EGFR-TKI 治疗肺癌耐药的对 策和困境 上海市肺科医院肿瘤科 周彩存

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1 EGFR-TKI 治疗肺癌耐药的对 策和困境 上海市肺科医院肿瘤科 周彩存

2 Chemotherapy for advanced NSCLC MST (M) ORR (%) SWOG 9509 (N=410) PCAR VCIS PCIS ECOG 1594 (N=1163) GCIS DCIS PCAR ITALIAN STUDY (N=1770) GCIS PCAR VCIS EORTC (N=480) PCIS GCIS GP

3 Mutations of some driver genes in adenocarcinoma of the lung NO MUTATION DETECTED EML4- ALK 7% KRAS 22% EGFR 17% Unknown EML4-ALK 2% 2% 2% 2% 17% 9% 66% EGFR KRAS P13K P53 BRAF T790M/ EGFR Mut = 5 Caicun Zhou, data on file

4 Possible clinical consequences of EGFR Mut+ NSCLC Oncogenic drivers sufficient for malignant transformation and maintenance EGFR activating mutations affect the binding of both ATP and EGFR TKIs to EGFRs Compared with wild-type EGFRs ATP binds less strongly EGFR TKIs bind more strongly Carey, et al. Cancer Res 2006; 2. Karaman, et al. Nat Biotechnol Yun, et al. Cancer Cell 2007; 4. Eck, et al. Biochim Biophys Acta 2010

5 First Line EGFR TKI therapy in advanced NSCLC Giaccone Jackman TORCH IPASS SLCG NSCLC unselected unselected unselected selected* EGFR +** Agent erlotinib erlotinib erlotinib gefitinib Erlotinib Phase (N) II(53) II(80) III(380) III(609) II(113) CR/PR 23% 10% 10% 43% 78% MPFS 2.8m 3.5m 2.2m 5.7m 14m MST 12.9m 10.9m 8.5m 18.6m 28m *by clinical features (smoking status, Histology) **EGFR + = presence of activating EGFR mutation

6 First-Line TKI therapy in advanced NSCLC: IPASS Study (Iressa Pan-Asia Study) PatientsChemonaïve Age 18 years Adenocarcinoma histology Never or ex-light smokers* Life expectancy 12 weeks WHO PS 0-2 Measurable stage IIIB / IV disease Gefitinib (250 mg / day) 1:1 randomization Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # End points Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression *Never smokers, <100 cigarettes in lifetime; ex-light smokers, stopped 15 years ago and smoked 10 pack years; # limited to a maximum of 6 cycles. Carboplatin/paclitaxel was offered to gefitinib patients upon progression WHO, World Health Organization; PS, performance status; AUC, area under the curve; EGFR, epidermal growth factor receptor Mok et al NEJM 2009 p947-57

7 Probability of PFS IPASS Study PFS by mutation status Gefitinib EGFR M+ (n=132) Gefitinib EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) Gefitinib HR=0.19, 95% CI 0.13, 0.26, p< No. events M+ = 97 (73.5%) - No. events M- = 88 (96.7%) Carboplatin/paclitaxel HR=0.78, 95% CI 0.57, 1.06, p= No. events M+ = 111 (86.0%) - No. events M- = 70 (82.4%) Time from randomisation (months) Hazard ratio <1 implies a lower risk of progression in the M+ group than in the M- group M+, mutation positive; M-, mutation negative Mok et al NEJM 2009 p947-57

8 Randomized Phase III studies of gefitinib in Japanese population with EGFR mutations Advanced NSCLC Sensitive EGFR mutation PS 0-1 No Prior chemo Advanced NSCLC EGFR mut (exon 19 or 21) PS 0-2 No Prior chemo R Stratified for Institution Sex Stage R 1:1 Gefitinib N=160 Tax/Carbo N=160 Gefitinib Doc/cDDP Primary Endpoint PFS Secondary Endpoints OS ORR, QOL Safety Kobayashi K, et al ASCO 8016a Mitsudomi et al. Lancet Oncology 2010

9 Randomized Phase III studies of gefitinib in Japanese population with EGFR mutations HR=0.357, 95%CI ,P<0.001 HR= %CI ,P<0.001 Kobayashi K, et al ASCO 8016a Mitsudomi et al. Lancet Oncology 2010

10 OPTIMAL Study Design Chemonaїve Stage IIIB/IV NSCLC EGFR Act Mut+ (exon 19 deletion or exon 21 L858R mutation) ECOG PS 0 2 (n=165) Primary endpoint Progression-free survival (PFS) Secondary endpoints Overall survival (OS), objective response rate (ORR), time to disease progression, duration of response, safety, HRQoL (FACT-L, LCSS), exploratory biomarker analyses R 1:1 Erlotinib 150mg/day Gemcitabine (1,000 mg/m 2 d1,8) Carboplatin (AUC5 d1) q3w, up to 4 cycles Stratification factors Mutation type Histology Smoking status Efficacy assessment Every 6 weeks

11 OPTIMAL study Baseline characteristics Erlotinib (n=82) Gem/carbo (n=72) Median age (range), years 57 (31 74) 59 (36 78) Age <65 yrs / 65 yrs, % 77 / / 29 Male / Female, % 42 / / 60 Adenocarcinoma / non-adenocarcinoma, % 88 / / 14 Current or former smoker / never-smoker, % 28 / / 69 Exon 19 deletion / L858R mutation, % 52 / / 46 PS 0 1 / 2, % 92 / 8 96 / 4 Stage IIIB / IV, % 13 / 87 7 / 93 Current = smoked >100 cigarettes in entire lifetime and are either currently smoking or quit smoking <1 year ago; Former = smoked >100 cigarettes in entire lifetime and quit smoking 1 year ago; Never = smoked 100 cigarettes in entire lifetime or never smoked

12 PFS probability Updated PFS analysis by treatment group Erlotinib G/C n Events, n (%) (70.73) (88.89) Median, months 95% CI HR=0.164 (95% CI: ) Log-rank p< Patients at risk Time (months) Erlotinib G/C CI = confidence interval; HR = hazard ratio

13 OPTIMAL study Subgroup analysis of PFS Overall Stage IV Stage IIIB Female Male Age 65 Age <65 PS 0 1 PS 2 Never smoker Current/former smoker Adenocarcinoma Non-adenocarcinoma HR (95% Cl) n 0.16 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Favours Tarceva HR Favours gem/carbo Zhou, et al. ESMO 2010

14 Patients with clinically relevant improvement during the study, % Clinically relevant improvements in QoL scores and symptoms OR (95% CI) Covariates Total FACT-L TOI LCS PS, smoking 6.90 ( ) 7.79 ( ) 6.77 ( ) history and gender p< p< p< Exon mutation 6.93 ( ) 8.63 ( ) 7.05 ( ) type, smoking p< p< p< Erlotinib (n=74) G/C (n=54) history and 80 histological type Total FACT-L TOI LCS Includes all patients with a baseline and 1 post-baseline QoL assessment OR = odds ratio

15 Why EGFR TKI in first-line treatment A EGFR Act MUT+ NSCLC First-line EGFR TKI PD PD Second-line chemotherapy (3rd line) Death B First-line chemotherapy PD Second-line EGFR TKI PD (3 rd line) Death C D First-line EGFR TKI First-line chemotherapy PD Rapid worsening PD Rapid worsening Death Death Patients who receive only one line of therapy Theoretical survival Gridelli, et al. Lung Cancer 2011

16 TORCH: Treatment received 760 randomized patients 380 standard arm 380 experimental arm 15 dead without documented PD 21 dead without documented PD 82 censored without PD 40 censored without PD 283 (74%) progressive disease 319 (84%) progressive disease 72 did not start 2 nd line erlotinib 133 did not start 2 nd line CisGem 211 (55%) started 2 nd line erlotinib 186 (49%) started 2 nd line CisGem Gridelli, et al. ASCO 2010.

17 INFORM 研究设计 患者 年龄 18 岁 完成 4 周期一线含铂化疗后未进展或未出现不可耐受毒性 生存预期 12 周 WHO PS 0-2 有可测量病灶 IIIB/IV 期疾病 中位随访 16.8 个月 吉非替尼 (250 mg/d) 1:1 随机 安慰剂 ( 每日一次 ) 终点主要 无进展生存期 (PFS) 次要 客观缓解率 (ORR) 疾病控制率 (DCR) 总生存期 (OS) 疾病相关症状 安全性与耐受性探索性 生物标记物 EGFR 突变 ( 组织 ) EGFR 突变 ( 血浆 ) EGFR= 表皮生长因子受体 ;PD= 疾病进展 ;PS= 体力状态 ;WHO= 世界卫生组织 Zhang L, et al ASCO Abstract # LBA 7511.

18 基线特征 (ITT) 吉非替尼 (n=148) 安慰剂 (n=148) 年龄 <65 岁 (%) 中位年龄 [ 范围 ] ( 岁 ) 54 [31-79] 54 [20-75] 性别 : 女性 (%) 亚裔 (%) WHO PS:0/1/2 (%) 46.6/51.4/ /48.6/2.7 吸烟状态 : 是 / 否 (%) 46.6/ /54.7 组织学 : 腺癌 / 鳞癌 (%) 70.9/ /20.3 疾病分期 :IIIB/IV (%) 28.4/ /77.7 一线含紫杉类化疗 (%) 一线治疗疗效 (CR/PR, SD) (%) 39.2/ /65.5 随机因素 Zhang L, et al ASCO Abstract # LBA 7511.

19 PFS 概率 (%) PFS (ITT) 中位 PFS, 月 6- 个月 PFS, % 12- 个月 PFS, % 吉非替尼 (n=148) 安慰剂 (n=148) HR (95% CI) = 0.42 (0.33, 0.55); p< 自随机时间 ( 周 ) Zhang L, et al ASCO Abstract # LBA 7511.

20 EGFR TKI in the 1st line treatment of Advanced NSCLC with EGFR mutation RR(%) Median PFS(mo) Median OS(mo) TKI Chemo TKI Chemo TKI Chemo IPASS Mut First-SIGNAL Mut+ NEJ OPTIMAL N/A N/A WJTOG N/A EURTAC N/A N/A

21 困惑一 PD 标准 定义 RECIST or WHO vs Molecular (T790M 或 cmet 扩增 )

22 Jackman s Criteria Criteria 1 以前曾接受过 EGFR TKI 单药治疗, 吉非替尼或厄洛替尼 2 符合下列标准,1) 肿瘤存在与药物敏感性相关的 EGFR 突变,2)EGFR TKI 治疗获得客观临床受益, 即 RECIST 或 WHO 的 PR 或 CR 或 SD>6 月 3 持续使用 EGFR TKI 治疗过程中出现疾病进展 4 在停用 EGFR TKI 与开始新治疗措施之间, 无其它全身治疗措施 RECIST 或 WHO 标准???? 为何检测 T790M 或 c-met 扩增? Jackman et al, JCO 28:357, 2010

23 困惑二 : 脑 PD?

24 Criteria for acquired resistance to EGFR TKIs Consideration: CNS progression A question of resistance or penetration? Patient 吉非替尼剂量 CSF 浓度 (nm) 血浆浓度 (nm) CSF 细胞学反应 1 750mg Yes 2 750mg No 3 750mg No mg No mg Yes mg Yes mg No Jackman, unpublished data. ASCO 2010

25 困惑三 : PD 后 TKI 停止还是继续? DC=Disease control, DP= PD 中国人腺癌为主不吸烟为主特罗凯治疗无 PR

26 PD 后 TKI? 停用 继续 + 另一种策略? 脑 PD----- 继续 + 局部治疗全身缓慢 PD---- 继续 + 另一种治疗策略

27 困惑四 : 分子靶标 -----T790M 原发或获得性 如何克服? 不可逆 TKI?

28 T790M mutation H3255 (L858R mutation), H1975 (both T790M and L858R mutations), and H2030 (wild-type EGFR, mutant KRAS)

29 T790M: Acquired mutation (Presence at re-biopsy after TKI) Oxnard et al ASCO 2010

30 T790M: pre-existing (presence prior to EGFR TKI) 11/261 patients in the IPASS study were found to harbour EGFR T790M mutation Rosell: 35% were found to harbour EGFR T790M mutation

31 Frequency of T790M in SLCG 45 out of 129 pts (35%) harbour T790M mutation All patients N=129 N (%) T790Mpositive N=45 N (%) T790Mnegative N=84 N (%) P value Age, median (range) 67 (22-86) 68 (22-80) 65.5 (35-86) 0.31 Sex 0.31 Male 36 (27.9) 10 (22.2) 26 (31) Female 93 (72.1) 35 (77.8) 58 (69) Bone metastases No Yes 99 (76.7) 30 (23.3) 29 (64.4) 16 (35.6) 70 (83.3) 14 (16.7) 0.03 Brain metastases 1 No Yes 116 (89.9) 13 (10.1) 41 (91.1) 4 (8.9) 75 (89.3) 9 (10.7) Erlotinib therapy 0.58 First-line 65 (50.4) 21 (46.7) 44 (52.4) Second-line 64 (49.6) 24 (53.3) 40 (47.6) Type of EGFR mutation 0.05 del (62.8) 23 (51.1) 58(69) L858R 48 (37.2) 22 (48.9) 26(31) Response 0.39 Complete or partial response 80 (68.9) 28 (63.6) 52 (72.3)

32 PFS: T790M positive versus T790M negative

33 BIBW 2992 maintains inhibitory activity in cell line with resistant mutation (T790M) In vitro kinase assay Kinases BIBW 2992 Lapatinib Gefitinib EGFR wt EGFR L858R EGFR L858R/T790M 10 > Anchorage independent growth EC 50 [nm] wild type H1666 L858R H3255 L858R+T790M NCI1975 Target Binding mode gefitinib >4000 EGFR reversible erlotinib >4000 EGFR reversible BIBW EGFR/HER2 irreversible CP 714,724 > >4000 HER2 reversible lapatinib >4000 EGFR/HER2 reversible

34 LUX-Lung 1: Afatinib + BSC vs BSC Alone in Relapsed/Refractory NSCLC Afatinib (BIBW2992): irreversible EGFR and HER2 TKI Randomized 2:1 Patients with stage IIIB/IV lung cancer, 1-2 previous chemotherapies, and progression on EGFR TKIs (N = 585) Afatinib 50 mg QD + Best Supportive Care Best Supportive Care + Placebo Phase IIB/III study Primary endpoint: OS; secondary endpoints: PFS, ORR, DCR, safety, QoL Miller VA, et al. ESMO Abstract LBA1.

35 Afatinib + BSC vs BSC Alone in NSCLC: Outcomes Primary endpoint: OS not significantly improved with afatinib However, significant PFS, ORR, DCR benefit with afatinib Most common toxicities associated with afatinib: diarrhea (87%; grade 3: 17%) and rash/acne (78%; grade 3: 14%) Outcome Afatinib + BSC BSC HR P Value Median PFS, mos <.0001 Confirmed ORR, % <.01 Confirmed DCR at 8 wks, % <.0001 Median OS, mos Miller VA, et al. ESMO Abstract LBA1. Reprinted with permission.

36 困惑五 : 分子靶标 C-MET 扩增 C-MET 小分子抑制剂 单抗

37 % of control Inhibition of both EGFR and MET is necessary for growth inhibition of HCC827 GR cells Gefitinib PHA Gefitinib/PHA Drug Concentration ( M) Irreversible EGFR inhibitors have no effect on HCC827 GR MET shrna restores sensitivity to gefitinib Engelman et al. Science 2007

38 MET amplification can be detected in gefitinib resistant NSCLC patients # Specimen EGFR mutation T790M Method MET copy no (S.D.) 1 Pre L858R No QPCR 2.10 (0.27) Post L858R No QPCR 5.83 (1.41)* 2 Pre Del L747_P753 ins S No QPCR 1.83 (0.45) Post Del L747_P753 ins S Yes QPCR 1.97 (015) 3 Pre Del L747_P753 ins S No QPCR 1.87 (0.38) Post Del L747_P753 ins S No QPCR 1.75 (0.94) 4 Pre Del L747_E749, A750P No QPCR 3.07 (0.81) Post Del L747_E749, A750P Yes QPCR 3.17 (0.63) 5 Pre Del L747_S752del,E746V No FISH 0% Post Del L747_S752del,E746V No FISH 0% 6 Pre Del L747_E749del, A750P No FISH 1% Post Del L747_E749del, A750P No FISH 2% 7 Pre Del L747_E749del, A750P No FISH 0% Post Del L747_E749del, A750P Yes FISH 3% 8 Pre Del E746_A750 No FISH 0% Post Del E746_A750 No FISH 26%*

39 EGFR T790M and MET amplification can occur in the same patient # Specimen EGFR mutation T790M Method MET copy no (S.D.) 9 Post Del E746_A750 No QPCR 2.30 (0.25) 10 Post L858R No QPCR 1.98 (0.48) 11 Post L858R Yes QPCR 1.92 (0.46) 12 Post Del L747_T751,K754E Yes QPCR 3.90 (0.61) 12 Post Del L747_T751,K754E No QPCR 6.58 (1.35)* 13 Post L858R Yes QPCR (7.69)* 14 Post L858R Yes QPCR 1.86 (0.23) 15 Post L858R No QPCR 1.92 (0.23) 16 Post Del E746_A750 Yes FISH 0% 17 Post Del L747_T751 Yes FISH 0% 18 Post L858R Yes FISH 0% Engelman et al., Science /18 (22%) of EGFR resistance have MET amplification

40 ARQ : Study Design Randomized, placebo-controlled, double-blind clinical trial NSCLC Inoperable locally adv/metastatic dz. 1 prior chemo (no prior EGFR TKI) R A N D O M I Z E D Erlotinib 150 mg PO QD + ARQ mg PO BID 28-day cycle Erlotinib 150 mg PO QD + Placebo 28-day cycle PD Endpoints 1 PFS 2 ORR, OS Subset analyses Crossover: ORR 33 sites in 6 countries Study accrual over 11 months (10/08-9/09) Randomization stratified by prognostic factors incl. sex, age, smoking, histology, performance status, prior therapy and best response, and geography (U.S. vs. ex-u.s.) Schiller JH, et al. ASCO Abstract LBA7502.

41 ARQ : Histology and Molecular Characteristics Histology ARQ 197/erlotinib (n=84) Placebo/erlotinib (n=83) Adenocarcinoma 45 (54%) 53 (64%) Squamous Cell Carcinoma 26 (31%) 24 (29%) Large Cell 2 (2%) 3 (4%) Unspecified/Other 11 (13%) 3 (4%) Molecular Markers* EGFR mutant 6 (7%) 11 (13%) EGFR wt 51 (61%) 48 (58%) c-met positive (FISH >4 copies) 19 (23%) 18 (22%) c-met negative (FISH 4 copies) 54 (64%) 50 (60%) KRAS mutant 10 (12%) 5 (6%) KRAS wt 49 (58%) 45 (54%) * 58 (25/33), 51 (27/24), and 26 (11/15) patients with indeterminate or missing results for KRAS, EGFR, and c-met status respectively. Schiller JH, et al. ASCO Abstract LBA7502.

42 Proportion of patients progression-free ARQ : Progression-Free Survival (ITT Population) 1.0 HR=0.81 (95% Cl: 0.57, 1.15); p=0.24 Adjusted HR=0.68 (95% Cl: 0.47, 0.98); p=0.05* Erlotinib + ARQ 197: 16.1 wks (n=84) Erlotinib + Placebo: 9.7 wks (n=83) Time from randomization (weeks) * Cox regression model PFS also measured by independent radiographic review: median 15.6 vs. 8.4 wks; unadjusted/adjusted HR=0.74/0.51 Schiller JH, et al. ASCO Abstract LBA7502.

43 Proportion of patients surviving ARQ : Overall Survival (ITT Population) 1.0 HR=0.88 (95% Cl: 0.60, 1.3); p=0.50 Adjusted HR=0.88 (95% Cl: 0.6, 1.3); p=0.52* Erlotinib + ARQ 197: 36.6 wks (n=84) Erlotinib + Placebo: 29.4 wks (n=83) Survival time (weeks) * Cox regression model Schiller JH, et al. ASCO Abstract LBA7502.

44 ARQ : crossover patients 34 Crossover patients 23 Evaluable for response 2PR 9SD 3-18wks Pt 24: EGFR IND KRAS WT CMET>4 Pt 58 EGFR Mut KRAS WT cmet>5 12PD

45 困惑六 : 分子靶标不明 25% 左右 EGFR TKI+ 抗血管生成 EGFR TKI+AKTi EGFR TKI+PI3Ki PAN HERi EGFR TKI+HSPi EGFR TKI+MEKi

46 that are currently under investigation? Switch to doublet chemotherapy Clinical benefit with first-line EGFR TKI in EGFR Mut+ NSCLC PD Switch to an irreversible EGFR TKI +/ another agent (e.g. afatinib, PF ) Continue with the same TKI and then add another agent (e.g. cetuximab) Use the same EGFR TKI Use another agent and then rechallenge with the same TKI at a later stage (e.g. dasatinib)

47 EGFR TKI may not influence chemosensitivity in NSCLC Switch to doublet chemotherapy recommended by NCCN guideline 2011 ORR to chemotherapy comparable between those receiving first-line or after failure of gefitinib Gefitinib 1st line 73.7% (n=114) 2nd line 28.8% (n=52) Carbo/Pac 30.7% (n=114) 58.5% (n=102)

48 Change from baseline (%) Is there a clinical rationale for continuing an EGFR TKI after disease progression? CT unidimensional (RECIST) measurements Rebound effect or disease flare FDG-PET SUV max EGFR TKI Everolimus CT volume measurements weeks 3 weeks 3 weeks 3 weeks 3 weeks 3 weeks 3 weeks 3 weeks 3 weeks Imaging changes for individual patients after stopping and restarting erlotinib or gefitinib followed by the addition of everolimus Riely, et al. Clin Cancer Res 2007

49 Total no. viable cells Different scenarios of EGFR Mutant NSCLC when treated with a TKI Exon 19 deletion Exon 19 deletion & T790M Time Chemotherapy, no TKI TKI Progression No TKI Add TKI EGFR mutant tumour Acquired Resistance Re-growth Chemotherapy, with TKI Re-response AACR

50 Incidence :14/61 (23%, 95%CI 14-35%) Median time: 8day Related factors : shorter TTP(P=0.002), pleural disease (P=0.03), CNS disease (P=0.01) but not T790M

51 Best change from baseline (%) Phase II study of PF299 (PF ), another irreversible pan-her TKI Stage IIIB/IV NSCLC No prior chemotherapy ECOG PS 0 1 Adenocarcinoma Never or former light smoker Asian or KRAS WT non-asian OR Known EGFR mutation 20 0 Exon 19 deletion L858R Exon 18 and/or 20 R PR PF299 45mg/day (amended to 30mg/day) Endpoints primary: PFS at 4 months secondary: PFS, OS, ORR, QoL, safety n=33 (EGFR mutation-positive) All patients with typical EGFR mutations had some degree of tumour shrinkage Mok, et al. ESMO 2010

52 Afatinib+Cetuximab 用于 TKI 耐药患者 研究设计 : EGFR 突变 NSCLC 和特罗凯 / 易瑞沙治疗 SD>6 月 或特罗凯 / 易瑞沙治疗 PR 或 CR 疾病进展 停用特罗凯或易瑞沙 >72 小时 扩增例数研究 剂量递增方式 每个剂量 3-6 例 Afatinib 每日口服 + C225 递增剂量 IV q2w 递增开始剂量 : afatinib 40mg+ C mg/m2 最大耐受剂量模式增加到 80 例 EGFR 突变阳性病人 : 40 例 T790M 阳性和 40 例 T790M 阴性 Y. Y. Janjigian, et al. ASCO 2011, Abstract # 7525

53 Afatinib+Cetuximab 用于 TKI 耐药患者 研究结果 : Y. Y. Janjigian, et al. ASCO 2011, Abstract # 7525

54 结论 已知耐药分子机制 T790M MET 扩增 治疗策略不可逆 TKI 联合 METi 联合下游抑制剂 考虑一线 二线或二线以后 PD 继续 TKI+ 化疗或其它措施?

55 Overall survival Treatment of Advanced NSCLC EGFR TKI in EGFR Act mutation-positive disease >24 months 1 5 Bevacizumab + platinum doublet 12.3 months 6 Platinum doublet 8-10 months 7 Platinum singlet 6-8 months BSC 2-5 months SurvivalTime (months) 1 Janne, et al. ASCO 2010; 2 Lee, et al. WCLC Maemondo, et al. NEJM 2010; 4 Mitsudomi, et al. Lancet Oncol Rosell, et al. NEJM 2009; 6 Sandler, et al. NEJM 2006; 7 Schiller, et al. NEJM 2002

56 谢谢大家