晚期NSCLC分子靶向藥物最新進展課件

1、晚期NSCLC分子靶向藥物最新進展NSCLC治療發(fā)展的里程碑Gefitinib approval for EGFR-mutant NSCLCCrizotinib approval for ALK+ NSLCLEML4-ALK translocation discovered in NSCLC Identification of EGFR mutations in patients responsive to gefitinib2007201120042009Nat Rev Clin Oncol 2015;12:511-26 2015肺癌的分子分型和靶向治療的地位ALK: Crizotinib,

2、 Ceritinib, Alectinib, AP26113, PF-06463922EGFR: Gefitinib, Erlotinib, Icotinib, Afatinib, DacomitinibROS1: CrizotinibRET: CabozantinibMET: CrizotinibBRAF: DabrafenibHER2: Dacomitinib, AfatinibKRAS: SelumetinibAdenocarcinomaSquamous cell carcinoma_ CFDA approvalASCO 2014, Education BookLancet Oncol

3、2011;12:175-80WCLC 2015 NSCLC個體化治療新進展Total Presentations of WCLC 2015: 2499NSCLC基因組學研究包括個體間和瘤內異質性ALK/ EGFR TKI一線治療的優(yōu)化TKIs獲得性耐藥的治療策略ALK/ EGFR+ NSCLC腦轉移的治療NSCLC治療新靶點EGFR+ NSCLC基因組學圖譜和TKI耐藥新機制9個EGFR+ NSCLC手術后標本，分成47份；30份EGFR+ NSCLC耐藥后活檢標本，來自25個患者全外顯子測序（正常組織配對）和轉錄組測序突變特征在沒有用過EGFR TKI的手術標本，所有區(qū)域均檢測到EGFR突變

4、，EGFR突變?yōu)楦赏蛔?，均沒有測到T790M突變TKI耐藥后突變負荷增加，突變負荷與年齡，吸煙，及APOBEC蛋白表達相關耐藥突變圖譜TKI耐藥突變呈異質性，多種耐藥相關的突變共存TKI耐藥圖譜表明在原發(fā)性耐藥，在治療開始前即存在多種driver干突變結論未使用過TKI的東亞EGFR+ 患者存在基因組學等級結構EGFR突變是干突變突變負荷低亞克隆的多樣性高TKI耐藥患者突變負荷增加與吸煙及APOBEC突變圖譜類似多種TKI耐藥機制共存如MED12改變可能調節(jié)亞克隆耐藥原發(fā)性耐藥者存在多種driver干突變WCLC 2015 NSCLC個體化治療新進展Total Presentations of

5、 WCLC 2015: 2499NSCLC基因組學研究包括個體間和瘤內異質性ALK/ EGFR TKI一線治療的優(yōu)化TKIs獲得性耐藥的治療策略ALK/ EGFR+ NSCLC腦轉移的治療NSCLC治療新靶點JMIT研究：吉非替尼與培美曲塞聯(lián)合的一線治療吉非替尼與培美曲塞聯(lián)合延長吉非替尼單藥治療的PFS吉非替尼與培美曲塞聯(lián)合一線治療與吉非替尼單藥相比，明顯延長PFS無論是19外顯子缺失還是21外顯子L858R點突變，吉非替尼聯(lián)合培美曲塞均有PFS的獲益WCLC 2015 NSCLC個體化治療新進展Total Presentations of WCLC 2015: 2499NSCLC基因組學研究

6、包括個體間和瘤內異質性ALK/ EGFR TKI一線治療的優(yōu)化TKIs獲得性耐藥的治療策略ALK/ EGFR+ NSCLC腦轉移的治療NSCLC治療新靶點三代ALK/ROS1 TKI：lorlatinib (PF-06463922)在晚期ALK/ROS1 NSCLC中的療效和安全性ORRLorlatinib對ALK G1202R突變的療效 顱內病灶的療效Lorlatinib在ALK+和ROS1+ NSCLC中顯示出了抗腫瘤活性，尤其是這些患者大部分具有腦轉移及經過1 TKI治療顯著的腦轉移的抗腫瘤活性表明lorlatinib能夠透過血腦屏障，達到 有效的抗腫瘤活性PF-06463922 Is

7、Active Against All Known ALK and ROS1 Resistance Mutations1,* Based on results in BaF3 cell line 1. Zou HY, et al. AACR-NCI 2013, poster A277IMPRESS亞組分析T790M亞組分析T790M亞組PFST790M (-)T790M (+)T790M亞組OS41% maturity, HR (95%CI)=2.16 (1.26, 3.82); P=0.006723% maturity, HR (95%CI)=0.83 (0.36, 1.85); P=0.66

8、44T790M (+)T790M (-)RECIST標準進展時，對于T790M突變陽性的患者，吉非替尼不應該與二線化療聯(lián)合使用RECIST標準進展時，對于T790M突變陰性的患者，吉非替尼繼續(xù)使用，聯(lián)合化療的獲益需要進一步驗證WCLC 2015 NSCLC個體化治療新進展Total Presentations of WCLC 2015: 2499NSCLC基因組學研究包括個體間和瘤內異質性ALK/ EGFR TKI一線治療的優(yōu)化TKIs獲得性耐藥的治療策略ALK/ EGFR+ NSCLC腦轉移的治療NSCLC治療新靶點PROFILE 1014腦轉移亞組分析：克唑替尼一線治療與化療比較的顱內療效

9、分析Key entry criteriaALK-positive by central FISH testingaLocally advanced, recurrent, or metastatic non-squamous NSCLCNo prior systemic treatment for advanced diseaseECOG PS 02Measurable diseaseStableb treated brain metastases allowedEndpointsPrimaryPFS (RECIST 1.1, independent radiologic review IRR

10、)SecondaryORROSIntracranial TTPeSafety Patient-reported outcomesCrossover to crizotinib permitted after progressiond N=343RANDOMIZEcCrizotinib 250 mg BID PO, continuous dosing (n=172)Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 56 q3w for 6 cycles (n=171)Intracranial efficacy was pro

11、spectively evaluated in the ITT population and patients with and without brain metastases at baselineeAbstract 1238Baseline Characteristics of Patients With/without Brain Metastases at BaselineaCarc., carcinoma; aby IRR; bpreviously treated per protocol, although this criterion was not fulfilled in

12、all cases cAt screening; data for 1 patient missing for crizotinibBrain metastasesb presentBrain metastases absentCharacteristicCrizotinib (n=39) Chemo(n=40)Crizotinib (n=132) Chemo (n=131)Age, yearsMedian (range)48 (2970)51 (2576)53 (2276)56 (1978)Sex, n (%)Male20 (51)9 (23)47 (36)54 (41)Race, n (%

13、)CaucasianAsianOther20 (51)17 (44)2 (5)19 (48)18 (45)3 (8)70 (53)60 (45)2 (2)66 (50)62 (47)3 (2)Smoking, n (%)Never smokedEx-smokerCurrent smoker23 (59)13 (33)3 (8)28 (70)12 (30)083 (63)43 (33)6 (5)84 (64)42 (32)5 (4)Histology, n (%)Adenocarc.Large cell carc.Adenosquamous carc.Other35 (90)1 (3)2 (5)

14、1 (3)38 (95)01 (3)1 (3)123 (93)2 (2)3 (2)4 (3)121 (92)8 (6)02 (2)ECOG PS,c n (%)0/1235 (90)4 (10)34 (85)6 (15)125 (95)6 (5)129 (98)2 (2)Time since first diagnosis, moMedian (range)2.4(036.0)2.4(1.274.4)1.2 (0114.0)1.2(093.6)Antitumor Activity PFS and ORRaaBy IRRbAt baselinecTwo-sided log-rank test (

15、ITT population: stratified; patient subgroups with/without baseline brain metastases: unstratified)dCrizotinib vs. chemotherapyeTwo-sided Pearson 2 testITT populationBrain metastases presentbBrain metastases absentbCrizotinib (N=172)Chemo (N=171)Crizotinib (n=39)Chemo (n=40)Crizotinib (n=132)Chemo (

16、n=131)Median PFS, mo (95% CI)10.9(8.313.9)7.0(6.88.2)9.0(6.815.0)4.0(1.56.8)11.1(8.314.0)7.2(6.98.3)HR (95% CI)0.45(0.350.60)0.40(0.230.69)0.51(0.380.69)Pc0.0010.0010.001ORR, % (95% exact CI)74(6781)45(3753)77(6189)28(1544)74(6682)50(4259)Differenced (95% exact CI)29(2039)49(3069)24(1335)Pe0.0010.00

17、10.001Intracranial DCRa in Patients With Brain Metastases at BaselineDCR, disease control rate (% CR + PR + SD)aBy IRR; btwo-sided Pearson 2 test12 weeks24 weeksIntracranial DCR (95% exact CI; %)Difference: 40% (95% CI: 2159) P0.001bDifference: 31% (95% CI: 1152) P=0.006b100806040200Intracranial TTP

18、a in ITT PopulationCrizotinib (n=172)Chemotherapy (n=171)Events, n (%)25 (15)26 (15)Median, moNR17.8HR (95% CI)0.60 (0.341.05)Pb0.069NR, not reachedaTime from randomization to first documentation of intracranial tumor progression by IRR bTwo-sided log-rank testProbability of no progression (%)100806

19、040200051015202530351721711191076539401421 3811000CrizotinibChemotherapy No. at riskTime (months)Intracranial TTPa in Patients With/without Brain Metastases at BaselineBrain metastases presentBrain metastases absentCriz(n=39)Chemo(n=40)Events, n (%)9 (23)12 (30)Median, mo15.712.5HR (95% CI)0.45 (0.1

20、91.07)Pb0.063NR, not reachedaTime from randomization to first documentation of intracranial tumor progression by IRR bTwo-sided log-rank testProbability of no progression (%)10080604020005101525353940CrizotinibChemotherapy No. at riskTime (months)26159773103020100000Probability of no progression (%)

21、0132131CrizotinibChemotherapy No. at riskTime (months)93925632331120 37110001008060402005101525302035Criz(n=132)Chemo (n=131)Events, n (%)16 (12)14 (11)Median, moNRNRHR (95% CI)0.69 (0.331.45)Pb0.323Duration of Treatment Before/After Intracranial PD in Patients Randomized to CrizotinibTreatment dura

22、tion (weeks)070 80 90100100908070605040302010605040302010*BM at baselineNo BM at baselineRadiotherapy after intracranial PDOn treatment at data cutoffHad intracranial PD in existing lesion*Duration of treatment beyond intracranial PD:a median 20.4 weeks (range: 3.384.4) aAmong the 22 patients receiv

23、ing crizotinib for 3 weeks beyond intracranial PD 結論無論有無腦轉移，對于ALK陽性NSCLC，克唑替尼一線治療優(yōu)于標準化療。-克唑替尼12周和24周DCR優(yōu)于化療-克唑替尼在顱內TTP方面，顯示出數(shù)值上的優(yōu)勢 克唑替尼是ALK陽性NSCLC的標準治療，包括腦轉移患者WCLC 2015 NSCLC個體化治療新進展Total Presentations of WCLC 2015: 2499NSCLC基因組學研究包括個體間和瘤內異質性ALK/ EGFR TKI一線治療的優(yōu)化TKIs獲得性耐藥的治療策略ALK/ EGFR+ NSCLC腦轉移的治療NSCLC治療新靶點MET 14外顯子跳躍剪接突變發(fā)生率和患者的臨床特征201