Lessons learned from gefitinib and crizotinib clinical trials in NSCLC

Transcription

1 Lessons learned from gefitinib and crizotinib clinical trials in NSCLC Shun Lu Shanghai Lung Cancer Center Shanghai Chest Hospital affiliated to Jiao Tong University

2 New Era of Cancer Care: Genomic Era * Change the Paradym Cancer Care: Old Paradigm It is time to change the paradigm, and begin Organ Oriented: lung, breast thinking directing therapy at a molecular Histologic classification eg: Squamous, Adeno target rather than developing organ-specific Genomic era may profoundly alter the landscapes of cancer care, clinical research, and scientific investigation treatments. George Sledge

3 Gefitinib and Crizotinib: 9 year and 4 year Gefitinib Any line Gefitinib in EGFR M+ (EMEA) Phase I trial 2/3L IDEAL EGFR M+ 2/3L ISEL Gefitinib vs placebo IPASS 2L INTEREST Gefitinib vs Texotere 1L Gefitinib 1L vs CP in Gefitinib vs EGFR DP in EGFR MUT+ MUT+ 1L IPASS Gefitinib vs CP in EGFR MUT+ 1LM INFORM Crizotinib EML4 ALK transgenic mice developed lung cancer All objective responders were ALK+ cancer patients 2010 Phase III trials about ALK+ NSCLC 2011 NEJM: the clinical data of Crizotinib to treat ALK+ NSCLC 2011 Aug 26 Crizotinib approved for ALK+ NSCLC by FDA 1.Fokuoka 2002; Kris Thatcher Lancet 2005; 3. Kim 2007; 4 Mok, et al. NEJM 2008; 5. Mitsdomi 2009; 6. NEJ ; 7. Zhou, et al.2010; 8.Bang ASCO 2010

4 2011: A new treatment era is just beginning

5 Lung Cancer Mutation Consortium Incidence of Single Driver Mutations Kris et al ASCO 2011 Mutation found in 54% (280/516) of tumors completely tested (CI 50-59%)

6 Driver genes Mutations for Adeno: East vs. West LCMC China Japan EGFR 17% 40% 50% KRAS 22% 7% 15% ELM4-ALK 7% 7% 5% BRAF 2% 2% 1% HER2 1% NA 3% PIK3CA 1% 4% NA PTEN NA 6% NA MET Amp 1% 5% 4% Nil 46% 29% 22%

7 ISEL A double-blind Phase III survival study comparing IRESSA (250mg) plus BSC vs placebo plus BSC in patients with advanced NSCLC who have received 1 2 prior chemotherapy regimens and are refractory or intolerant to their most recent regimen 2:1 Randomisation IRESSA 250mg daily + BSC Placebo + BSC Primary endpoint Overall survival Secondary endpoints TTF, OR, QoL, Safety 1692 patients in 210 centres across 28 countries 342 patients of Asian origin no Japanese / US sites BSC = best supportive care TTF = time to treatment failure OR = objective response QoL = quality of life

8 ISEL: Overall survival, time-to-treatment failure and objective response rate OS: TTF HR=0.89 (0.77, 1.02) HR=0.82 (0.73, 0.93) n=1692, deaths=976 n=1316, progressions=1137 Median survival: IRESSA 5.6m, Placebo 5.1m Median TTF: IRESSA 3.0m, Placebo 2.6m Proportion surviving Stratified log rank test, p= Cox analysis, p= IRESSA Placebo Proportion without treatment failure Stratified log rank test, p= Cox analysis p= Objective Response Rate 8.0% vs 1.3%, p< Months Months HR <1 implies a lower risk of event on IRESSA

9 ISEL: Overall survival in Asians and never-smokers Asians: HR=0.66 (0.48, 0.91), p=0.010 n=342, events=173 Never Smokers: HR=0.67 (0.49, 0.92), p= n=375, events= Proportion surviving IRESSA Placebo Proportion surviving IRESSA Placebo Months HR <1 implies a lower risk of event on IRESSA Months

10 IDEAL 1 & 2: Design scheme Patients Received 1 or 2 (IDEAL 1) or 2 (IDEAL 2) previous chemotherapy regimens Randomisation ZD mg once daily ZD mg once daily Primary endpoints Response rate (both trials) Safety profile (IDEAL 1) Symptom relief (IDEAL 2) Continue ZD1839 until disease progression or unacceptable toxicity

11 IDEAL 1: overall survival Proportion event free 1.0 ZD1839 (mg/day) Patients (n) Deaths (n) Median (months) Months from randomisation

12 IDEAL 2: overall survival Proportion event free 1.0 ZD1839 (mg/day) 250 Patients (n) 102 Deaths (n) 75 Median (months) Months from randomisation

13 INTEREST Patients Age 18 years Life expectancy 8 weeks Progressive or recurrent disease following CT Considered candidates for further CT with docetaxel 1 or 2 CT regimens ( 1 platinum) PS 0-2 IRESSA 250 mg/day 1:1 randomization Docetaxel 75 mg/m 2 every 3 weeks Endpoints Primary Overall survival (co-primary analyses a of non-inferiority in all patients and superiority in patients with high EGFR gene copy number) Secondary Progression-free survival Objective response rate Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers A Modified Hochberg procedure applied to control for multiple testing CT, chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor

14 Overall survival in overall PP population Probability of survival N Events (82.0%) (81.1%) Primary Cox analysis without covariates HR (96% CI) = (0.905, 1.150) Median OS (months) 1-year survival IRESSA Conclude non-inferiority in the overall PP population % Docetaxel % At risk : IRESSA Docetaxel Pre-specified NI limit in HR terms (translates to 50% effect retention [Rothmann 2003]) = % of historical docetaxel advantage over BSC from TAX-317 retained by IRESSA (96% CI: 52%, 129%) Indirect comparison of IRESSA with BSC: HR (96% CI) = 0.63 (0.42, 0.92), p= PP, per-protocol; NI, non-inferiority; HR, hazard ratio; CI, confidence interval; OS, overall survival; BSC, best supportive care Months Douillard et al 2007

15 Overall survival by racial origin 1.0 Asian origin 1.0 Non-Asian origin Probability of survival IRESSA Docetaxel Probability of survival IRESSA Docetaxel At risk: Months Months IRESSA Docetaxel IRESSA Docetaxel IRESSA Docetaxel N N Events Events HR (95% CI) = 1.04 (0.80, 1.35) p = HR (95% CI) = 1.01 (0.89, 1.14) p = Median (mo) Median (mo) Racial origin by treatment interaction, p =

16 Overall survival by biomarkers (ITT population) Overall EGFR FISH + EGFR FISH - EGFR expression + EGFR expression - EGFR mutation + EGFR mutation - K-RAS mutation + K-RAS mutation - N=1466 N=174 N=200 N=284 N=96 N=44 N=253 N=49 N=226 Cox analysis without covariates HR (IRESSA vs. docetaxel) and 95% CI Favors IRESSA Favors docetaxel Douillard et al 2007

17 IPASS Patients Chemonaïve Age 18 years Adenocarcinoma histology Never or light exsmokers* Life expectancy 12 weeks PS 0-2 Measurable stage IIIB / IV disease Gefitinib (250 mg / day) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # Endpoints 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; light ex-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 ; PS, performance status; EGFR, epidermal growth factor receptor Mok et al NEJM 361:

18 IPASS: EGFR Mutation and Progression-free survival EGFR mutation positive EGFR mutation negative Probability of progression-free survival Gefitinib (n=132) Carboplatin / paclitaxel (n=129) HR (95% CI) = 0.48 (0.36, 0.64) p< No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) Probability of progression-free survival Gefitinib (n=91) Carboplatin / paclitaxel (n=85) HR (95% CI) = 2.85 (2.05, 3.98) p< No. events gefitinib, 88 (96.7%) No. events C / P, 70 (82.4%) At risk : Gefitinib C / P ITT population Cox analysis with covariates Months Treatment by subgroup interaction test, p< Months Mok et al NEJM 361:

19 IPASS: 2010 OS by EGFR mutation status (ITT) Gefitinib (n=132) Carboplatin/paclitaxel (n=129) Gefitinib (n=91) Carboplatin/paclitaxel (n=85) Probability of survival HR (95% CI) 1.00 (0.76, 1.33); p=0.990 No. events G 104 (79%) C / P 95 (74%) Median OS G 21.6 months C / P 21.9 months Probability of survival HR (95% CI) 1.18 (0.86, 1.63); p=0.309 No. events G 82 (90%) C / P 74 (87%) Median OS G 11.2 months C / P 12.7 months 0.0 Patients at risk: Gefitinib 132 C / P Time from randomisation (months) EGFR Mutation Time from randomisation (months) EGFR Mutation Treatment by subgroup interaction test p=0.480

20 Phase III studies comparing 1st line gefitinib to standard chemotherapy for advanced NSCLC with EGFR mutations NEJ002 EGFR mutated chemo-naïve NSCLC, PS0-1 Carboplatin + Paclitaxel Gefitinib Primary Endpoint: PFS Sample size: 320 (stopped at 230) Maemondo, N Engl J Med 2010

21 Progression-free survival in NEJ002 Gefitinib CBDCA/TXL ORR 74% 31% Median PFS 10.8 m 5.4 m HR (95%CI) 0.30 ( ) P value** <0.001 Maemondo, N Engl J Med 2010 Inoue, ASCO2011

22 Toxicity Common adverse events in NEJ002 Gefitinib (n = 114) Grade >3 CBDCA+TXL (n = 114) Grade >3 Grade % % P value Diarrhea <0.001 Appetite loss <0.001 Fatigue Rash <0.001 Neuropathy <0.001 Arthralgia <0.001 Pneumonitis * AST/ALT <0.001 Nuetropenia <0.001 Anemia ,3 <0.001 Platelet <0.001 Any * <0.001 Generally, gefitinib is less toxic than chemotherapy

23 Good QOL was maintained longer in gefitinib arm For pain and dyspnea (in physical category) For daily functioning (in life-wellbeing category) Yoshizawa, ESMO2010 (paper in submission)

24 WJTOG3405:PFS EGFR mutated chemo-naïve NSCLC, PS0-1 Cisplatin + Docetaxel Gefitinib Primary Endpoint: PFS Sample size: 200 (stopped at 177) Mitsudomi T et al. Lancet, December 21, 2009

25 Clinical trials about EGFR mutation positive NSCLC first line therapy Author Study N (EGFR mut +) RR Median PFS OS Mok et al IPASS (Gefitinib) % vs vs 6.4 months 18.8 vs 17.4 months Lee et al First-SIGNAL (Gefitinib) % vs 37.5% 8.4 vs 6.7 months 21.3 vs 23.3 months Mitsudomi et al WJTOG 3405 (Geftinib) % vs 32.2% 9.2 vs 6.3 months 30.9 vs not reached Maemondo et al NEJGSG002 (Gefitinib) % vs 30.7% 10.8 vs 5.4 months 30.5 vs 23.6 months Zhou et al OPTIMAL (Erlotinib) % vs 36% 13.1 vs 4.6 months ND Rosell et al EURTAC (Erlotinib) % vs 36% 13.1 vs 4.6 months Mok et al NEJM 2009, Lee et al WCLC 2009, Mitsudomi et al Lancet Oncology 2010, Maemondo NEJM 2010

26 Western guidelines already been revised ASCO guideline ESMO guideline

27 : The history of Crizotinib Crizotinib; cmet and ALK inhibitor Crizotinib: Phase I trial Indentified EML4 ALK fusion gene in NSCLC Phase I trial Modified: AKL+ NSCLC were enrolled ALK+ NSCLC: phase III trial Crizotinib approved by the FDA for treatment of ALK+NSCLC Antitumor activity of crizotinib for ALK + cells EML4 ALK transgenic mice developed lung cancer All objective responders were ALK+ Response rate of Crizotinib for ALK+ NSCLC >50% NEJM: Clinical data of Crizotinibto treat ALK+ NSCLC

28 A A : Phase I Trial of Crizotinib (Year 2006) Cohort mg BID Cohort mg BID MDZ sub-study Cohort mg BID MTD/RP2D Cohort 1 50 mg QD Cohort mg QD MDZ sub-study Cohort mg QD 37 patients were enrolled 3 patients: PR MTD = Maximum tolerated dose; RP2D = Recommended phase 2 dose MDZ = Midazolam (in-vitro data indicated that PF is a major substrate and inhibitor of CYP3A activity) Kwak EL, et al. ESMO/ECCO 2009 (Abstract G6 and oral presentation)

29 First Description of EML4-ALK Translocation in NSCLC (Year 2007)

30 Evidence for EML4-ALK as a Lung Cancer Oncogene Insertion of EML4-ALK into NIH 3T3 fibroblasts was tumorigenic when implanted subcutaneously into nude mice. Engineered the specific expression of EML4-ALK fusion gene in lung progenitor cells using a surfactant protein C gene promoter. 100% of EML4-ALK transgenic mice developed lung adenocarcinoma that were + for ALK by IHC. No other primary cancers were observed. Following IV injection of EML4-ALK/3T3 cells into nude mice, all developed lung cancer. Ten animals were treated with an ALK-specific TKI and 10 were observed:

31 A A : phase I clinical trial Of the 3 objective responders, all had ALK translocations: Inflammatory myofibroblastic sarcoma: NPM-ALK translocation NSCLC (2): EML4-ALK translocation Key Collaboration: Pfizer and Massachusetts General Hospital Protocol modified,alk+ NSCLC were enrolled: 82 patients were evaluated for response rate Kwak EL, et al. ESMO/ECCO 2009 (Abstract G6 and oral presentation)

32 Clinical and Demographic Features of Patients with ALK-positive NSCLC Young Non-smoker Adeno N=82 Mean (range) age, years 51 (25 78) Gender, male/female 43/ (29) Performance status,* n (%) Race, n (%) Smoking history, n (%) Histology, n (%) Prior treatment regimens, n (%) 1 44 (54) 2 13 (16) 3 1 (1) Caucasian 46 (56) Asian 29 (35) Never smoker 62 (76) Former smoker 19 (23) Current smoker 1 (1) Adenocarcinoma 79 (96) Squamous 1 (1) Other 2 (2) 0 5 (6) 1 27 (33) 2 15 (18) 3 34 (41) Not reported 1 (1) Y Bang et al: ASCO 2010

33 A 肿 瘤 直 径 的 最 大 变 化 比 例 (%) Tumor Responses Rate (57%) to Crizotinib for 82 Patients with ALK-positive NSCLC % Objective RR = 57% (95% CI: 46-68%) DCR (CR+PR+SD): 87% (95% CI: 77-93%) Progressive disease Stable disease Confirmed partial response Confirmed complete response 100 * Partial response patients with 100% change have non-target disease present Kwak et al. NEJM 2010;363: Bang et al. JCO 2010;28:18S abstract 3 *

34 A & A The response rates of ALK+ NSCLC patients who received Crizotinib were 61% and 51% 2 1. Camidge R et al ASCO; Abstract Riely GJ et al. WCLC, 2011; Abstract 1618

35 A & A Crizotinib for ALK+ patients Response rate Age Patients A <65 岁 65 岁 N=116 % (n/n) 60 (60/100) 69 (11/16) A N=133 % (n/n) 50 (58/115) 56 (10/18) Sesx Male Female 61 (36/59) 61 (35/57) 44 (28/64) 58 (40/69) ECOG PS Therapy before Crizotinib (21/39) 63 (39/62) 79 (11/15) 80 (12/15) 57 (16/28) 62 (13/21) 59 (13/22) 57 (17/30) 56 (20/36) 53 (38/72) 40 (10/25) NA 44 (7/16) 58 (23/40) 55 (21/38) 44 (17/39) Race Asia Non-asia 82 (28/34) 52 (43/82) 62 (26/42) 46 (42/91) Y Bang et al: ASCO 2010

36 A & A The results of these 2 trials A N=116 A N=133 Best overall response Complete response 2 1 Partial response Stable disease Progressive disease 6 10 Other 8 10 Objective response (CR+PR) rate 61% (95% CI: 52%, 70%) 51% (95% CI: 42%, 60%) Duration of response 48 weeks (median) 7-42 weeks (range) Duration of treatment, median 32 weeks 22 weeks Median PFS 10.0 months (95% CI: 8.2, 14.7) Not mature Study Independent Radiology Review ORR (n=105) 52% (95% CI: 42%, 62%), as assessed by RECIST version 1.0 Study 1005 from 60-day clinical data update - Independent Radiology Review ORR (n=105) 41.9% (95% CI: 32.3%, 51.9%), as assessed by RECIST version 1.1 Including indeterminate and early death 1. Camidge R et al. Presented at 2011 ASCO; Abstract Riely GJ et al. To be presented at WCLC on July 6, 2011; Abstract 1618

37 A & A The safety of Crizotinib A (N=119) A (N=136) Adverse event All grades, n (%) All grades, n (%) Visual effects 74 (62) 80 (59) Nausea 58 (49) 78 (57) Diarrhea 51 (43) 58 (43) Vomiting 42 (35) 59 (43) Edema 33 (28) 39 (29) Constipation 32 (27) 37 (27) Decreased appetite 20 (17) 30 (22) Fatigue 17 (14) 37 (27) AE occurring in 20% of patients in one arm of the study 1. Camidge R et al. Presented at 2011 ASCO; Abstract Riely GJ et al. To be presented at WCLC on July 6, 2011; Abstract 1618

38 A & A Grade 3/4 treatment related AE A (N=119) A (N=136) Adverse event Grade 3/4, n (%) Grade 3/4, n (%) Increased ALT 5 (4) 9 (7) Increased AST 4 (3) 1 (1) Neutropenia 4 (3) 8 (6) Fatigue 2 (2) 2 (2) Neuropathy 1 (1) 0 (0) Lymphopenia 2 (2) 3 (2) Pneumonitis 2 (2) 1 (1) Constipation 1 (1) 0 (0) Leukopenia 0 (0) 1 (1) Electrocardiogram QT prolonged 0 (0) 2 (2) Renal Cyst 0 (0) 1 (1) 1. Camidge R et al. Presented at 2011 ASCO; Abstract Riely GJ et al. To be presented at WCLC on July 6, 2011; Abstract 1618

39 The trial of 1027and 1029 approved by SFDA: ALK+ is the key point Study A Design: Single Arm, Open Label Endpoints: 1º: ORR, Safety 2º: PFS, DR, 1 YR PFS, OS Advanced NSCLC Non- Squamous ALK translocation positive 1 platinum-based prior therapy ECOG PS 0-2 N=50 Countries: 40 China, 10 Hong Kong and Taiwan Crizotinib 250 mg BID Continuous dosing schedule (cycle = 21 days)

40 The trial of 1027and 1029 approved by SFDA: ALK+ is the key point Study A Trial Design Multi-center, randomized, open-label Interim analysis safety and efficacy: sequential filing at 75% events Endpoints 1º:PFS 2º: OS, ORR, DR, DCR, Safety, biomarkers Stratification: PS status (0,1 vs. 2) Key Entry Criteria: Positive for ALK gene translocation No prior chemo for metastatic disease Non-squamous histology N=200 R A N D O M I Z E 1:1 Countries: 150 patients China and 50 from 2-3 other Asian countries Crizotinib: 250mg BID continuous dosing schedule Cisplatin/Pemetrexed or Carboplatin/Pemetrexed Study Sites: China Singapore Thailand Hong Kong Taiwan

41 Key entry criteria; N=318 ALK-positive advanced or metastatic stage IIB/IV NSCLC ECOG 0-2 Phase III (A ) - Second line therapy for NSCLC 1 prior platinum-based chemotherapy R A N D O M I Z E N=159 N=159 Crizotinib 250 mg BID continuous dosing schedule Pemetrexed 500 mg/m 2 OR Docetaxel 75 mg/m 2 (Day 1/21) Trial design Endpoints Stratification Worldwide Multicenter Open-label Randomized Primary: PFS* Secondary: OS; ORR, DCR, DR, safety, QoL, PK *Based on RECIST v 1.1 and confirmed by independent radiology review (NCT ) ECOG PS (0/1 vs 2) Previous anti-egfr TKI Brain metastases

42 Phase III (A ) - Third line therapy for NSCLC Key entry criteria; N=250 ALK-positive NSCLC with prior chemotherapy Not eligible for Phase 3 (A ) RECIST-defined PD in chemo arm of study A or >1 prior chemotherapy Brain metastases allowed Crizotinib 250 mg BID continuous dosing schedule (21-day cycles) Trial design World-wide Multicenter Single-arm Open-label Endpoints Primary: ORR, safety Secondary: OS, DR, DCR, PFS, EML4-ALK fusion variant ALK protein expression biomarker expression in tumor samples (NCT )

43 Phase III (A ) - First line therapy for NSCLC Key entry criteria; N=334 ALK-positive locally adv/metastatic nonsquamous NSCLC No prior treatment for advanced disease R A N D O M I Z E N=167 N=167 Crizotinib 250 mg BID continuous dosing schedule Crossover on PD Pemetrexed/ cisplatin or pemetrexed/ carboplatin (Day 1/21) Trial design Endpoints Stratification World-wide Multicenter Randomized Open-label Focused screening Primary: PFS* Secondary: OS, ORR*, DR, safety, QoL, Lung cancer-specific symptoms ECOG PS (0/1 vs. 2) Ethnicity (Asian vs. non- Asian) Brain metastases *Based on RECIST v 1.1 and confirmed by independent radiology review (NCT )

44 2012NCCN guideline for Crizotinib and ALK

45 2012 NCCN guideline: EML4-ALK,EGFR and KRAS as a molecular diagnostic marker

46 Many key targets still await drugs Cancer Mutant target Small-molecule drug Bladder FGFR3 TBA Acute leukemia Flt3 TBA Papillary renal cell c-met TBA Endocrine neoplasia c-ret TBA Lung/CRC K-Ras TBA Breast PIK3CA TBA Disease Wild-type target Large-molecule drug Breast cancer HER3 IGF-1 TBA

47 MODELS FOR MOLECULAR SELECTION Scenario I: Test a Single Biomarker During the Screening Phase of the Phase II Clinical Trial Scenario II: Assess a Limited Number of Relevant Molecular Alterations Outside Phase II Clinical Trials Scenario III: Perform a Molecular Screening Based on High-Throughput Technologies Scenario IV: Use Clinical Surrogates for Molecular Testing

48 Informed consent signed for molecular test and biology-driven phase II trial Progressive disease under Previous regimen Phase of molecular testing : Diagnosis of the molecular alteration targeted by the drug Molecular alteration present 10% A Inclusion in the biology-driven trial Molecular alteration not present Screen failure not eligible for the biology-driven trial Implication: No time for a new molecular screening for other trial means patient will not be treated based on biology

49 Target A Informed consent signed for clinical trial B Target B Trial A Informed consent signed for Molecular testing done at any time Target C IF progressive disease Target B Trial B Trial C

50 Molecular screening using high-throughput technologies (gene expression array and/or CGH plus sequenome) Informed consent signed for clinical trial C Trial A Informed consent signed for molecular screening done at any time IF progressive disease Target B Trial B Trial C Trial X,Y, Z

51 Informed consent signed for clinical trial D Patients presenting a clinical feature correlated with molecular alteration (men, nonsmoker for EML4-ALK) Clinical trial with Targeted agent Molecular alteration present Efficacy of drug when the target is present Molecular alteration not present 100% treatment failure experienced by patients who did not present the target

52 Table 1. Strengths and Weaknesses of Each Molecular Selection Model Model Strength Weaknesses Test single biomarker during the screening phase of the biologydriven phase II trial (common model) Test a limited number of biomarkers outside the screening phase of biology-driven trials (Best-Rx model) Test molecular screening using high-throughput technologies outside the screening phase of the biology-driven trials (SAFIR01 model) Select patients based on clinical characteristics that correlate with the genomic alteration Uses FDA-approvable bioassay Uses same technology for each patient Decreases the rate of screen failure by performing several tests outside the screening phase of the phase II trials Uses FDA-approvable tests Identifies a large number of patients who are eligible for biology-driven trials, which minimizes the risk of screen failure Detects rare genomic events Avoids implementing a bioassay for each target Has no need for molecular tests Rate of screen failure for the trial is high because of single biomarker and because the test is performed during the screening phase of the trial Misses high number of relevant molecular alterations Needs to implement bioassay for target under investigation Technology is not available in each center Exposes some patients to a drug that is not expected to work (lack of targets)

53 Take home message Strategy From single biomarker to multi-biomarker 3M:Multi-way detection, multi-biomarker and multi-center Prospective confirm of biomarker Technical methods IHC, qrt-pcr, mutation test, FISH, microarray Optimal criterion and management of standardization Biology problem Second mutation Re-biopsy

54 Crizotinib和ALK的3篇文献 + 1篇述评 新英格兰医学杂志发表