# Presentation: 698345

## ODACSeptember 13th, 2005

- Tarceva® (erlotinib)
- Adrian Senderowicz, M.D.
- DDODP, CDER
- FDA

## sNDA 21,743Tarceva® (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”

## Overview of FDA Presentation

- Available therapies for pancreatic carcinoma
- Single pivotal study (PA. 3): Design
- Study results
- Conclusions

## Pivotal study Gemcitabine vs 5-FUAdvanced Pancreatic carcinoma (N=123)

## Advanced Pancreatic carcinomaGemcitabine randomized trials 

## PA. 3 TrialAdministrative 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)

## 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

## Study schema

- R

- A

- N

- D

- O

- M

- I

- Z

- E

- Gemcitabine

- 1000 mg/m

- 2

- 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

- No prior

- chemoRx**

- EGFR Status

- not required

- Gemcitabine

- 1000 mg/m

- 2

- 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

## PA.3 TrialEndpoints

- 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

## PA. 3 Study Results100 mg cohort

## PA.3 TrialBaseline 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. .

## Protocol Violations

- Major violations: pathological confirmation
- FDA assessment: other tumor types or  unable to confirm the diagnosis of adenocarcinoma pancreas: N=18

## Major Protocol violationsLack 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).

## PA3. TrialPopulations 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

## PA.3 TrialPatient 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* | 57 | (22) | 37 | (14) |
|    Intercurrent Illness  | 10 | (4) | 10 | (4) |
|    Patient Refusal  | 22 | (8) | 15 | (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

## PA3. Pancreatic Carcinoma TrialsOverall 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

## Kaplan Meier Survival CurveErlotinib/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

- Proportion surviving

- * 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

## Sensitivity AnalysesOverall survival in  analysis population minus patients with major protocol violations

- Exclusion of patients without pathological confirmation

## Erlotinib/Gem in Advanced Pancreas Sensitivity Analyses of Overall Survival using Stratified* Log-Rank test

- 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

- 0.035

- 0.82

- 0.69-0.98

- 0.060

- 0.82

- 0.67-1.0004

- 18 excluded

- HR**

- 95 % CI

- p*

**381 deaths**

- 0.055

- 0.81

- 0.66-0.99

**504 deaths**

- 0.028

- 0.81

- 0.68-0.97

- 0.031

- 0.81

- 0.67-0.98

- 18 excluded

**443 deaths**

- 0.017

- 0.79

- 0.65-0.95

## Exploratory analysesOverall survival

- Role of baseline characteristics
- Role of rash

## Survival by Pretreatment Characteristics

## PA.3 trialPresence of Rash and Survival

## PA.3 trialSecondary 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

## PA.3 TrialSecondary 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%).

## PA.3 TrialSafety Profile

| 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 * | 180  | (69)  | 163  | (64)  |
| Patients with at least one SAE*  | 131  | (51)  | 99  | (39)  |
| Patients who discontinued study due to AEs* | 31  | (12)  | 19  | (7)  |
| Patients who died on treatment or within 30 days of last treatment* | 81  | (31)  | 68  | (27)  |

- PA.3 TrialSafety Profile

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

## PA. 3 TrialDeath 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 |

## PA. 3 TrialSevere 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) |

## PA.3 Safety AnalysisIncidence 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.

## PA.3 TrialSevere 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

## PA.3 TrialSevere 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.

## PA.3 TrialSevere 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.

## Causes for dropouts in patients that refused further therapy

| 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

## PA.3 trialSummary 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.

## 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

## 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.