Background

cis-platin based chemotherapy has already been the standard care for IB-IIIA NSCLC

Trial Stage N Chemotherapy 5 yr Survival

BMJ-Meta I-IIIA 1484 Cisplatin-Based +5%

ALPI I-IIIA 1209 Cisplatin-MV +1%

IALT I-IIIA 1867 Cis+Etop/Vinca +4%

BR.10 IB-II 482 Cis+Vinorelbine +15%

CALGB IB 344 Carbo+Tax + 3%

ANITA IB-IIIA 840 Cis+Vinorelbine +9%

LACE-Meta IB-IIIA 4584 Cisplatin-Based +4%

NCCN: 2007 NSCLC treatment guideline (conclusion section)

Only 5-year post-operative survival reports are available, whilelarge-scale investigation results for post-operative adjuvant chemotherapy are absent

China has the largest population of lung cancercases, but lacks of corresponding phase III clinical study

Clinical trials on lung cancer have already fallen behind neighbouring countries or areas, like Japan, Korea, Taiwan and Hongkong

Results from Phase III clinical trials of adjuvante therapy following surgery for NSCLC is needed for chinese edition of guideline

Situation and issues concerning NSCLC post-operative adjunctive therapy in China

Surgery outcome for NSCLC in China

Reporter （ year ） Number of surgery cases 5-year survival rate

Xiaomai Huang et. （ 1987 ） 765 33.6%

Meilin Liao et. （ 1988 ） 2636 40.6%

Jia’an Ding et. （ 1988 ） 2048 31.8%

Guangyan Pei et. （ 1991 ） 1336 33.4%

Shiye Lee et. （ 1992 ） 3568 34.6%

Nugang Zhang et. （ 1993 ） 2025 40.8%

Yilong Wu et. （ 1999 ） 1757 39.8%

Dekang Fang et. （ 1999 ） 1471 42.4%

Survival rate of NSCLC patients after surgical excision

Yan Sun et. Medical Oncology ， People‘s Medical Publishing House 2001 ，P658

The research of multi-disciplinary treatment for NSCLC has been the important part of China National Science & Technology Infrastructure Program of 11th 5-year Plan, which consists of series of clinical tries according to evidence based medicine principals and basic studies. The research will provide important theoretic support for the guideline for NSCLC, which is suitable for Chinese population.

LACE study indicates that post operative platin-containing chemotherapy only increased the 5-year survival rate by 5%

Searching for new treatment modality is ergent

According to the treatment outcome for late stage tumor, chemo-therapy combined with target treatment (antiangiogenesis therapy) Improves efficacy and is feasible.

Such as E4599, Endostar combined chemotherapy, Shenyi combined chemotherapy, etc.

Limitations of the traditional adjuvant chemotherapy

Angiogenesis is a complicated process mediated

by vascular endothelial growth factors (VEGF)

and their receptors

Rationales for adjuvant chemotherapy combined with anti-angiogenesis agents for NSCLC

Treatment on angiogenesis will put the tumor

cells downstream of vessels into necrosis This therapy will reverse the resistance of tumor

cells, effect on existing tumor microvasculature

system to atrophy

Combination of

Chemotherapy and Anti-

angiogenesis agents

Enhance the cytotoxicity of chemotherapy agents

Chemotherapy increases DNA repairment, thus

demands supportion from oxygen and nutrition

Initially, it helps with vasculature

to facilitate chemotherapy agents reaching tumor site

In the later period, it causes the apoptosis of endothelial cells, thus influences the growth of tumor cells

Molecular target treatment in each stage of lung cancer

Onn A, et al. Lancet. 2005; 366:1507-1508.Thatchera N, et al. Lancet. 2005; 366:1527-1537.

precancerous lesions (Chemical prevention)

Localized tumor(adjunctive therapy)

Tumor in local progression stage

Late stage or metastasis

S (RT) CT CT + RT CT

Molecule targeted treatment

Alone

ECOG1505 Study

Phase III clinical trial of adjuvant chemotherapy± Bevacizumab ）

Chemotherapy q 3 wk x 4

• Vinorelbine-cisplatin

• Taxotere-cisplatin

• Gemcitabine-cisplatin

Target enrollment = 1,500 patients

Primary endpoint = Overall survival Secondary endpoints: Disease-free survival, safety

RANDOMIZATION

Chemotherapy q 3 wk x 4 +Bevacizumab q 3 wk x 1 year

Eligibility

•Resected B( ≥4cm )– Ⅰ ⅢA

•≥ lobectomy

•No previous chemo

•No planned XRT

•No CVA/TIA

•No ATE in 12 months

regimen selection: NVB/DDPThe most widely used regimen in adjuvant

chemotherapy for NSCLC :

IALT ， BR.10, ANITA

• The most stages are benefited: IIA-IIIA

• Cost-effective: follow the rules in therapy

economics

Endostar Endostar is a recombinant human endostatin. Preclinical data revealed that Endostar could inhibit tumor

angiogenesis and growth. In a phase III trial, patients with advanced NSCLC were treated with

cisplatin/vinorelbine (NP) plus Eendostar or placebo. The addition of Endostar to NP regimen resulted in higher response rate, median time to progression, and clinical benefit rate compared with NP alone in advanced NSCLC patients. (Sun Y, Wang JW, Liu Y et al, Results of phase III trial of rh-endostatin (YH-16) in advanced non-small lung cancer (NSCLC) patients. Proc ASCO 2005; 23:7138a)

Because of the promising results in advanced NSCLC, we investigated adjuvant NP regimen with or without Endostar in early-stage NSCLC, and the preliminary results of the first enrolled 545patients were reported.

•Primary Objective

To compare the OS of early-

stage NSCLC patients who

receive either Navelbine ＋Cis-platin

(NP) ＋ Endostar or

Navelbine ＋ Cis-platin (NP)

after operation

•Secondary objectivesCompare both groups (with or without Endostar) :Relapse free survival (RFS)SafetyAnalyze the quality of lifeEstablish prognosis factors of NSCLC through the analysis on tissue and blood samplesInvestigate the relationship between smoking and prognosis

Objectives of the Study

IB-IIIA NSCLC

post-operative patients

randomization

Vinorelbine+Cis-platin+RecombinedHuman EndostatinVinorelbine 25mg/m2 IV d1.8Cis-platin 80mg/m2 IV d1, or divided into d 1-3Recombined Human Endostatin 7.5mg/m2 IV d1-14 in 21 days cycle for 4 cycles

Vinorelbine+Cis-platinVinorelbine 25mg/m2 IV d1.8Cis-platin 80mg/m2 IV d1, or divided into d 1-3 in 21 days cycle for 4 cycles

Study design

Main reference ： ANITA study and ECOG1505 study

The median post-operative survival time in the NP

group is defined as 55.8 months (ANITA 65.8 months)

Recombined Human Endostatin combined therapy is expected to prolongmedian survival time by 27% (26.5%,for ECOG1505), that is from 55.8 months to 70.9 months

The significance level will be 0.05 (bilateral), statistical power80%, enrollment time 2 years, sample size for each group will be 503, lost to follow-up 10%, total size 1107.

Sample size

1. NSCLC patients who are pathologically determined

to suffer from adenocarcinoma, squamous cell carcinoma,

large cell carcinoma, or mixed type of above.

2. Clinical stage will be classified as IB-IIIA phase with the tumors completely excised (left total lung excision, lobi pulmonisexcision, sleeve resection);The scope of clearance includes homonymy hilus pulmonis and mediastinum lymph nodes(including eminence); incisal edge should be trimmed.

3. Surgery date to adjunctive treatment ≤8 weeks ；4. No evidence of tumor relapse from examination performed

before adjunctive therapy5.Aged between 18~70, physical status score ECOG 0 ～ 1 ；6. Subjects have no major organ dysfunction; blood routine, hepatic, renal, cardio function (examination) all turn out normal; laboratory test indicators must meet following requirements:Hematology: Leukocyte≥4.0×109/L; Neutrophils≥2.0×109/L Platelet count≥100×109/L; Hemoglobin≥95g/L 。Renal function: Serum bilirubin is below 1.5 X upper normal limit; ALT and AST are below 1.5 X upper normal limit.

7. Patients have no prior chemotherapy or radiotherapy;8. Patients are compliant with the treatment

and follow-ups, and understand the study well,

and sign informed consent form.

Inclusion criteria

1. Classified as a pathology category which does not

meet inclusion criteria;

Exclusion criteria

2. Total or partial resection of the right lung;3. Enrollment is more than 8 weeks away from the surgerydate;

4. Patients are complicated with any acute or chronic diseases

or mental disorders or laboratory abnormality; those complicated

diseases may Increase the risk of participating this study or taking

this test drug, or have an influence on the study results; it is judged

by investigators that under some circumstance patients are not

suitable to participate this trial ：

• Uncontrolled hypertension, unstable angina, myocardial infarction history or symptomatic congestive heart-failure or uncontrolled Arrhythmia in the past 12 months;• ECG shows there Is ischemia pathology or clinically diagnosed heart valve disease;• In bacteria, fungi or virus caused disease active phase;

5.Patients who are pregnant or breast-feeding ；6. Before enrollment, the patients who suffer from

other progressive malignant tumor than NSCLC will

be excluded; Except for nonmelanoma skin cancer,

in situ cervical carcinoma, and cured early-stage

Prostate cancer;

7. Have allergic constitution or known to be allergic to any test drug;

8. Patients who are poorly compliant to the treatment;9. Patients who are judged by the investigators not

suitable to participate this trial.

Follow up per protocal

Chest CT or X-ray

Abdominal B ultra inspection

Pulmonary tumor markers

Skull MRI and bone scan

Evaluation

time

Within 2years

3 months

3 months after

relapse

3-5years

Half year

Progress of the project

01 Cancer Hospital, Chinese Academy of Medical Sciences 02 Beijing Hospital

03 Capital Medical University Beijing ChaoYang Hospital 04Chinese Academy of Medical Sciences & Peking Union Medical College

05 Shangdon Cancer Hospital & Institute 06Shanghai Chest Hospital affiliated to Shanghai Jiaotong University

07 The Tumor Hospital of HARBIN Medical University 08 Beijing Cancer Hospital

09 Shandong University Qilu Hospital 10 Zhongshan Hospital Fudan University

11 Jinlin Cancer Hospital & Institute 12 The First Affiliated Hospital of Soochow University

13 Beijing Chest Hospital 14 The First Affiliated Hospital of Nanchang University

15Shanghai Shuguang Hospital of Shanghai University of T.C.M

16The First Affiliated Hospital of Fujian Medical University

17 Tumor Hospital of Guangzhou Medical college 18 Zhejiang Cancer Hospital

19 Shandong Chest Hospital 20 Sichuan Cancer Hospital

21 Yunnan 1st people's hospital 22 Jiangxi Cancer Hospital

23Fujian Medical college attached Xiehe Hospital

24 Liaoning Cancer Hospital & Institute

25 The First Attached Hospital of Wenzhou Medical college 26 The Affiliated Hospital of Xinjiang Medical University

27Tianjin Medical University Cancer Institute and Hospital

28 The Affiliated Hospital of Medical College Gingdao University

29 Yunnan Cancer Hospital & Institute 30 Shanghai First People’s Hospital

31Sichuan University - West China Center of Medical Sciences

32 Tianjin Medical University General Hospital

33Sir Run Run Shaw Hospital of Zhejiang University School of Medicine

34 Huadong Hospital Affiliated to Fudan University

35The 2nd Affiliated Hospital of Harbin Medical University

36 Shanghai Tenth People’s Hospital

37 Changhai Hospital of Shanghai 38 Xinhua Hospital Affiliated to Shanghai Jiaotong University

39 The First Hospital of China Medical University 40Tongji Medical College of Huazhong University of Science & Technology

41The Second Affiliated Hospital of Dalian Medical University

42 The First Affiliated Hospital of Zhejiang University

43Tangdu Hospital of The fourth Military Medical University

Total43centers

Approved by Ethical Commission, in

April,2007

Up to April 2, 2010, the Project had enrolled 926 patients.

Study name Study date NumberEnrollment

time

Patients enrolled

per month

JBR101994.7-2001.4

4826 years ＋ 9

months

81 months6

ANITA 1994.11-2000.11

8406 years

72 months11.7

101 centers

CALGB96331996.9-2003.11

3447 years ＋ 2

months

86 months4

CN11(5)2007.6-2010.3

9262 years ＋ 9

months

33 months28

Comparison of enrollment speed with large, multinational,multi-center clinical trials

Baseline for the patients enrolledFactor Factor Label Group A Group B 　　 A+B=N(926)

Stage

IB 161 161 322 （ 34.8% ）IIA 26 26 52 （ 5.6% ）IIB 107 108 215 （ 23.2% ）IIIA 169 168 337 (36.4%)

Pathology

Adeno 267 267 534 (57.7%)

Squamous 162 163 325 (35.1%)

Large cell 5 6 11 (1.2%)

Other 29 27 56 (6.0%)

GenderMale 320 321 641 (69.2%)

Female 143 142 285 (30.8%)Total 463 463 926

Group A （ NP+ Endostar ） Occurrence of SAE

NumberOccurrence date of SAE

Center number main description

Relationship with study drug

1 2007/12/5 0083 grade IV bone marrow suppression Probable2 2007/12/19 0046 Filgrastim caused hypersensitivity reaction Probable3 2008/1/1 0046 Chylothorax leaded to hospitalization Possible4 2007/12/31 0059 Deep vein thrombosis at left lower extremity Possible5 2007/11/1 0030 Symptomatic epilepsy Undetermined6 2008/7/21 0326 Pneumothorax Possible7 2008/5/19 0246 Chronic diarrhea, hypokalemia Definite8 2008/5/13 0230 Inflammation in right lung Possible9 2008/6/20 0295 Acute appendicitis Possible

10 2008/7/9 0252 Deep vein thrombosis phlebitis/bacteremia Undetermined11 2008/8/30 0365 1.Infection of pulmonary 2.Left heart dysfunction Undetermined

12 2008/8/11 0349

Shortness of breath, palpitation, oliguresis, and limb edema result in application of breathing machine Possible

13 2008/10/6 0423 Severe bone marrow suppression, agranulocytosis Possible14 2008/10/31 0448 Death of cerebrovascular accident Undetermined15 2008/11/19 0391 Subarachnoid hemorrhage Possible16 2009/2/4 0449 Inflammation in right lung Possible17 2009/2/25 0545 Hematemesis, death Possible18 2009/3/9 0566 Pulmonary embolism Undetermined19 2009/4/10 0591 Pulmonary embolism Possible

20 2009/3/23 0596 Intestinal obstruction Definite21 2009/1/19 0522 grade IV bone marrow suppression Possible

22 2009/12/29 0809grade III gastrointestinal reaction, grade III bone marrow suppression Definite

Group B （ NP ） Occurrence of SAE

NumberOccurrence date of

SAECenter number Primary description

Relationship with study drug

1 2007/7/2 0002 Acute appendicitis Unrelated

2 2007/11/15 0072 Unstable angina Possible

3 2007/12/6 0070 Bronchopleural fistula Unrelated

4 2008/1/12 0063 Pulmonary embolism Definite

5 2008/1/11 0147 Paralytic ileus Definite

6 2008/1/17 0152 Intestinal obstruction Definite

7 2008/4/14 0154 Acute myocardial infarction Definite

8 2008/6/30 0314 Bronchopleural fistula Possible

9 2007/9/2 0029 Chronic pulmonary embolism Undetermined

10 2008/11/5 0452 Neutrophilic granulocytopenia Possible

11 2008/10/24 0445 Cerebral infarction Possible

12 2009/7/24 0657Right acinic cell carcinoma of parotid Definite

13 2009/9/24 0725 Bacteremia/pneumonia Undetermined

14 2009/11/29 0802 Intestinal obstruction Possible

15 2009/12/3 0807 Cerebral infarction Possible

16 2010/1/19 0829 Death Possible

17 2010/2/7 0875

Acute pulmonary edema, acute inflammatory exudation of left lung Definite

Interim Summary of the first 588 patients

There are 43 patients (7.3%) who did not undergo

chemotherapy after randomization, thus the data from the rest 545

patients (92.7%) was analyzed for survival and safty. 78.63 %

patients in group A and 76.33% patients in group B completed 4

cycles of chemotherpy. Up to analysis, 26.4% patients in group A

and 23.6% patients in group B had the relapsed disease.

Baseline(545 patients)

Variable Factor Group A Group BComparability

Statistic P Value

Age

N 274 271

0.55 0.5825Mean±SD 56±8.5 56±8.1

Median(Min ～ Max) 57(32 ～ 70) 57(33 ～ 71)

Gender

N 274 271

1.0000 Female 85 85

Male 189 186

Baseline(545 patients)Variable Factor Group A Group B

Comparability

Statistic P Value

Days(operation ～

randomization ）

N 274 271

1.5538 0.1202Mean±SD 34±8.8 35±9.0

Median(Min ～ Max) 34(8 ～ 67) 35(8 ～ 63)

Operational Methods

Pneumonoresection 20 14

0.2967 Pulmonary lobectomy 240 236

 Sleeve lobectomy 14 21

Stage(post-operation)

0.4481 0.6541

IB 89 96

IIA 16 10

IIB 57 57

IIIA 112 108

Variable Factor Group A Group BComparability

Statistic P Value

lymphadenN0 97 114

1.4482 0.1476N1 73 65N2 104 92

Pathology

N 274 271

0.78

Adeno 153 162Squamous 89 87

Alveolar 8 4Large cell 4 2

Adenosquamous 14 10Mixed types 4 5

Other 2 1

Performance(ECOG ）

N 274 268

0.15530 93 1071 181 161

Baseline(545 patients)

Exposure(545 patients)

Group NCycles

(Mean±SD)

Comparability

Statistic p Value

Group A 274 3.32±1.27

0.27 0.7899

Group B 271 3.29±1.27

Results (545 patients)

Endpoints Group A Group B

Median overall survival (m) - -

Median RFS(m) 21.9 18 (p=0.3257)

Survival time: because the follow-up for most patients is not up to 5 years, the majority of them survive. Therefore, the comparison on the median survival time of both groups is not available.

Safety Profile (545 patients)

Type Of Toxic Effect

Group A (N=262) Group B (N=283)P valuen Incidence ( ％ ) n Incidence ( ％ )

Leukocyte count 234 89.31 237 83.75 0.0614

Granulocyte count 234 89.31 235 83.04 0.0361

Anemia 213 81.3 209 73.85 0.0406

Platelet count 70 26.72 70 24.73 0.6244

Febrile neutropenia 1 0.38 0 0 0.4807

Infection 7 2.67 5 1.77 0.5651

Nausea 213 81.3 220 77.74 0.3400

Vomiting 161 61.45 162 57.24 0.3378

Diarrhea 24 9.16 25 8.83 1.0000

Constipation 51 19.47 62 21.91 0.5262

Anepithymia 120 45.8 124 43.82 0.6669

Weakness 112 42.75 116 40.99 0.7282

Neuropathy 8 3.05 15 5.3 0.2082

Loss of hair 10 3.82 10 3.53 1.0000Cardiac toxic effects 74 28.24 49 17.31 0.0029

Safety Profile: Grade ¾ toxicities

Type Of Toxic Effect

Group A （ N ＝ 262 ） Group B （ N ＝ 283 ）Test Of Hypothesis

Grade Grade

3 4 3 4 Statistic P Value

Leukocyte count 116(49.57%) 30(12.82%) 82(34.60%) 23(9.70%) 3.7552 0.0002

Granulocyte count 73(31.20%) 124(52.99%) 73(31.06%) 105(44.68%) 2.2672 0.0234

Anemia 32(15.02%) 1(0.47%) 25(11.96%) 1(0.48%) 1.4471 0.1479

Platelet count 7(10.45%) 0(0.00%) 6(8.70%) 0(0.00%) 0.3674 0.7133

Febrile neutropenia 0(0.00%) 0(0.00%) 0(0.00%) 0(0.00%) . .

Infection 0(0.00%) 1(16.67%) 2(40.00%) 0(0.00%) 0.2909 0.7711

Nausea 35(16.51%) 2(0.94%) 28(12.73%) 2(0.91%) 0.1802 0.8570

Cardiac toxic effects 4(5.41%) 1(1.35%) 2(4.08%) 1(2.04%) 0.9910 0.3217

Vomiting 36(22.36%) 2(1.24%) 32(19.75%) 3(1.85%) 0.4165 0.6770

Diarrhea 0(0.00%) 0(0.00%) 2(8.00%) 0(0.00%) 0.6517 0.5146

Constipation 4(7.84%) 0(0.00%) 2(3.23%) 1(1.61%) 0.3473 0.7284

Anepithymia 7(5.83%) 0(0.00%) 2(1.63%) 1(0.81%) 1.6611 0.0967

Weakness 2(1.79%) 0(0.00%) 3(2.61%) 0(0.00%) 1.1400 0.2543

Neuropathy 1(12.50%) 0(0.00%) 2(13.33%) 0(0.00%) 0.0000 1.0000

Loss of hair 0(0.00%) 0(0.00%) 0(0.00%) 0(0.00%) 0.5493 0.5828

Discuss

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