1、Targeted Therapy in Non-Small-Cell Lung Cancer,非小細胞肺癌的標靶治療,胸腔內科 施穎銘,主要癌症每十萬人口死亡數,Fry WA, et al. Cancer. 1996;77:1953.,NSCLC- Survival by Stage,NSCLC Treatment,Early stage,Locally advanced,Metastastic,Surgery,CT+surgeryCT+RTCCRTSurgery+CT,CTTarget,Ia, IbIIa, IIb,IIIaIIIb no cy+ effusion,IIIb cy+ effu
2、sionIV,curative intent,palliative intent,metastasectomy,The “First Generation” Agents,Methotrexate, cyclophosphamide, vincristine, and doxorubicinwere essentially inactive in NSCLC, despite being widely used in the 1970s and 1980s.,Thorax. 58(4):352-6, 2003 Apr.,The “2nd Generation” Agents,Cisplatin
3、, ifosfamide, mitomycin, vindesine, vinblastine, and etoposide in late 1980.,Thorax. 58(4):352-6, 2003 Apr.,The “3rd Generation” Agents,Paclitaxel, docetaxel, gemcitabine and vinorelbine emerged in the chemotherapy of NSCLC In the middle 1990s.Cisplatin-based doublets are the mainstay of chemotherap
4、y for advanced NSCLC.,Thorax. 58(4):352-6, 2003 Apr.,ASCO. NSCLC treatment guideline, 2003,The “4th Generation” Agents,Targeted therapy in early 2000s.,Thorax. 58(4):352-6, 2003 Apr.,Target Validation,The target should be present and functionally abnormal relative to normal tissue.The target should
5、influence tumor biology manifested through differences in pt outcome.Interfering with target function in model systems should alter tumor biology.Interfering with the target in the clinics should alter pt survival or reverse clinical symptoms associated with the cancer under treatment.,Epidermal Gro
6、wth Factor Receptor Inhibition (EGFRI),EGFR expression in human tumours,NSCLC40-80%Prostate40-80%Gastric33-74%Head and neck90-100%Breast14-91%Colorectal25-77%Pancreatic30-50%Ovarian35-70%,InvasionMetastasis Late-stage diseaseChemotherapy resistanceHormonal therapy resistancePoor outcome,Tumours show
7、inghigh EGFR expression,High expressiongenerally associatedwith,Inhibition of the EGFR signaling pathway,Metastasis,Proliferation / maturation,Survival / apoptosis,Angiogenesis,MAPK,MEK,Gene transcriptionCell-cycle progression,PI3-K,RAS,RAF,SOS,GRB2,PTEN,AKT,STAT,K,pY,M,G1,S,pY,pY,K,EGFR,G2,HER1,Bas
8、elga 2002,Tyrosine kinase inhibitors (TKIs),Gefitinib (Iressa, 艾瑞莎),Erlotinib (Tarceva，得舒緩),IDEAL 1 & 2: design schema,Randomisation,IRESSA 250 mgonce daily,IRESSA 500 mgonce daily,Received 1 or 2(IDEAL 1)or 2 (IDEAL 2)previouschemotherapyregimens,Continue IRESSA until diseaseprogression or unaccept
9、able toxicity,Primary endpoints,Patients,Response rate (both trials)Safety profile (IDEAL 1)Symptom relief (IDEAL 2),J Clin Oncol 2003; 21: 223746.,JAMA 2003; 290: 214958.,IDEAL 1: tumour response rate,IRESSA250 mg/day,IRESSA500 mg/day,18.4,19.0,Patients with CR or PR (%),CR, complete response; PR,
10、partial response,IDEAL 1: disease control rate,Patients with CR, PR or SD (%),54.4,51.4,CR, complete response; PR, partial response; SD, stable disease,IRESSA250 mg/day,IRESSA500 mg/day,IDEAL 1: tumour response rate,Patients with CR or PR (%),Japanese (n=102),Non-Japanese (n=106),IRESSA 250 mg/day,I
11、RESSA 500 mg/day,27.5,9.6,11.1,27.5,IDEAL 2: tumour response rate,IRESSA250 mg/day,IRESSA500 mg/day,11.8,8.8,Patients with CR or PR (%),CR, complete response; PR, partial response,IDEAL 2: disease control rate,Patients with CR, PR or SD (%),42.2,36.0,IRESSA250 mg/day,IRESSA500 mg/day,CR, complete re
12、sponse; PR, partial response; SD, stable disease,Time to improvement (days),% patients,IDEAL 1: Time to Symptom improvement,(n=54),69,15,4,6,7,Baselga J et al 2001,Median = 8 days,IDEAL2:Time to Symptom Improvement,0,10,20,30,40,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,Median = 2 weeks,Percent,T
13、ime to Improvement (Weeks),Prognostic Factors Associated with an Objective Response,Adenocarcinoma non-AdenoFemale maleJapanese non-JapaneseBACNon-smoker,J Clin Oncol 21:2237-2246, 2003,J Clin Oncol 22:1103-1109, 2004,IDEAL 1: drug-related toxicities by dose,RashDiarrhoea PruritusDry skin Acne Nause
14、a ALT increasedAST increased,Grade 1263225241011109,IRESSA 250 mg/day,IRESSA 500 mg/day,Grade 3/410000120,Grade 1303432225161314,Grade 3/477102163,Values are % patientsALT, alanine aminotransferase; AST, aspartate aminotransferase,Grade 2198533112,Grade 23317388756,IDEAL 2: drug-related toxicities b
15、y dose,RashDiarrhoea Dry skin AcneVomiting Nausea,Grade 13941121997,IRESSA 250 mg/day,IRESSA 500 mg/day,Grade 3/4010011,Grade 136452418511,Grade 3/4350431,Values are % patients,Grade 2461625,Grade 2151731116,Pre-treatment,Post-treatment, 10 days,Accelerated approval regulations,FDA allow pharmaceuti
16、cal manufacturers to offer pts treatment for life-threatening diseases. This may occur when early evidence suggests that the agent is likely to improve survival or reduce symptoms, before confirmatory studies are safe and efficacious.Iressa was marketed in May, 2003 in U.S.A.AZ need another phase II
17、I trial.,Acute Interstitial Pneumonitis,Iressa was approved in Japan in July, 2002.From August to December, 19000 pts received iressa (1) 358 (1.9%) pts developed interstitial lung disease (ILD). (2) 114 (0.6%) had died.Epidemiological survey in Japan (1) 4.6% patients had developed ILD. (2) 1.5% ha
18、d died due to ILD by iressa.,WJTOG report,J Chin Med Assoc April 2005 Vol 68 No 4,Iressa-related AIP in Taiwan,Response rate for gefitinib in chemotherapy treated pts with advanced NSCLC was 22.7%.12 of 428 pts (2.8%) had AIP with gefitinib treatment.4 of 12 pts (0.9%) died.,Journal of Thoracic Onco
19、logy Volume 1, Number 6, July 2006,Iressa combined with chemotherapy,Iressa NSCLC Trial Assessing Combination Treatment 1and 2 (INTACT 1,2), chemonaive ptsINTACT1 : Gemcitabine + Cisplatin + IressaINTACT2 : Taxol + Carboplatin + IressaFailure to prolong survival and response rate.,J Clin Oncol 2004;
20、 22: 777-84.,J Clin Oncol 2004; 22: 785-94,End pointsPrimary:SurvivalSecondary:TTFORRQoL, symptomsSafetyExploratory:Tumour biomarker analysis (eg EGFR),Iressa Survival Evaluation in Lung Cancer, ISEL,1692 patients in 210 centres across 28 countries,Gefitinib (250mg/day) + BSC,Placebo + BSC,Randomisa
21、tion(2:1 ratio),CT, chemotherapy; BSC, best supportive care; TTF, time to treatment failure; ORR, objective response rate; QoL, quality of life,Patients with: Histologically / cytologically confirmed NSCLCLocally advanced or metastatic disease1 or 2 prior CT regimensIntolerant to most recent CT regi
22、men or progression 90 days of last CT cycle,Lancet. 2005; 366(9496): 1527-37.,Survival,HR and 95% CI,0.4,0.6,0.8,1.0,1.5,Adenocarcinoma,Gefitinib ORR,Subgroup analysis,Favours gefitinib,Favours placebo,Lancet. 2005; 366(9496): 1527-37.,Survival,Subgroup analysis,11.1%,8.0%,12.4%,7.4%,6.9%,9.0%,6.8%,
23、7.5%,10.1%,7.7%,6.4%,7.2%,10.2%,Gefitinib ORR,Favours gefitinib,Favours placebo,0.4,0.6,0.8,1.0,1.5,HR and 95% CI,Lancet. 2005; 366(9496): 1527-37.,Marketing Authorization Application Withdrawn in Europe,AZ收回歐洲市場的上市申請,Erlotinib in Previously Treated Non-small-cell Lung Cancer, BR 21,N Engl J Med 200
24、5; 353: 12332.,Tarceva combined with Chemotherapy,Chemonaive NSCLC (1) Tarceva + taxol + carboplatin (2) Tarceva + cisplatin + gemcitabineFailure to prolong survival.EGFR-TKI fail to be combined with conventional chemotherapy.,J Clin Oncol 2005; 23: 589299.,J Clin Oncol 2007; 25(12): 1545-52.,Who co
25、rrelated with EGFR-TKI response,EGFR is overexpressed in 40%-80% NSCLC. EGFR expression doesnt correlated with EGFR-TKI response.Adenocarcinoma squamous cell carcinoma.,EGFR Mutation,Conformational EGFR change, sensitive to EGF-TKI.Asian, never-smoker, female, adenocarcinoma have high EGFR mutation
26、rate.,Science 2004; 304: 1497-500,N Engl J Med 2004; 350: 2129-39,EGFR Mutation,Exon 19 deletion : 46%Exon 21 missense mutation : 41%.Exon 20 duplication/insertion : 5%Asian(34%) non-Asian(8%)Female(46%) male(18%)Never-smoker(56%) smoker(13%)Adenocarcinoma(39%) other NSCLC(2%),Signal 2005; 6: 4-8.,健
27、保局適應症,Gefitinib:(96/8/1) 限單獨使用於先前已使用過platinum類及docetaxel或paclitaxel化學治療後，但仍局部惡化或轉移之腺性非小細胞肺癌之第三線用藥。Erlotinib（96/8/1） 限單獨使用於先前已使用過platinum類及docetaxel或paclitaxel化學治療後，但仍局部惡化或轉移之非小細胞肺癌之第三線用藥。,EGFR Monoclonal Antibody,Cetuximab, Erbitux,Cetuximab,Human-murine chimeric monoclonal antibody.In experimental
28、studies, cetuximab combined with C/T or R/T has additive or synergistic effect.Proven effect in colorectal, head and neck cancer.,Expert Opin Pharmacother 2004;5:162133,Cetuximab,400 mg/m2 at first week, 250 mg/m2 weekly, 4 weeks as 1 cycle.Side effects include skin toxicity (21%), fever (13.5%), as
29、thenia (13.5%), transaminase elevation (11.5%) and nausea (11.5%),J Clin Oncol 2000;18:90414.,Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated pts with stage IV NSCLC.,The combination of cetuximab, paclitaxel, and carboplatin was safe and well tolerated stage IV
30、 pts. The response rate, time to progression, and median survival were slightly superior to historical controls treated with paclitaxel and carboplatin alone.,J Clin Oncol. 2005; 23(34):8786-93.,Phase II Trial of Cetuximab in Patients With PreviouslyTreated NonSmall-Cell Lung Cancer,The response rat
31、e with single-agent cetuximab in advanced NSCLC pts receiving at least one C/T was 4.5%. The disease control rates and overall survival seem comparable to that of pemetrexed, docetaxel, and erlotinib in similar groups of pts.,J Clin Oncol. 2006; 24(33): 5253-58.,Vascular Endothelial Growth Factor (V
32、EGF) Monoclonal Antibody,Bevacizumab, Avastin,Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.,Tumors absorb nutrients and oxygen by simple diffusion up to a size of 1-2 mm.Their further growth requires the elaboration of a vascular supply.,Carcinogenesis 200
33、0;21:505-515.,Phase II Trial Comparing BevacizumabPlus Carboplatin and Paclitaxel With Carboplatin andPaclitaxel Alone in Previously Untreated LocallyAdvanced or Metastatic NonSmall-Cell Lung Cancer,J Clin Oncol 2004; 22(11): 2184-91.,3 arms (1) bevacizumab 7.5 mg/kg + carboplatin (AUC=6) + paclitax
34、el (200 mg/m2). (2) bevacizumab 15 mg/kg + carboplatin + paclitaxel. (3) carboplatin +paclitaxel alone.bevacizumab (15 mg/kg) resulted in (1) higher response rate (31.5% v 18.8%). (2) longer median time to progression (7.4 v 4.2 months). (3) modest increase in survival (17.7 v 14.9 months).,J Clin O
35、ncol 2004; 22(11): 2184-91.,Bleeding side effect,Minor mucosal bleeding (eg, epistaxis), pulmonary hemorrhage.6/66 (9.1%) life-threatening pulmonary hemorrhages in pts receiving bevacizumab.4 (6%) pts died.Never noted in previous colorectal, breast, and renal cell carcinoma.,J Clin Oncol 2004; 22(11
36、): 2184-91.,Pulmonary Hemorrhage,High risk groups include : (1) centrally located tumors, (2) tumors closely adjacent to major blood vessels, (3) the presence of tumor cavitation, (4) squamous cell carcinoma.,J Clin Oncol 2004; 22(11): 2184-91.,PaclitaxelCarboplatin Alone or withBevacizumab for NonS
37、mall-Cell Lung Cancer,N Engl J Med 2006; 355: 2542-50.,ECOG conducted a randomized study in which 878 pts with recurrent or advanced chemonaive NSCLC (stage IIIB or IV) (1) paclitaxel and carboplatin alone (444) (2) paclitaxel and carboplatin plus bevacizumab (15 mg/kg) (434).Chemotherapy was admini
38、stered every 3 weeks for six cycles.,N Engl J Med 2006; 355: 2542-50.,Exclusion Criteria,Squamous-cell tumors, Brain metastases,Clinically significant hemoptysis, Inadequate organ function,ECOG performance status 1,Coagulopathy,Medically uncontrolled hypertension.,N Engl J Med 2006; 355: 2542-50.,Re
39、sult,The median survival was 12.3 months vs.10.3 months (BPC vs. PC) (P = 0.003).The median progression-free survival was 6.2 v.s. 4.5 months (BPC vs. PC) (P0.001).Response rates of 35% v.s. 15% (P0.001).Rates of clinically significant bleeding were 4.4% and 0.7%, (P0.001).,N Engl J Med 2006; 355: 2
40、542-50.,Treatment-related Death,Two deaths (gastrointestinal hemorrhage and febrile neutropenia) occurred in PC group.15 occurred in BPC group (1) 5 were attributed to pulmonary hemorrhage, (2) 5 to complications of febrile neutropenia, (3) 2 each to a cerebrovascular event or GI hemorrhage, (4) 1 t
41、o probable pulmonary embolus.Most of the deaths occurred during the first two cycles of therapy.,N Engl J Med 2006; 355: 2542-50.,適應症,美國食品藥物管理局目前核准它使用在晚期已轉移的大腸直腸癌病人的第一線療法、非鱗狀細胞的非小細胞癌與化療合併使用。台灣目前只核准使用在晚期已轉移的大腸直腸癌病人，健保仍未給付。晚期非小細胞肺癌的病人未納入使用範圍。,Future Direction,New targets for intervention.Better patient selection, less side effect.Combined C/T or R/T.Multi-targeted agents.,The End,
