOG no PD

IRF no PDECOG PD

PAC 12 (3.4%) 72 (20.3%)

PAC/BV 31 (8.4%) 59 (16.0%)

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Lack of Consistency between IRF and ECOG

for PFS Event Status

Treatment

No. of discordance (%)

IRF PDECOG no PD

IRF no PDECOG PD

PAC 12 (3.4%) 72 (20.3%)

PAC/BV 31 (8.4%) 59 (16.0%)

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Additional PFS Analyses (1)

Median (month)Hazard

RatioPAC PAC/BEV

Primary analysis-IRF 5.8 11.3 0.48

Time to IRF-PFS event, NPT or early discontinuation

4.2 8.1 0.49

Time to IRF-PFS event without censoring for NPT

6.1 11.2 0.57

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Additional PFS Analyses (2)

Median (month)

Hazard RatioPAC PAC/BEV

NPT and early discontinuation as events in PAC/BEV arm only

5.8 8.1 0.78

Time to earliest PFS event(IRF or ECOG)

4.9 9.0 0.46

Time to earliest PFS event (IRF or ECOG), NPT or early discontinuation

4.1 8.1 0.49

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E2100 Overall Survival - Final Analysis

PACn = 354

PAC/BVn = 368

No. deaths 238 (67%) 243 (66%)

Median OS (months) 24.8 26.5

HR (relative to PAC) 0.87

95% CI (0.72, 1.05)

p-value 0.14

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Cumulative Incidence

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

Dur at i on of Sur vi val ( Mont hs )

0 6 12 18 24 30 36 42 48 54 60

PAC

PAC/ BEV

# at r i sk

E2100 Overall Survival – Final Analysis

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PACn = 243

PAC/BVn = 229

No. with objective response 54 (22%) 112 (49%)

(PAC/BV − PAC) 27%

p-value < 0.0001

Median duration of response (month) 9.7 9.4

Objective Response (IRF)

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Summary of Issues

• Confidence in PFS results – Genentech unable to obtain scans

retrospectively for 10% of patients– 34% patients not followed until IRF-PFS event

or end of study – 34% discordance between IRF radiologists in

PFS status or date – 51% discordance between IRF and ECOG in

PFS status or date

• No effect on overall survival

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E2100 Safety Results

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Drug Exposure (Estimated)

PAC PAC/BV

PAC BEV

Duration of treatment 5 months 9 months

No. of cycles 6 10

Total cumulative dose 1440 mg/m2 1926 mg/m2 180 mg/kg

Relative dose intensity 95 % 85 % 93 %

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Dose Modification and Delays

PAC PAC/BV

Modification/omission 65% 88%

Delay 29 % 41%

Dose reduction 33% 49% 3%

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Treatment Discontinuation due to Toxicity

• 142 patients (19.6%) discontinued therapy due to SAE– 70 in PAC arm (20%), – 72 in PAC/BV arm (19.8%)

• Specific adverse event(s) leading to treatment discontinuation not collected in the E2100 study

• Based on temporal association:– PAC: neuropathy and allergic reactions– PAC/BV: neuropathy, thrombosis, proteinuria,

hypertension, arterial thromboembolic event, fatigue, left ventricular dysfunction

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ECOG Safety Data Collection

• AEs collected once every 3 cycles (12

weeks)

• Date of onset and resolution of AE not

collected

• Only grade 3-5 non-hematologic AEs and

grade 4-5 hematologic AEs collected

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ECOG Safety Data Collection

• NCI/AdEERS collected serious events

from only PAC/BEV arm

• Laboratory data not collected

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Grade 3, 4 and 5 Toxicity

PAC N=348 (%)

PAC/BV

N=363 (%)

Total 176 (51) 257 (71)

Grade 5 7 (2) 11 (3)

Grade 4 32 (9) 44 (12)

Grade 3 137 (39) 202 (56)

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Grade 3, 4 and 5 AEs Known to Occur with Bevacizumab

PAC

N=348 (%)

PAC/BV

N=363 (%)

Hypertension 5 (1.4) 57 (15.7)

Proteinuria 0 10 (2.8)

Arterial Thromboembolic Events

Cerebrovascular ischemia

Cardiac ischemia

0

0

0

10 (2.8)

7 (1.9)

3 (0.8)

Venous Thromboembolic Events 15 (4.3) 9 (2.5)

Bleeding/Hemorrhage 1 (0.3) 6 (1.7)

Congestive Heart Failure 1 (0.3) 5 (1.4)

GI perforation/fistula 0 3 (0.9)

Neutropenia/infection 28 (8) 62 (17.1)

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Additional Treatment Emergent Grade 3-4 AEs

PAC

% (N=348)

PAC/BV

% (N=363)

Sensory neuropathy 18 24

Vomiting

Diarrhea

Dehydration

2

1

1

6

5

3

Fatigue 5 11

Pain 10 16

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Deaths on Study per Genentech

Primary cause of death PAC

N = 348 (%)PAC/BV

N = 363 (%)

All deaths* 256 (74) 255 (70)

Due to this disease 241 (69) 243 (67)

Due to protocol treatment

1 (0.3) 0 (0)

Due to other cause 7 (2) 9 (2.5)

Unknown 7 (2) 3 (0.8)

Adapted from Genentech’s CSR, Table 14.3/26* Data from ECOG CRFs. All deaths included. No cut off date.

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Deaths on Study/within 30 days of End of Study Genentech and FDA’s Attribution of the Cause of Death

PAC PAC/BV

 Cause of deathApplicant FDA Applicant FDA

Death on study/within 30d 7 7 12 12

Due to treatment Definite Probable

00

00

00 2

3

Due to this disease 4 3 8 4

Due to other cause 2 1 4 1Unknown 1 2 0 2Insuf. information 0 1 0 0

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Deaths on Study Possibly/Definitively Related to Protocol Therapy per FDA

• ID 21010: 79 yo, after 6 cycles PAC/BEV, developed severe diarrhea, fatigue, muscle weakness and lethargy and death 11 days after last dose of protocol (Applicant’s attribution: death due to breast cancer)

• ID 21258: 64 yo, after 6 cycles PAC/BEV, developed abdominal pain with gastrointestinal perforation, neutropenia, sepsis and death. (Applicant’s attribution: death due to breast cancer)

• ID 21314: 84 yo, after 3 cycles of PAC/BEV, developed acute abdomen with gastrointestinal perforation, sepsis, respiratory failure and death. (Applicant’s attribution: death due to other cause)

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• ID 21403: 73 yo, 22 days after BEV/PAC developed progressive fatigue, pneumonitis, and fatal cardiac ischemia/infarction and LV dysfunction. (Applicant’s attribution: death due to other cause)

• ID 26004: 66 yo, after 11 cycles of PAC/BEV was admitted with severe diarrhea, black tarry stool and abdominal pain. Symptoms were attributed to diverticulitis and PAC/BEV. 22 days later became hypotensive, bradycardic and died. (Applicant attribution: death due to other cause)

• ID 21390: 69 yo, discontinued protocol after 3 cycles of BEV/PAC due to grade 4 proteinuria (nephrotic syndrome). Patient had a fatal acute myocardial infarction 7 weeks after being discontinued from protocol (Applicant’s attribution: death due to other cause)

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Cumulative Incidence

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

Dur at i on of Sur vi val ( Mont hs )

0 6 12 18 24 30 36 42 48 54 60

PAC

PAC/ BEV

# at r i sk

E2100 - Overall Survival

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AVF2119g

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AVF2119g

N = 462• Progressive metastatic breast cancer• Previously treated with anthracycline and taxane

Capecitabine 2500 mg/m2 d 1-14

Cycles q 3 wks

Capecitabine 2500 mg/m2 d1-14

Bevacizumab 15 mg/kg q 3 wks

Cycles q 3 wks

StratificationECOG PS (0 or ≥ 1)N of prior chemo for MBC (0 or ≥ 1)

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Primary Endpoint - PFS

CAP

N=230 (%)

CAP + AVF

N=232 (%)

Median (months)4.17

(3.71, 5.13)

4.86

(4.17, 5.52)

HR 0.98 (0.77, 1.25)

P-value 0.857

66Tr eat ment Gr oup ( Char ) CAP Al one CAP+AVF

Cumulative Incidence

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

Dur at i on of Sur vi val ( mont hs )

0 2 4 6 8 10 12 14 16 18 20

CAP CAP+AVF

Median (month) 14.5 15.1

HR 1.08

P-value 0.63

AVF2119g Overall Survival

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AVF2119g Response Rate

CAP

N=230 (%)

CAP+BEV

N=232 (%)

ORR 21 (9.1) 46 (19.8)

95% CI 4.3%, 17.0%

P-value 0.001

Duration of response

7.5 months 4.9 months

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AVF2119g - AEs

• Common AEs in both arms: asthenia, pain, diarrhea, nausea, vomiting, hand-foot syndrome

• Common AE in CAP/Bev arm: headache, hypertension, epistaxis and proteinuria

CAP N=215 (%)

CAP + BEV N=229 (%)

Grade 3-4 All grades Grade 3-4 All grades

Any AE 124 (57.7) 211 (98.1) 165 (72.1) 229 (100)

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Grade 3-4 AEs Known to Occur with Bevacizumab

CAPN=215 (%)

CAP + BEVN=229 (%)

Hypertension 0.5 20.1

Thromboembolism 3.7 6.1

CHF/Cardiomyopathy 1.0 3.5

Proteinuria 0 0.9

Bleeding 0.5 0.4

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Summary of Findings

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E2100 Efficacy

• Estimated 5.5 months improvement in PFS by independent review

• PFS improvement is similar to the ECOG investigators’ findings

• No survival advantage

objective response

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E2100 Efficacy Robustness of effect: YES

Magnitude of effect: No

Factors affecting confidence in magnitude of PFS finding:

– Missing scans(10%) – 34 % patients not followed until IRF-PFS event or

end of study – Lack of reliability in determination of radiologic

disease progression and date of progression between independent radiologists and investigators and independent radiologists.

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E2100 - Safety

• Incomplete assessment of toxicity profile:– Grade 1-2 not collected– Laboratory data not collected

• 20.2% increase in grade 3-5 toxicity

• 1.7 % treatment related death in the bevacizumab plus paclitaxel arm

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AVF2119g

• Did not increase PFS in MBC patients • No survival advantage

objective response (short duration)

• 14.4% in grade 3-4 toxicity

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Thank you

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Questions to ODAC

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Question 1 (non-voting)

In the E2100 study, PFS is not a surrogateendpoint for overall survival (OS) in first-line breast cancer.

Please discuss whether PFS alone without a demonstrated survival advantage should be considered a measure of direct clinical benefit in the initial treatment of metastatic breast cancer.

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Questions 2Summary results:

• Estimated 5.5 month improvement in median PFS

claimed by Genentech• No improvement in OS • Increased toxicity/toxic death • No effect on PFS or OS in 2nd and 3rd line MBC

Are the data provided sufficient to establish a favorable risk/benefit analysis for the use of bevacizumab plus paclitaxel for first-line treatment of patients with metastatic

breast cancer ?