Erlotinib (Tarceva®) ISN OSI-774-302 Name of Sponsor ... of Sponsor/Company:Astellas Pharma Global...

Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29

Name of Sponsor/Company: Astellas Pharma Global

Development, Inc. on behalf of OSI Pharmaceuticals,

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Name of Finished Product: Tarceva®

Name of Active Ingredient: Erlotinib

Dec 2014 Astellas Synopsis of 19

SYNOPSIS

Title of Study: A multicenter, randomized, double-blind, placebo-controlled, phase 3 study of single-agent

Tarceva® (erlotinib) following complete tumor resection with or without adjuvant chemotherapy in patients

with stage IB-IIIA non-small cell lung carcinoma who have EGFR-positive tumors

(OSI-774-302 [5901-CL-0302])

This synopsis presents results from the subset of 277 patients who were originally enrolled in

Study OSI-774-302 but were evaluated separately from the main study population (randomized cohort) due to a

breach in the protocol.

Investigators/Coordinating Investigator: , MB BCh, MRCP, MD (

UK)

Study Centers: The study was conducted at 109 sites in a total of 16 countries and regions including Argentina,

Australia, Austria, Belgium, Canada, France, Germany, Hungary, Poland, Romania, Russia, South Korea,

Spain, Taiwan, the United Kingdom/England and the United States of America.

Publication Based on the Study: None.

Study Period: Up to 2 years on treatment with long-term follow-up until death or until the primary disease-free

survival (DFS) objective in the randomized cohort study was satisfied.

Study Initiation Date (Date of First Enrollment): 19 September 2006

Study Completion Date (Date of Last Evaluation): 08 April 2013

Phase of Development: Phase 3

Objectives: The study objectives remained the same as described in the randomized cohort Study OSI-774-302

clinical study report (CSR). Data from patients in the breached-protocol cohort (BPC) were not included in the

assessments of primary or secondary endpoints in the randomized cohort and were not considered part of the

primary analyses. Efficacy data were considered exploratory.

Methodology: After the initiation of the randomized cohort study, OSI Pharmaceuticals became aware of an

error in the drug dispensing module of the interactive voice response system (IVRS) that resulted in a protocol

violation for patients who were randomized prior to 07 November 2007. Codes associated with study drug

bottle assignments were incorrect, resulting in approximately 80% of the patients randomized by this date

having been assigned an incorrect bottle at least once and often multiple times during their participation in the

study. These patients (a total of 277) are referred to as the BPC. The independent Data Safety and Monitoring

Board (DSMB) overseeing Study OSI-774-302 was consulted, and in their judgment, the issue had no effect on

patient safety and did not introduce additional health risks to the patients.




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Study OSI-774-302 was an international, multicenter, phase 3 study in patients with stage IB to IIIA epidermal

growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) that was conducted under a

special protocol assessment (SPA) and had the following phases: screening, baseline, on-treatment,

posttreatment and long-term follow-up. The BPC of protocol OSI-774-302 consisted of patients randomized to

the study before 07 November 2007. The patients who permanently discontinued blinded study drug treatment

on or before 07 November 2007 were to be followed in long-term follow-up as outlined in the protocol. The

patients who had not discontinued blinded study drug treatment were offered the option of receiving open-label

erlotinib for up to 2 years (including posttreatment and long-term follow-up assessments), not receiving open-

label erlotinib but remaining in the study for posttreatment and long-term follow-up assessment, or withdrawing

consent from treatment and further assessments. Since these patients had completed the screening and baseline

assessments, patients who consented to receive open-label erlotinib continued on-treatment and were to resume

the prescribed visit schedule for on-treatment assessments as stipulated in the protocol. The posttreatment and

long-term follow-up assessments were also to be followed as per protocol. Patients who were eligible but who

chose not to receive open-label erlotinib had the option to be followed for all post-treatment and long-term

follow-up procedures according to the protocol or withdraw consent from further assessments.

Patients in the BPC who met all of the eligibility criteria and consented to receive open-label erlotinib were to

have received erlotinib at the same dose as the last dispensed dose during blinded treatment, regardless of

whether their last bottle assignment was placebo or erlotinib. These patients could receive erlotinib for up to

2 years from commencing open-label erlotinib or until 1 of the following occurred: relapse, death, patient

request or Investigator decision to discontinue study drug, intolerable toxicity, or until the primary objective of

the study was satisfied.

The DSMB continued to evaluate data for patients in the BPC when they reviewed safety for the blinded

treatment arms of the randomized cohort study.

Number of Patients (Planned, Enrolled and Analyzed): No sample size was planned. A total of 277 patients

comprised the BPC, with 145 patients in the BPC-no open-label cohort (BPC-NOLC; 71 [originally reported as

61 in the protocol] patients who discontinued blinded study drug treatment on or before 07 November 2007 and

74 patients who elected to not receive open-label erlotinib after the breach) and 132 patients in the BPC-open-

label cohort (BPC-OLC; patients who consented to continuing in the study).

Diagnosis and Main Criteria for Inclusion: The initial inclusion/exclusion criteria at screening and the

inclusion criteria for participation in the on-treatment phase of the randomized cohort study were provided in

the randomized cohort Study OSI-774-302 CSR. At the time of the breach, additional eligibility criteria were

established. To be eligible to receive open-label erlotinib or to be eligible for long-term follow-up without

receiving open-label erlotinib, patients in the BPC must have met all of the following criteria: were randomized

to Study OSI-774-302 before 07 November 2007, had not permanently discontinued from blinded study drug




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treatment and had not refused further follow-up, did not have evidence of NSCLC relapse at the time of consent

to receive open-label erlotinib based on their last clinical or radiological assessment, had provided written

informed consent by 01 March 2008 to receive open-label erlotinib or to participate in the long-term follow-up

assessments only.

Test Product, Dose and Mode of Administration, Batch Numbers: Erlotinib (OSI-774), 150 mg orally once

daily; dose reductions to 100 mg/day or 50 mg/day were allowed in the event of toxicities

Lot numbers:

Blinded Period

(25 mg tablets); (100 mg tablets); (150 mg tablets)

Open-label Period

and (25 mg tablets), , and (100 mg tablets),

and (150 mg tablets)

Duration of Treatment (or Duration of Study, if applicable): Patients received study drug once daily for

2 years or until 1 of the following: relapse, death, patient request or investigator decision to discontinue study

drug, or intolerable toxicity.

Reference Product, Dose and Mode of Administration, Batch Numbers: Matching placebo, 150 mg orally

once daily or matching placebo for dose reductions; administered while patients were in the blinded period

Lot numbers: (25 mg tablets); (100 mg tablets); (150 mg tablets),

Criteria for Evaluation:

Efficacy: Data from patients in the BPC were not included in the assessments of primary or secondary endpoints

in the randomized cohort and were not considered part of the primary analyses. Efficacy data were considered

exploratory. The primary efficacy endpoint was DFS in the overall population. The 3 key secondary efficacy

variables were overall survival (OS) in the overall population, DFS in patients with EGFR mutation-positive

tumors and OS in patients with EGFR mutation-positive tumors.

Safety: The safety assessments included evaluation of adverse events (AEs) (including serious adverse events

[SAEs] and discontinuations or dose modifications of study drug due to AEs) and clinical laboratory tests

(hematology, chemistry and hepatotoxicity). Eastern Cooperative Oncology Group (ECOG) performance status

was also assessed as a safety variable.

Statistical Methods: The BPC-NOLC included any patients who did not participate in the open-label erlotinib

period and who previously received or were randomized to receive either erlotinib or placebo. For data analysis

purposes, the following definitions of the treatment groups were used for all summaries of the BPC-NOLC: the




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erlotinib/placebo arm was composed of patients who had received at least 1 dose of erlotinib, and the placebo

arm was composed of patients who received at least 1 dose of placebo but never received erlotinib and patients

who did not receive any study drug. The BPC-OLC included patients who received at least 1 dose of study drug

after being randomized, who consented to participate in the open-label erlotinib period (whether or not the

patient was treated with open-label erlotinib) and who met all of the additional eligibility criteria established at

the time of the breach.

The primary efficacy variable was DFS. Summaries were provided for the BPC-NOLC erlotinib/placebo group

and the overall BPC-OLC. No statistical comparisons were provided. Kaplan-Meier curves were constructed

for each treatment arm. Median time to event and 95% CIs were estimated from the Kaplan-Meier curves. The

event-free rates and their 95% CIs at years 2, 3, 4 and 5 were also estimated. The 3 key secondary efficacy

variables were OS in the overall population, DFS in patients whose tumors were EGFR activating

mutation-positive and OS in patients whose tumors were EGFR activating mutation-positive. The same type of

summary as provided for the primary endpoint was provided for these secondary endpoints.

Exploratory DFS and OS analyses were also performed in subgroups of patients, including subgroups based on

tumor EGFR and Kirsten rat sarcoma (KRAS) mutation status.

Summary of Results/Conclusions:

Population: The most frequent reasons off treatment for patients who received erlotinib/placebo treatment in

the BPC-NOLC, were discontinuation due to an AE (59/134 [44.0%]) and patients who discontinued treatment

at their request (43/134 [32.1%]). In the BPC-OLC, the reason off treatment was reported for 33/134 (25.8%)

patients as due to an AE and for 7/132 (5.3%) patients was patient request Table 1 . Patients in the

BPC-NOLC who chose not to receive open-label erlotinib were not followed further in terms of routine study

assessments. In the BPC-OLC, nearly half of the patients completed 2 years of study therapy (60/132 [45.5%]).

A total of 34/132 (25.8%) of patients in the BPC-OLC discontinued the study due to an AE and 7/132 (5.3%)

patients discontinued treatment at their own request. A total of 61/134 (45.5%) patients in the BPC-NOLC

erlotinib/placebo group and 38/132 (28.8%) patients in the BPC-OLC died.

Of the 145 patients in the BPC-NOLC, 49 (33.8%) were female and 96 (66.2%) were male [Table 2 . The

majority of patients in this group were ≥ 65 years of age (78/145 [53.8%]) and most patients were white

(124/145 [85.5%]). Of the 132 patients in the BPC-OLC, 57 (43.2%) were female and 75 (56.8%) were male.

The majority of patients in the BPC-OLC were < 65 years of age (83/132 [62.9%]) and most patients were

white (111/132 [84.1%]). The majority of patients in both analysis sets were former smokers (BPC-NOLC

112/145 [77.2%], BPC-OLC 104/132 [78.8%]). Approximately 40% of the patients in the BPC-NOLC were

located in Western Europe (62/145 [42.8%]); this percentage included all 12 patients in France as an agreement

with the Central Ethics Committee had stipulated these patients would not receive open-label erlotinib.




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Approximately one-third of the patients in the BPC-NOLC were located in North America (47/145 [32.4%]).

Half the patients in the BPC-OLC were located in North America (66/132 [50.0%]).

Efficacy Results: Data from patients in the BPC were not included in the assessments of primary or secondary

endpoints in the randomized cohort, and were not considered part of the primary analyses. Efficacy data were

considered exploratory. No statistical comparisons were provided for the efficacy variables.

Median treatment duration in the BPC-NOLC erlotinib/placebo group was approximately 2 months, and the

median treatment duration in the BPC-OLC was approximately 20 months Table 3 . For the BPC-NOLC

erlotinib/placebo group, the median DFS was 22.2 months and the median OS was 51.9 months Table 4 and

Table 5 . For the BPC-OLC, the median DFS was 69.3 months and the median OS was not estimable. For both

groups, the OS data were immature. In the BPC-NOLC erlotinib/placebo group and the BPC-OLC, 10 and

16 patients, respectively, had tumors with EGFR activating mutations. The median DFS was 60.2 months for

this subgroup in the BPC-NOLC erlotinib/placebo group and 70.1 months for this subgroup in the BPC-OLC

Table 6]. The median OS for these subgroups was not estimable for either analysis set. Exploratory analyses

were also performed to evaluate DFS and OS by baseline characteristics and by a series of EGFR and KRAS

mutation assessments of patients’ tumors.

Safety Results:

No new safety findings were identified. The AEs observed in this trial were consistent with erlotinib’s

established safety profile [Tarceva™ (Erlotinib) Prescribing Information, 2013]. Drug-related TEAEs were

reported most frequently in the SOCs of Skin and Subcutaneous Tissue Disorders and Gastrointestinal

Disorders Table 7 . The proportion of patients with treatment-related AEs leading to study drug

discontinuation was higher (41.0% in the BPC-NOLC erlotinib/placebo group and 21.2% in the BPC-OLC)

Table 8] than that reported in advanced NSCLC studies (9.5% in EURTAC; 4.6% in SATURN; and 5% in

BR.21). The most common AEs consisted of the following: BPC-NOLC erlotinib/placebo group: diarrhea,

rash, acneiform dermatitis, fatigue, and pruritus; BPC-OLC: diarrhea, rash, acneiform dermatitis, dry skin,

fatigue, cough, pruritus, nausea, alopecia and anorexia [Table 9].

Drug-related TEAEs of “RASH” as defined by the standard AE group term “EGFR-associated rash” occurred in

most erlotinib-treated patients (BPC-NOLC erlotinib/placebo group 79.9%, BPC-OLC 91.7%) Table 10 . The

proportions of erlotinib-treated patients experiencing a severe (grade ≥ 3) RASH event (21.6% in the

BPC-NOLC erlotinib/placebo group and 25.8% in the BPC-OLC) were greater than that previously reported in

advanced NSCLC trials (9% in SATURN and BR.21 and 14% in EURTAC). The relationship between the

incidence of RASH events and treatment duration has not been assessed.

A TEAE coding to the MedDRA PT “interstitial lung disease” occurred in 1/134 (0.7%) and in 3/132 (2.3%) of

erlotinib-treated patients in the BPC-NOLC erlotinib/placebo group and BPC-OLC, respectively Table 11 .

When the broad SMQ for ILD events was used, the incidence of ILD-like events in erlotinib-treated patients




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was 1.5% (2/134) in the BPC-NOLC erlotinib/placebo group and 3.8% (5/132) in the BPC-OLC. Based on

sponsor assessment, 2 of these events ("radiology CT changes: small element of interstitial fibrosis" and

"necrotizing granulomas: left upper lobe lung"), both grade 1, which resolved while patient remained on study

drug, likely do not represent true events of “interstitial lung disease”. The incidence of ILD-like events reported

in erlotinib-treated patients in the RADIANT (Study OSI-774-302) randomized cohort was 1.8% (11/611) and

the overall incidence of ILD in approximately 32000 erlotinib-treated patients in uncontrolled studies and

studies with concurrent chemotherapy was approximately 1.1% [Tarceva™ (Erlotinib) Prescribing Information,

2013]. In the BR.21 study of erlotinib as second or third line therapy in patients with advanced NSCLC, the

incidence of ILD-like events was 3%. While interpretation is limited by the small sample size, the incidence of

ILD-like events in erlotinib-treated patients in the BPC is consistent with the large body of safety data for

erlotinib therapy in NSCLC.

CONCLUSIONS: No new safety findings were identified. The safety results observed in the BPC are

consistent with those observed in the RADIANT randomized cohort. In both populations, the safety results

were generally consistent with the established safety profile of erlotinib, although the proportion of

erlotinib-treated patients experiencing a severe (grade ≥ 3) RASH event was greater than that previously

reported in advanced NSCLC trials. Additionally, the proportion of erlotinib-treated patients experiencing

treatment-related TEAEs leading to permanent discontinuation was higher than that previously reported in

advanced NSCLC trials.

Efficacy data are considered exploratory due to the breach; therefore, no conclusions regarding efficacy can be

made.

Date of Report: 09 December 2014



Table 1 Patient Disposition

ParameterCategory

BPC-NOLC BPC-OLCErlotinib/Placebo

(n = 134)Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Patients remaining on treatmentYes 0 0 0 0No 134 (100%) 11 (100%) 145 (100%) 132 (100%)

Not treated 0 4 (36.4%) 4 (2.8%) 0Reason not treated

Relapse of NSCLC 0 1 (9.1%) 1 (0.7%) 0Medical/ethical/ noncompliance reason

0 1 (9.1%) 1 (0.7%) 0

Patient request 0 2 (18.2%) 2 (1.4%) 0Treated 134 (100%) 7 (63.6%) 141 (97.2%) 132 (100%)

Reason off treatment†Completion of 2 years of study drug therapy

0 0 0 60 (45.5%)

Relapse of NSCLC 19 (14.2%) 1 (9.1%) 20 (13.8%) 26 (19.7%)Adverse event 59 (44.0%) 0 59 (40.7%) 34 (25.8%)Medical/ethical/ noncompliance reason

10 (7.5%) 1 (9.1%) 11 (7.6%) 5 (3.8%)

Patient request 43 (32.1%) 4 (36.4%) 47 (32.4%) 7 (5.3%)Patient death 3 (2.2%) 1 (9.1%) 4 (2.8%) 0

Death 61 (45.5%) 5 (45.5%) 66 (45.5%) 38 (28.8%)Death after withdrawal of consent

1 (0.7%) 0 1 (0.7%) 2 (1.5%)

Withdrawal of consent‡ 37 (27.6%) 2 (18.2%) 39 (26.9%) 17 (12.9%)Long-term follow-up 35 (26.1%) 3 (27.3%) 38 (26.2%) 71 (53.8%)Lost to follow-up 2 (1.5%) 1 (9.1%) 3 (2.1%) 8 (6.1%)

The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.

The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period. Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.

BPC: breached-protocol cohort; NSCLC: non-small cell lung cancer

† Patients may have fit into multiple categories, but the primary reason for coming off treatment was reported in the case report form.

‡ Follow-up data beyond 5 years from the last treatment period visit was removed from the database for 4 patients (Patient Nos. , , and ) based on query responses that confirmed these patients did not sign the updated informed consent (issued in 2012) that extended the long-term follow-up period beyond 5 years. The patients appear in the disposition table as included in long-term follow-up because the investigator did not report withdrawal of consent for these patients.

Source: Tables 12.1.2.1 and 12.1.2.2



Table 2 Summary of Demographics and Baseline Characteristics

ParameterCategory/Statistics


(n = 134)Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Sex, n (%)Female 47 (35.1%) 2 (18.2%) 49 (33.8%) 57 (43.2%)Male 87 (64.9%) 9 (81.8%) 96 (66.2%) 75 (56.8%)

Age, yearsMean (SD) 64.4 (9.33) 62.7 (6.23) 64.3 (9.13) 61.8 (9.35)Median 65.0 65.0 65.0 62.0Min - Max 33 - 85 52 - 70 33 - 85 34 - 83

Age, n (%)< 65 years 62 (46.3%) 5 (45.5%) 67 (46.2%) 83 (62.9%)≥ 65 years 72 (53.7%) 6 (54.5%) 78 (53.8%) 49 (37.1%)

Age, n (%)< 75 years 118 (88.1%) 11 (100%) 129 (89.0%) 120 (90.9%)≥ 75 years 16 (11.9%) 0 16 (11.0%) 12 (9.1%)

Race, n (%)White 114 (85.1%) 10 (90.9%) 124 (85.5%) 111 (84.1%)

4 (3.0%)17 (12.9%)16 (12.1%)

1 (0.8%)0

Black 4 (3.0%) 0 4 (2.8%)Asian 15 (11.2%) 1 (9.1%) 16 (11.0%)

Far East 13 (9.7%) 1 (9.1%) 14 (9.7%)Southeast Asia 2 (1.5%) 0 2 (1.4%)

American Indian/Alaska Native 1 (0.7%) 0 1 (0.7%)Ethnicity, n (%)

Not Hispanic or Latino 123 (91.8%) 11 (100%) 134 (92.4%) 124 (93.9%)Hispanic or Latino 11 (8.2%) 0 11 (7.6%) 8 (6.1%)

ECOG Performance Status, n (%)0 75 (56.0%) 5 (45.5%) 80 (55.2%) 77 (58.3%)1 55 (41.0%) 6 (54.5%) 61 (42.1%) 54 (40.9%)2 3 (2.2%) 0 3 (2.1%) 1 (0.8%)Not done at baseline 1 (0.7%) 0 1 (0.7%) NA

Cigarette smoking history, n (%)Never smoked or ≤ 100 cigarettes in lifetime

19 (14.2%) 1 (9.1%) 20 (13.8%) 19 (14.4%)

Former smoker 103 (76.9%) 9 (81.8%) 112 (77.2%) 104 (78.8%)Current smoker 12 (9.0%) 1 (9.1%) 13 (9.0%) 9 (6.8%)

Region, n (%)Asia Pacific 14 (10.4%) 1 (9.1%) 15 (10.3%) 17 (12.9%)Western Europe† 55 (41.0%) 7 (63.6%) 62 (42.8%) 22 (16.7%)Eastern Europe‡ 17 (12.7%) 1 (9.1%) 18 (12.4%) 26 (19.7%)Latin America 3 (2.2%) 0 3 (2.1%) 1 (0.8%)North America 45 (33.6%) 2 (18.2%) 47 (32.4%) 66 (50.0%)

Weight, kgn 133 11 144 131Mean (SD) 74.6 (15.91) 80.4 (20.59) 75.0 (16.30) 73.7 (18.18)Median 74.8 70.0 74.4 71.0Min - Max 42 - 116 61 - 130 42 - 130 39 - 133

Height, cmn 132 11 143 130Mean (SD) 169.2 (9.15) 171.0 (10.54) 169.3 (9.24) 167.7 (10.08)Median 169.0 172.0 169.5 168.0Min - Max 148 - 195 158 - 194 148 - 195 144 - 195

Footnotes appear on next page





BPC: breached-protocol cohort; ECOG: Eastern Cooperative Oncology Group; Max: maximum; Min: minimum

† Western Europe included Austria, Belgium, France, Germany, Greece, Italy, Spain and the United Kingdom/England.

‡ Eastern Europe included the Czech Republic, Hungary, Poland, Romania and Russia.

Source: Tables 12.1.4.1.1 and 12.1.4.1.2



Table 3 Study Drug Exposure

A) BPC-NOLC

ParameterCategory/Statistic

BPC-NOLCErlotinib/Placebo

(n = 134)Placebo(n = 11)

Total(n = 145)

Total study drug exposure, months†n 134 7 141Mean (SD) 2.693 (2.2134) 0.780 (0.3791) 2.598 (2.1987)Median 2.085 0.990 1.910Min - Max 0.07 - 9.72 0.16 - 1.05 0.07 - 9.72

B) BPC-OLC


Blinded Period for BPC-OLC‡Open-label Period

for BPC-OLCErlotinib/Placebo

(n = 126)Placebo(n = 6)

Total(n = 132)

Erlotinib(n = 132)

Total study drug exposure, months†n 126 6 132 130Mean (SD) 5.300 (3.0643) 0.948 (0.0392) 5.102 (3.1285) 14.747 (8.5528)Median 5.520 0.950 5.375 19.780Min - Max 0.56 - 13.54 0.89 - 0.99 0.56 - 13.54 0.23 - 25.95

C) Cumulative


Cumulative Exposure in BPC-NOLC

Cumulative Exposure in BPC-OLC§

Erlotinib/Placebo(n = 134)

Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Cumulative calendar months of exposure†, n (%)≤ 3 months 86 (64.2%) 7 (63.6%) 93 (64.1%) 5 (3.8%)> 3 to 6 months 42 (31.3%) 0 42 (29.0%) 10 (7.6%)> 6 to 12 months 6 (4.5%) 0 6 (4.1%) 21 (15.9%)> 12 to 18 months 0 0 0 17 (12.9%)> 18 to 20 months 0 0 0 2 (1.5%)> 20 to 22 months 0 0 0 4 (3.0%)> 22 to 24 months 0 0 0 19 (14.4%)> 24 months 0 0 0 54 (40.9%)



BPC: breached-protocol cohort; Max: maximum; Min: minimum

† A month was defined as 30.4375 days.

‡ Dosing period when a patient took blinded study drug before open-label erlotinib began.

§ Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.

Source: Tables 12.2.1.1.1, 12.2.1.1.2, 12.2.1.2.1 and 12.2.1.2.2



Table 4 Summary of DFS



(n = 134)Erlotinib(n = 132)

Patients with event, n (%) 67 (50.0%) 60 (45.5%)Death 12 (9.0%) 6 (4.5%)Relapse 55 (41.0%) 54 (40.9%)

Patients without event,† n (%) 67 (50.0%) 72 (54.5%)Time to event (months)

Median‡ 22.2 69.395% CI for median‡ [14.0, 40.3] [49.9, 73.7]25% and 75% percentiles 6.6, NE 28.1, 73.7Range§ 0.0+ to 74.3+ 0.0+ to 73.7

2-Year estimatePatients remaining at risk 46 94Event-free rate 0.48 0.7795% CI for rate [0.388, 0.582] [0.699, 0.847]





The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.

BPC: breached-protocol cohort; DFS: disease-free survival; NE: not estimable

† Censored

‡ Kaplan-Meier estimates

§ Range includes censored observations which are indicated with ‘+’.




Table 5 Summary of OS




Patients with event, n (%) 61 (45.5%) 38 (28.8%)Death 61 (45.5%) 38 (28.8%)


Median‡ 51.9 NE95% CI for median‡ [35.2, NE] NE25% and 75% percentiles 21.6, NE 61.3, NERange§ 0.5+ to 76.2+ 3.9+ to 76.4+







BPC: breached-protocol cohort; NE: not estimable; OS: overall survival

† Censored


§ Range includes censored observations; ‘+’ indicates a censored observation.




Table 6 DFS in Patients with EGFR Activating Mutation-positive Tumors




Patients with event, n (%) 3 (30.0%) 8 (50.0%)Death 0 1 (6.3%)Relapse 3 (30.0%) 7 (43.8%)


Median‡ 60.2 70.195% CI for median‡ [0.2, 60.2] [43.0, 70.1]25% and 75% percentiles 48.8, 60.2 46.0, 70.1Range§ 0.0+ to 60.2 23.2 to 70.1







BPC: breached-protocol cohort; DFS: disease-free survival; EGFR: epidermal growth factor receptor

† Censored


§ Range includes censored observations; ‘+’ indicates a censored observation.

Source: Tables 12.3.3.1 and 12.3.3.2



Table 7 Drug-related TEAEs by Body System (Reported in ≥ 5% of Patients in Either Analysis Set [BPC-NOLC or BPC-OLC])

SOC (MedDRA v9.1)†


(n = 134)Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Skin and Subcutaneous Tissue Disorders 105 (78.4%) 1 (9.1%) 106 (73.1%) 125 (94.7%)Gastrointestinal Disorders 60 (44.8%) 1 (9.1%) 61 (42.1%) 91 (68.9%)General Disorders and Administration Site Conditions

31 (23.1%) 0 31 (21.4%) 35 (26.5%)

Metabolism and Nutrition Disorders 18 (13.4%) 0 18 (12.4%) 16 (12.1%)Eye Disorders 13 (9.7%) 0 13 (9.0%) 16 (12.1%)Respiratory, Thoracic and Mediastinal Disorders

13 (9.7%) 0 13 (9.0%) 19 (14.4%)

Infections and Infestations 11 (8.2%) 0 11 (7.6%) 28 (21.2%)Nervous System Disorders 9 (6.7%) 2 (18.2%) 11 (7.6%) 18 (13.6%)Investigations 3 (2.2%) 0 3 (2.1%) 8 (6.1%)Musculoskeletal and Connective Tissue Disorders

3 (2.2%) 0 3 (2.1%) 8 (6.1%)



Within an SOC, a patient may have reported more than 1 type of adverse event.

A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. Long term follow-up adverse events were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing. A drug-related TEAE was defined as any TEAE with at least a possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship.

BPC: breached-protocol cohort; TEAE: treatment-emergent adverse event

† Sorting order: descending in incidence by SOC within the BPC-NOLC total




Table 8 Overview of TEAEs

Category


(n = 134)Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Any TEAE 129 (96.3%) 5 (45.5%) 134 (92.4%) 131 (99.2%)Grade 3 or higher TEAEs 61 (45.5%) 1 (9.1%) 62 (42.8%) 76 (57.6%)Serious TEAEs 21 (15.7%) 1 (9.1%) 22 (15.2%) 41 (31.1%)TEAEs leading to permanent discontinuation of study drug

64 (47.8%) 1 (9.1%) 65 (44.8%) 35 (26.5%)

TEAEs leading to death 3 (2.2%) 1 (9.1%) 4 (2.8%) 1 (0.8%)TEAEs leading to dose reduction 17 (12.7%) 0 17 (11.7%) 41 (31.1%)TEAEs leading to dose interruption 28 (20.9%) 0 28 (19.3%) 45 (34.1%)TEAEs leading to dose interruption and reduction

13 (9.7%) 0 13 (9.0%) 36 (27.3%)

Drug-related TEAEs† 115 (85.8%) 2 (18.2%) 117 (80.7%) 128 (97.0%)Drug-related serious TEAEs† 7 (5.2%) 0 7 (4.8%) 5 (3.8%)Drug-related TEAEs leading to permanent discontinuation of study drug

55 (41.0%) 0 55 (37.9%) 28 (21.2%)



A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. Long term follow-up adverse events were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing. Serious TEAEs included both investigator agreed and sponsor upgraded serious adverse events based on the Astellas Always Serious List.


† A drug-related TEAE was defined as any TEAE with at least a possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship.




Table 9 Common TEAEs (Reported in ≥ 5.0% of Patients in Either Analysis Set [BPC-NOLC or BPC-OLC])

SOC (MedDRA v9.1)Preferred Term†


(n = 134)Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Skin and Subcutaneous Tissue DisordersRash 51 (38.1%) 0 51 (35.2%) 72 (54.5%)Dermatitis acneiform 37 (27.6%) 0 37 (25.5%) 45 (34.1%)Pruritus 21 (15.7%) 0 21 (14.5%) 29 (22.0%)Dry skin 15 (11.2%) 0 15 (10.3%) 41 (31.1%)Alopecia 12 (9.0%) 0 12 (8.3%) 22 (16.7%)Erythema 10 (7.5%) 0 10 (6.9%) 13 (9.8%)Rash erythematous 6 (4.5%) 0 6 (4.1%) 12 (9.1%)Skin exfoliation 6 (4.5%) 0 6 (4.1%) 8 (6.1%)Rash maculo-papular 4 (3.0%) 0 4 (2.8%) 7 (5.3%)Exfoliative rash 2 (1.5%) 0 2 (1.4%) 11 (8.3%)Rash macular 2 (1.5%) 0 2 (1.4%) 8 (6.1%)Nail disorder 1 (0.7%) 0 1 (0.7%) 9 (6.8%)Rash papular 1 (0.7%) 0 1 (0.7%) 7 (5.3%)Skin fissures 1 (0.7%) 0 1 (0.7%) 9 (6.8%)

Gastrointestinal DisordersDiarrhoea 55 (41.0%) 0 55 (37.9%) 86 (65.2%)Nausea 18 (13.4%) 1 (9.1%) 19 (13.1%) 28 (21.2%)Vomiting 11 (8.2%) 0 11 (7.6%) 13 (9.8%)Stomatitis 8 (6.0%) 0 8 (5.5%) 15 (11.4%)Constipation 7 (5.2%) 0 7 (4.8%) 14 (10.6%)Dry mouth 7 (5.2%) 0 7 (4.8%) 7 (5.3%)Abdominal pain 6 (4.5%) 0 6 (4.1%) 14 (10.6%)Dyspepsia 4 (3.0%) 0 4 (2.8%) 15 (11.4%)Abdominal pain upper 0 0 0 11 (8.3%)Cheilitis 0 0 0 8 (6.1%)

General Disorders and Administration Site ConditionsFatigue 23 (17.2%) 0 23 (15.9%) 34 (25.8%)Pyrexia 6 (4.5%) 1 (9.1%) 7 (4.8%) 9 (6.8%)Mucosal inflammation 6 (4.5%) 0 6 (4.1%) 12 (9.1%)

Respiratory, Thoracic and Mediastinal DisordersCough 17 (12.7%) 0 17 (11.7%) 29 (22.0%)Dyspnoea 15 (11.2%) 0 15 (10.3%) 18 (13.6%)Epistaxis 4 (3.0%) 0 4 (2.8%) 11 (8.3%)Rhinorrhea 3 (2.2%) 0 3 (2.1%) 7 (5.3%)

Metabolism and Nutrition DisordersAnorexia 20 (14.9%) 1 (9.1%) 21 (14.5%) 20 (15.2%)

Nervous System DisordersDizziness 9 (6.7%) 1 (9.1%) 10 (6.9%) 14 (10.6%)Headache 10 (7.5%) 0 10 (6.9%) 14 (10.6%)Dysgeusia 5 (3.7%) 0 5 (3.4%) 13 (9.8%)

Psychiatric DisordersInsomnia 6 (4.5%) 0 6 (4.1%) 16 (12.1%)Anxiety 5 (3.7%) 0 5 (3.4%) 7 (5.3%)

Table continued on next page



SOC (MedDRA v9.1)Preferred Term†


(n = 134)Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Musculoskeletal and Connective Tissue DisordersArthralgia 4 (3.0%) 0 4 (2.8%) 14 (10.6%)Back pain 3 (2.2%) 0 3 (2.1%) 12 (9.1%)Pain in extremity 3 (2.2%) 0 3 (2.1%) 13 (9.8%)Musculoskeletal pain 2 (1.5%) 0 2 (1.4%) 9 (6.8%)Muscle spasms 1 (0.7%) 0 1 (0.7%) 10 (7.6%)

Infections and InfestationsRash pustular 3 (2.2%) 0 3 (2.1%) 13 (9.8%)Sinusitis 3 (2.2%) 0 3 (2.1%) 7 (5.3%)Nasopharyngitis 2 (1.5%) 0 2 (1.4%) 18 (13.6%)Bronchitis 1 (0.7%) 0 1 (0.7%) 9 (6.8%)Upper respiratory tract infection 0 0 0 13 (9.8%)

InvestigationsWeight decreased 2 (1.5%) 0 2 (1.4%) 19 (14.4%)

Vascular DisordersHypertension 2 (1.5%) 0 2 (1.4%) 8 (6.1%)




A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. Long term follow-up adverse events were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing.


† Sorting order: descending in incidence by SOC and within that descending by preferred term in the BPC-NOLC total

Source: Tables 12.6.1.2.1, 12.6.1.2.2, 12.6.1.4.2.1 and 12.6.1.4.2.2



Table 10 Overview of Sponsor-defined Constellation of RASH TEAEs (BPC-NOLC or BPC-OLC)

Category


(n = 134)Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Any RASH† 109 (81.3%) 1 (9.1%) 110 (75.9%) 123 (93.2%)Severity Grade of RASH TEAEs

Grade 1 31 (23.1%) 1 (9.1%) 32 (22.1%) 33 (25.0%)Grade 2 49 (36.6%) 0 49 (33.8%) 56 (42.4%)Grade 3 27 (20.1%) 0 27 (18.6%) 34 (25.8%)Grade 4 2 (1.5%) 0 2 (1.4%) 0Grade 5 0 0 0 0

Drug-related TEAEs of RASH 107 (79.9%) 1 (9.1%) 108 (74.5%) 121 (91.7%)TEAEs of RASH leading to permanent discontinuation of study drug

39 (29.1%) 0 39 (26.9%) 15 (11.4%)

TEAEs of RASH leading to dose reduction

13 (9.7%) 0 13 (9.0%) 32 (24.2%)

TEAEs of RASH leading to dose interruption

14 (10.4%) 0 14 (9.7%) 19 (14.4%)

TEAEs of RASH leading to dose interruption and reduction

7 (5.2%) 0 7 (4.8%) 23 (17.4%)

Serious TEAEs of RASH 1 (0.7%) 0 1 (0.7%) 0



A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing.


† The term RASH (capitalized) represents a sponsor-defined constellation of adverse event preferred terms associated with rash including rash, macular rash, acne, dermatitis, acneiform dermatitis, eczema, urticaria, etc.




Table 11 Summary of Interstitial Lung Disease (BPC-NOLC or BPC-OLC)

Interstitial Lung Disease(Broad Standardized MedDRA Query)

Preferred Term

BPC-NOLC BPC-OLC

Erlotinib/Placebo(n = 134)

Placebo(n = 11)

Total(n = 145)

Erlotinib(n = 132)

Patients with ≥ 1 adverse event 2 (1.5%) 0 2 (1.4%) 5 (3.8%)Interstitial lung disease 1 (0.7%) 0 1 (0.7%) 3 (2.3%)Acute respiratory distress syndrome 1 (0.7%) 0 1 (0.7%) 0Pneumonitis 0 0 0 1 (0.8%)Pulmonary fibrosis 0 0 0 1 (0.8%)Pulmonary granuloma 0 0 0 1 (0.8%)




BPC: breached-protocol cohort

Source: Tables 12.6.1.25.5.1 and 12.6.1.25.5.2

Erlotinib (Tarceva®) ISN OSI-774-302 Non-small cell lung cancer (5901-CL-0302) CONFIDENTIAL EudraCT Number 2005-001747-29

Apr 2015 Astellas Page 1 of 1

Protocol Amendments Protocol Version

Number Date Summary of Substantial Changes

Original Protocol 09 May 2006 ● Original Protocol Amendment 1 21 November

2007 ● Addressed the error in the drug dispensing

procedure, defined the Breached Protocol Cohort (BPC) and stipulated the procedures to be followed for this cohort

Amendment 2 13 December 2010

● Revised the coprimary and secondary endpoints in response to new findings relating to EGFR gene copy number and activating mutations in NSCLC. All patients were enrolled prior to the issuance of amendment 2

Erlotinib (Tarceva®) ISN OSI-774-302 Name of Sponsor ... of Sponsor/Company:Astellas Pharma Global...

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