1

ODACSeptember 13th, 2005

Tarceva® (erlotinib)Adrian Senderowicz, M.D.

DDODP, CDERFDA

2

sNDA 21,743Tarceva® (erlotinib)

Applicant’s Proposed Indication:“TARCEVA® in combination with gemcitabine is indicated for

the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer”

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Overview of FDA Presentation

• Available therapies for pancreatic carcinoma

• Single pivotal study (PA. 3): Design

• Study results

• Conclusions

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Pivotal study Gemcitabine vs 5-FUAdvanced Pancreatic carcinoma (N=123)

Gem: median OS: 5.7 mos (95% CI: 4.7-6.9)

5-FU: median OS: 4.25 mos (95% CI: 3.1-5.1)

p= 0.0009

Gem: clinical benefit response: 22%

p= 0.004

5-FU: clinical benefit response: 5%

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Advanced Pancreatic carcinomaGemcitabine randomized trials

Gem vs Gem Ox (2)

Gem Gem/oxali N = 156 N = 157

7.1

9.0

HR = 0.83

p = 0.13**

26.9 38.2

p = 0.03

27.8 34.7

3.7

5.8

p = 0.04

16.7 28.7

p = 0.02

Gem vs Gem/CEF (3)

Gem Gem/ CEF N = 47 N = 52

NA

NA

HR = 0.65

p = 0.047

25 65

p = 0.01

21.3 38.5

3.3

5.4

p = 0.003

8.5 38.5

p <0.001 NS

Gem Vs FU (1)

5-FU Gem N = 63 N = 63

4.41

5.65

HR = NA

p = 0.0025

4.8 22.2

p = 0.004

2 18

0.92

2.33

p = 0.0002*

0 5.4

Median

Survival (mos)

Clinical benefit response (%)

% 12-month

survival

PFS (months)

% Response

Note: (1)Gemcitabine (1000 mg/m2) versus 5-FU (600 mg/m2). Burris, H et al J Clin Oncol, 15: 2403-2413, 1997. (2) Gem(1000 mg/m2) versus Gemcitabine (1000 mg/m2) + oxaliplatin (100 mg/m2). J Clin Oncol, 23: 3509-3516, 2005. (3) Gem (1000 mg/m2) versus Gemcitabine (600 mg/m2) + CDDP (40 mg/m2) + Epirubicin (40 mg/m2) + 5-FU 200mg/m2, CIV. Reni M et al Lancet Oncol, 6: 369-376, 2005. (4) Gemcitabine (1000 mg/m2) + 100 mg erlotinib versus Gemcitabine (1000 mg/m2) + placebo (sNDA). NA = not available, *unadjusted cox proportional ratios. ** cox proportional adjusted for PS and disease status. .

(4)

Plac/Gem Gem/Erlo N = 260 N = 261

5.95

6.38

HR = 0.81*

p = 0.02*

NA NA

17 24

3.55

3.81

p = 0.004**

8.0 8.6

p = 0.875

Gem vs Gem Erlo

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PA. 3 TrialAdministrative History

• Protocol Final Version August 10th, 2001

• First Patient recruited November 29th, 2001

• Last Patient recruited January 31st, 2003

• Data Cutoff January 15th, 2004

– (484 deaths/85 censored)

• Statistical Analyses Plan (FDA) August 2004

• sNDA Submission April 29th, 2005

• Update sNDA data June 20th, 2005

– (551 deaths/18 censored)

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PA.3 Study Design • Single, randomized, double-blinded, placebo-controlled, Phase

3, multinational• 2 Arms:

– Erlotinib/gemcitabine (E/G) vs – Placebo/gemcitabine (P/G)

• Planned sample size to obtain 381 deaths:

470 patients*• Stratified by:

– ECOG (PS ≤ 1 vs PS 2)

– Extent of disease (local vs metastatic)

– Center**

• Designed to show superiority

* sample was changed twice. **Center was removed as stratification factor at the time of the SAP, 9/2004

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Study schema

RANDOMIZE

Gemcitabine 1000 mg/m2 weekly x 7 of 8 wks, then weekly q 3 wks of 4

Erlotinib 100/150 mg PO daily

N=285 (100 mg, N=261)

+ Placebo (Double-Blind)

N=284 (100 mg, N=260)

Metastatic or locally advanced Dz

ECOG

No prior chemoRx**

EGFR Status not required

Gemcitabine 1000 mg/m2 weekly x 7 of 8 wks, then weekly q 3 wks of 4.

Center*

*Center was removed as stratification factor as of 9/04. ** concomitant chemo/radiation as radiation sensitizer was allowed

Extent Dz

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PA.3 TrialEndpoints

• Primary: Overall Survival– based on median PG survival of 6.6 months, expected increase by 33% to 8.8 months in

the EG, 80% power, hazard ratio of ~ 0.75. – Covariates:

• ECOG PS 0/1 vs PS2

• Extent of disease: locally advanced vs metastatic

• Pain intensity *: > 20 vs ≤ 20 vs not measured.

• Secondary: – PFS

– Response Rate and duration of Response

– Correlation of EGFR status and response rate

– Quality of life

– Toxicity

* SAP 8/2004: exclude pain score adjustment only if majority of patients have missing values

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PA. 3 Study Results100 mg cohort

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PA.3 TrialBaseline Characteristics

E/G, N= 261

%

P/G, N= 260

%

Extent of disease: LA vs Mets 23/77 24/76

ECOG PS: ≤ 1 vs 2 83/17 82/18

Gender: Female/Male 51/49 44/56

Age (median)* 64 yrs* 63 yrs*

Pain intensity**: ≤ 20 vs > 20 46/ 51** 46/52**

Race: white, black and other 86/ 3/ 11 89/ 2/ 9

EGFR status***:

positive/negative 16/13*** 11/12***

LA: locally-advanced. Mets: metastatic at baseline. *ages range: EG: range: 37-84 and PG: 36-92. **Missing values: 3% and 2 %, respectively. ***Missing values: 71% and 77%, respectively. .

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Protocol Violations

• Major violations: pathological confirmation

– FDA assessment: other tumor types or

unable to confirm the diagnosis of

adenocarcinoma pancreas: N=18

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Major Protocol violationsLack of pathological confirmation

Sponsor/FDA assessment

(N =18)

No pathological report 2

Lack of confirmation of malignancy 3

Other primary tumor* 10

Metastatic without proof of pancreatic origin 3

*Tumors discovered: ampula vater (N=5), acinar cell carcinoma (N=2), colon cancer (N=1), gastric cancer (N=1) and adenocarcinoma of non-pancreatic origin (N=1).

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PA3. TrialPopulations for Analysis

Patients E/G Arm

N (%)

P/G Arm

N (%)

All Pts

N (%)

Analysis Population (patients randomized)

261

(100)

260

(100)

521

(100)

Analysis population minus major protocol violations* Sponsor/FDA discussion (N=18)

251 (96)

252 (97)

503 (97)

Safety Population (patients who received study drug)

259 (99) 256 (98) 515 (99)

*Protocol violations: wrong tumor diagnosis, lack of pathological confirmation of malignancy or lack of confirmation of adenocarcinoma of the pancreas

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PA.3 TrialPatient Disposition

E/G(N=261)

P/G(N=260)

n (%) n (%)

Patients Never Treated 2 (<1) 4 (2)

Patients Off drug therapy 251 (96) 252 (97)

Reasons Off drug therapy

Progressive Disease 162 (62) 185 (71)

Adverse Events* 5757 (22)(22) 3737 (14)(14)

Intercurrent Illness 10 (4) 10 (4)

Patient Refusal 2222 (8)(8) 1515 (6)(6)

Death 25 (10) 21 (8)

Other 6 (2) 8 (3)

On drug therapy 8 (3) 4 (2)

Note: * adverse events that lead to drug discontinuation

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PA3. Pancreatic Carcinoma TrialsOverall Survival analysis population

Survival time was defined as the time from the date of randomization to the date of death *Cox proportional adjusted by ECOG PS and Extent of disease. EG: Erlotonib/gemcitabine. PG: EG: Erlotonib/gemcitabine

0.03

0.06

0.02

Strat . Log Rank

p value

0.810.68 to 0.96

0.800.65 to 0.98

0.790.64 to 0.97

HR *adjusted95% CI

5.956.37443(data cutoff

5.946.47381(original

sample size)

5.946.37504(updated database)

P/GMedian OS

E/GMedian OS

Number of Deaths

0.810.68 to 0.96

0.800.65 to 0.98

0.790.64 to 0.97

HR *adjusted95% CI

5.956.37443(data )

5.946.47381(original

sample size)

5.946.37504(updated database)

P/GMedian OS

E/GMedian OS

95% CI(months)

Number of Deaths

95% CI(months)

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Kaplan Meier Survival CurveErlotinib/Gem vs Placebo/Gem (504 deaths)

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25 30 35

Pro

port

ion

surv

ivin

g

* Stratified log-rank test

Erlotinib/Gem: median OS: 6.37 mos (95% CI: 5.84 to 7.33)

Placebo/Gem: median OS: 5.94 mos (95% CI: 5.09 to 6.70)

HR: 0.811 (95% CI: 0.68 to 0.97)

p= 0.017

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Sensitivity AnalysesOverall survival in analysis population minus

patients with major protocol violations

• Exclusion of patients without pathological confirmation

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Erlotinib/Gem in Advanced Pancreas Sensitivity Analyses of Overall Survival using

Stratified* Log-Rank test

All unadjusted analyses showed NS results. *adjusted for ECOG PS and extent of disease. ** adjusted cox proportional hazard ratio

18 excluded 0.0350.82 0.69-0.98

0.0600.82 0.67-1.000418 excluded

HR** 95 % CI p*

381 deaths 0.0550.81 0.66-0.99

504 deaths 0.0280.81 0.68-0.97

0.0310.81 0.67-0.9818 excluded

443 deaths 0.0170.79 0.65-0.95

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Exploratory analysesOverall survival

• Role of baseline characteristics

• Role of rash

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Survival by Pretreatment Characteristics

0.71 0.4-1.2 66

0.76 0.5-1.3 70EGFR pos

EGFR neg

HR 95 % CI N

0.0 0.5 1.0 1.5 2.0

HR

0.76 0.6-1.0 274Age < 65 ys

0.75 0.6-1.0 273male

distant-rand.

0.5 0.3-0.8 88Ps 2-at rand.

E/G: P/G 0.83 0.7-1.0 521

Canada/US 0.74 0.6-0.9 280

Pain ≤ 20

0.77 0.6-1.0 369

0.70 0.5-0.9 238

0.93 0.7-1.3 152local- at rand.

0.89 0.7-1.1 433Ps 0-1 at rand.

Rest of World 0.96 0.7-1.3 241

0.91 0.7-1.2 247Age ≥ 65 ys

0.95 0.7-1.2 248female

Pain > 20 0.99 0.8-1.3 268

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PA.3 trialPresence of Rash and Survival

Pro

port

ion

surv

ivin

g

Time (months)

Note: * log-Rank test. rash ≥ grade 2 (95% CI: 8.0 to 12.6 and : 4.2 to 8.8) and ≤ grade 1 (95 % CI: 4.8 to 6.0 and 4.9 to 6.6)

≥ grade 2 rash

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25 30

E/G: OS: 10.7 mos

P/G: OS: 7.1 mosp= 0.02*

Pro

port

ion

Sur

vivi

ngTime (months)

≤ grade 1 rash

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25 30 35

E/G: OS: 5.7 mos

P/G: OS: 5.9 mosp= 0.35*

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PA.3 trialSecondary Endpoints

E/G P/G P value

Response rate (PR/CR, %) 1 8.6 7.9 ND

Duration of response (wks) 2 23.9 23.3 ND

Median PFS (months) 3 3.8 3.6 0.006

Survival by EGFR (months)

Positive4

Negative

6.6

6.0

5.3

6.0

NS

NS

Note: 1 number of patients with measurable disease: 244 vs 241, respectively. number of patients with responses: 21 vs 19, respectively. 2 Range (3.7 to 56.0+ vs 6.7+ to 65.3 +). 3 Adjusted cox proportional: 0.76. 4 total number of patients with EGFR positive and negative: 41 vs 34 and 32 vs 29, respectively. NS: not significant. ND: not done

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PA.3 TrialSecondary endpoints (cont’d)Quality of Life assessment by EORTC QLQ-C30

• Mixed results do not confirm QoL benefit

• E/G worse diarrhea (p<0.001)

• E/G worse in some variables (e.g. cognitive

functioning, fatigue, dyspnea, appetite, global

QOL) while improved in other categories (e.g.

pain, sleep, social functioning, constipation).

• EG worse in global health status (32% vs 25%).

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Category E/G (N=259) P/G (N=256)

n (%) n (%)

Patients with at least one AE 256 (99) 248 (97)

AEs (worst severity) regardless of causality

Grade ≤2 76 (29) 85 (36)

Grade 3/4 Grade 3/4 * 180 (69) 163 (64)

Patients with at least one SAE* Patients with at least one SAE* 131 (51) 99 (39)

Patients who discontinued study due to AEs*Patients who discontinued study due to AEs* 31 (12) 19 (7)

Patients who died on treatment or within 30 Patients who died on treatment or within 30 days of last treatment*days of last treatment*

81 (31) 68 (27)

PA.3 TrialSafety Profile

*Similar results for treatment-related AEs and regardless of causality

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PA. 3 TrialDeath on therapy or within 30 days of therapy

Erlotinib/Gem

(N=81)

Placebo/Gem

(N=68)

N % N %

Toxicity from protocol Rx 2 2.5 0 0

Combination of pancreatic cancer and Rx

3 3.7 0 0

Other conditions 10 12.3 9 13.2

Other primary malignancy 1 1.2 0 0

Pancreatic cancer 65 80.2 59 86.8

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PA. 3 TrialSevere AEs (grade ≥ 3)

Note: Severe: ≥ Grade 3 AEs. Stroke (ischemic and hemorrhagic). CHF: congestive heart failure

E/G (N=259) P/G (N=256)N (%) N (%)

Cardiovascular

Edema 12 (4.6) 5 (2)

Syncope 6 (2.3) 4 (1.6)

Arrhythmias 6 (2.3) 2 (0.8)

CHF 2 (0.8) 3 (1.2)

Hypertension 3 (1.2) 5 (2)

Hypotension 3 (1.2) 4 (1.6)

Ischemic events

Myocardial ischemia/infarction 7 (2.7) 3 (1.2)

Peripheral ischemia 1 (0.4) 0 (0)

Troponin elevation 1 (0.4) 0 (0)

Stroke 6 (2.3) 0 (0)

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PA.3 Safety AnalysisIncidence of Stroke in erlotinib group

• There were 6 patients with stroke (incidence 2.3 %)– 5 ischemic– 1 hemorrhagic

• Median time to stroke was 24 days.

• The earliest case of stroke occurred by 2 days from drug initiation and the latest was 35 days after drug initiation.

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PA.3 TrialSevere AEs (cont’d)

E/G (N=259) P/G (N=256)N (%) N (%)

Thrombotic

DVTs 9 (3.5) 3 (1.2)

PE 6 (2.3) 5 (2)

Other thrombosis 17 (6.6) 18 (7)

TTP 2 (0.8) 0 (0)

Pulmonary

Interstitial Lung disease 6 (2.3) 1 (0.4)

Pneumonitis 4 (1.5) 1 (0.4)

Hypoxia 1 (0.4) 1 (0.4)

Dyspnea 15 (5.8) 13 (5.1)

Pneumonia/lung infiltration 13 (5.0) 6 (2.4)

Note: Severe: ≥ Grade 3 AEs. DVTs: deep venous thrombosis. PE: pulmonary embolism. TTP: thrombotic thrombocytopenic Purpura. ARDS: acute respiratory disorder syndrome

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PA.3 TrialSevere AEs (cont’d)

EG (N=259) P/G (N=256)N (%) N (%)

Gastrointestinal

Diarrhea 15 (5.8) 5 (2)

LFT elevation 19 (7.3) 15 (5.9)

GI bleeding 15 (5.8) 8 (3.1)

Ileus 4 (1.5) 1 (0.4)

Pancreatitis 5 (1.9) 2 (0.8)

Odynophagia 3 (1.2) 0 (0)

Hematology

Hemolytic anemia 2 (0.8) 0 (0)

Thrombocytopenia 4 (1.5) 1 (0.4)

Bleeding disorders 3(1.2) 1 (0.4)

Rash 12(4.6) 3(1.2)

Note: GI: gastrointestinal, LFT: liver function test. Severe: ≥ Grade 3 AEs.

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PA.3 TrialSevere AEs (cont’d)

E/G (N=259) P/G (N=256)

N (%) N (%)

Central Nervous System

Neuropathy 5(1.9) 1(0.4)

Depression 5(1.9) 3(1.2)

Infections

Sepsis/bacteremias 22(8.5) 22(8.6)

Other infections 13(5.0) 2(0.8)

Bone

Bone pain 13(5.0) 9(3.5)

Aseptic bone necrosis 2(0.8) 1(0.4)

Others

Renal failure 3(1.2) 0(0)

Severe: ≥ Grade 3 AEs.

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Causes E/G (N=259) P/G (N= 256)Total number of patients 22 15

Severe (≥ Grade 3) toxicity 12 3

Other causes 10 12

AEs E/G (N=12)** P/G (N= 3)**Liver enzymatic elevations 6 0

Deep venous thrombosis 3 0

Sepsis 3 0

Pneumonia 2 0

GI bleed 2 0

Others* 3 3

Causes for dropouts in patients that refused further therapy

Note: Others: EG: Congestive heart failure (N=1), Ileus/dehydration (N=1), Dysphagia (N=1), PG: Aseptic necrosis of bone (N=1), Arrhythmia (N=1), Arthralgias/muscle weakness (N=1). ** Total does not add up as patients could refuse further therapy due to more than 1 event

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PA.3 trialSummary of Toxicity profile

• Erlotinib/gemcitabine arm has higher incidence of: – Grade 3/4 (regardless of causality and treatment related)

– SAEs (regardless of causality and treatment related)

– Discontinuation due to AEs (regardless of causality and treatment related)

– Toxic deaths

– Refusal of therapy

– Death on treatment or within 30 days of last treatment

• Most frequent AEs in the E/G group: Rash and diarrhea

• E/G has higher incidence of ILD-like disease

• Other severe AEs were higher in the EG arm: Stroke, TTP, myocardial

infarction, arrhythmias, edema, renal failure, bleeding disorders (GI and

non-GI related), ileus, pancreatitis, odynophagia and neuropathy.

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FDA Guidance of Evidence of effectiveness from a single study without

independent substantiation• Large multicenter study: No single investigator

or site disproportionally responsible for favorable effects

• Consistency across study subjects (e.g. age, gender, disease state)

• Multiple endpoints (primary and secondary) involving different events are positive

• Statistically very persuasive finding (e.g. very low p-value): unethical to repeat trial

*Taken from guidance: Clinical Evidence of Effectiveness for human Drug and biological products, 5/98, pp 12-16

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PA.3 trial Pancreatic Carcinoma Conclusions

• Single add-on trial: erlotinib adds marginal efficacy (clinical

and statistical) and adds severe toxicity.

– E/G increased overall survival (median difference ~ 12 days)

– E/G increased PFS (median difference ~10 days)

– No difference in response rate or duration of response

– No improvement in quality of life. However, diarrhea significantly worse in the E/G arm.

– No relationship between EGFR expression and survival was shown

– E/G had worse safety profile: greater number of AEs Grade 3/4, SAEs, discontinuation due

to AEs, refusal of therapy, toxic death and death on treatment or within 30 days of last

treatment.

– Stroke, TTP and other toxicities in the E/G are a safety concern.