1、ALK陽性晚期NSCLC治療進展NP-ALE-2017.10-004 Valid Until 2019.101.ALK陽性晚期NSCLC治療進展ALK 陽性NSCLC治療現狀ALK 陽性NSCLC一線治療的突破ALK 陽性患者整體治療策略22016ALK+可見于約5%左右的晚期NSCLC病人每年新確診75,000以上例患者ALK通路及藥物發展簡史2011Crizotinib, the first ALK inhibitor, approved2014 (Jul)Alectinib approved in Japan2013 (Jun)FDA granted Alectinib BTD for

2、ALK+ NSCLC patients who have progressed on crizotinib2007Japanese researchers identified ALK oncogene in NSCLC patients2015 (Dec)Alectinib FDA approval for ALK-positive NSCLC progressing on/or intolerant to crizitinib2016 (Sep)FDA granted Alecensa 2nd BTD for 1L ALK+ NSCLC 2017(Feb)Alectinib approve

3、d in EU2017 (Jun)ALEX Data presented at ASCO /NCCN guidelines update 1.Dearden, et al. Ann Oncol 2013; 2. Gridelli, et al. Cancer Treat Rev 2014 3. Hallberg, et al. Nat Rev Cancer 2013; 4. Rikova, et al. Cell 2007 5. Soda, et al. Nature 2007; 6. American Cancer Society 2013 7. Torre, et al. CA Cance

4、r J Clin 2015; 8. Perez, et al. Lung Cancer; 9/Lancet. 2016 ;388(10048):1012-24.2017 (May)Ceritinib FDA 1L approval2014 (Apr)Certinib FDA approved for ALK-positive, crizotinib resistant NSCLCALK-TKIsCrizotinibAlectinibCertinibALK基因重排3目前指南推薦的ALK抑制劑（NCCN，2017V9）ALK抑制劑適應證（FDA）適應證（CFDA）III期研究克唑替尼2011年8月

5、（1線）2013年7月（1線）PROFILE 1014、1029克唑替尼優于化療Ceritinib2014年4月（2線）2017年5月（1線）？ASCEND 4Ceritinib優于化療Alectinib2015年12月（2線）2016年9月突破進展（1線）？ALEX、J-ALEXAlectinib優于克唑替尼首個在頭對頭III期研究中證實優于另一種TKI藥物的靶向治療藥物細胞信號激酶ALKKDRSRCINSREGFR2ABLIGF1RPDFGRMETRONEGFRHER2KITCDK1PKAMEK1PKCRaf-1AKT1PKC1AuroraAJAK1CDK2PKC2ROS1RETIC50

6、(nM)10,0001,000100101CeritinibROS1IGF1RALKKDRSRCINSRFGFR2ABLIGF1RPDFGRMETRONEGFRHER2KITCDK1PKAMEK1PKCRaf-1AKT1PKC1AuroraAJAK1CDK2PKC2ROS1RETIC50 (nM)AKT2AKT310,0001,000100101AlectinibALKKDRSRCINSREGFR2ABLIGF1RPDFGRMETRONEGFRHER2KITCDK1PKAMEK1PKCRaf-1AKT1PKC1AuroraAJAK1CDK2PKC2ROS1RETIC50 (nM)10,0001

7、,000100101METROS1克唑替尼4ALK 陽性NSCLC治療現狀Crizotinib首個在國內上市的針對ALK陽性患者的靶向治療藥物:1. Soda et al., Nature 2007;448:56166; 2. Kwak et al., NEJM 2010;363:16931703; 3. Solomon et al., NEJM 2014;371:216777; ALK, 間變性淋巴瘤激酶 視力異常腹瀉嘔吐便秘轉氨酶升高粒細胞減少71%61%46%43%36%21%PROFILE1014視力異常腹瀉嘔吐轉氨酶升高粒細胞減少56%59%53%69%41%PROFILE1029（

8、東亞）克唑替尼一線治療后通常在1年內出現疾病進展（中位PFS 11個月）且不良事件發生率高5ALK 陽性NSCLC治療現狀Ceritinib1. Solomon et al., NEJM 2014;371:216777; 2. Lu, et al. ASCO 2016; 3. Soria JC, et al. Lancet 2017;CeritinibASCEND-4（一線）Ceritinib化療HRORR72.5%50%0.55mPFS16.6月8.1月對比化療，而非克唑替尼ASCEND-4Ceritinib (N=189)化療(N=175)AEs (所有因果關系相關的), n (%)189

9、 (100.0)170 (97.1)SAEs (all-causality), n (%)70 (37.0)62 (35.4) 腹瀉160 (84.7)10 (5.3)19 (10.9)2 (1.1) 惡心130 (68.8)5 (2.6)97 (55.4)9 (5.1) 嘔吐125 (66.1)10 (5.3)63 (36.0)10 (5.7)AEs導致劑量調整，中斷或延遲（所有因果關系）, n (%) 131 (69.3)69 (39.4)ASCEND-5Ceritinib（N=115）化療（N=116）SAEs（研究藥物相關）, n（%）最常見于2%患者13（11.3）惡心（3.5%）嘔

10、吐（2.6%）12（10.6）無2%AEs導致劑量中斷（所有因果相關）, n（%）最常見于10%患者84（73.0）ALT/AST升高、嘔吐、腹瀉及惡心27（23.9）無10%AEs導致劑量降低（所有因果相關）, n（%）最常見于10%患者42（36.5）無10%24（21.2）無10%安全性差于化療的靶向藥物6ALK 陽性NSCLC治療現狀腦轉移1. Costa, et al. Clin Oncol 2011；2. Guerin, et al. J Med Econ 2015; 3. Johung, et al. J Clin Oncol 2015 1.00.90.80.70.60.50.4

11、0.30.20.10OS率0306090120150180克唑替尼停藥后時間（天）無腦轉移 (n=81)腦轉移(n=38)Log-rank p=0.018腦轉移患者最常見的癥狀患者出現癥狀(%)ALK+ NSCLC患者診斷時大約30%具有CNS轉移超過40克唑替尼/Ceritinib治療患者以腦轉移作為首個進展部位 46%接受克唑替尼治療的患者1 42%接受Ceritinib治療的患者2腦轉移嚴重影響患者生存及生活質量腦轉移患者預后更差腦轉移患者癥狀加重ALK陽性晚期NSCLC治療進展ALK 陽性NSCLC治療現狀ALK 陽性NSCLC一線治療的突破ALK 陽性患者整體治療策略8Alectin

12、ib in ALK+ NSCLCCNS ORR 64% (95% CI (49.277.1)CNS mDOR 10.8 months (95% CI (7.614.1)臨床療效 (克唑替尼耐藥 ALK+ NSCLC)Day 16121824302251711301049179614291Months100806040200生存概率 (%)NP28673和NP28761研究匯總分析 ORR by IRC 51.3% (95% CI: 44.058.6)中位PFS 8.3 月 (95% CI: 7.011.3) No. at Risk70605040302010010304050607080901

13、00最長徑之和, 從基線縮小的最大值(%)20既往CNS放療是 (n=34)否 (n=16)1. Ou et al., JCO 2016;34:6618; 2. Shaw et al., Lancet Oncol 2016;17:23442; 3. Yang et al., WCLC 2016; 6. Gadgeel et al., JCO 2016;34:407985Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008IRC評估ORRRE整體人群*(n=189)接受過化療的患者(n=148)未接受過化療的患者(41)ORR, %(95% CI)5

14、1.3(44.058.6)49.3(41.0-57.7)58.5(42.1-73.7)9Alectinib vs crizotinib：J-ALEX首個頭對頭比較Alectinib與Crizotinib一線治療晚期ALK陽性NSCLC的III期臨床研究首要終點：獨立評審（IRF）評估的PFS次要終點：OS、ORR、DOR、至緩解時間、CNS PFS、HRQOL、安全性、PK關鍵入組標準：20歲IIIB/IV期或復發的ALK+ NSCLCALK中央檢測（IHC和FISH或RT-PCR）ECOG PS 0-2研究者評估的1個可測量病灶允許入組經治或無癥狀的腦轉移1線化療Alectinib 300m

15、g PO BID 每周期28天(N=103)克唑替尼 250mg PO BID 每周期28天(N=104)R 1：110J-ALEX：Alectinib顯著延長PFS主要終點：IRF評估的PFS15.7mo進展風險62%Y. Takiguchi, et al. ASCO 2017 Abstract No. 9064.IRF, 獨立評審委員會11J-ALEX：Alectinib具有更好的安全性不良事件，n (%)所有級別34級Alectinib(n=103)克唑替尼(n=104)Alectinib(n=103)克唑替尼(n=104)惡心11 (10.7)77 (74.0)02 (1.9)腹瀉9(

16、8.7)76 (73.1)02 (1.9)嘔吐6(5.8)60 (57.7)02 (1.9)視物模糊1(1.0)57 (54.8)00味覺異常19 (18.4)54 (51.9)00便秘36 (35.0)46 (44.2)1 (1.0)1 (1.0)ALT升高9(8.7)3 (31.7)1 (1.0)13 (12.5)AST升高11 (10.7)32 (30.8)1 (1.0)5 (4.8)鼻咽炎21 (20.4)24 (23.1)00發熱10 (9.7)21 (20.2)1 (1.0)0食欲下降1(1.0)21 (20.2)1 (1.0)1 (1.0)Nokihara, et al. ASC

17、O 201612Alectinib vs Crizotinib：ALEX關鍵入選標準晚期或轉移性ALK+ NSCLCALK+ 中心實驗室IHC檢測初治ECOG PS 02可測量病灶允許無癥狀腦轉移Alectinib600 mg BID PO 克唑替尼250 mg BID PO研究終點主要PFS (RECIST 1.1), 研究者評估次要PFS （IRC評估）至CNS進展時間ORR, DOROS安全性和耐受性患者報告的結局隨機方案不允許交叉ALK, 間變性淋巴瘤激酶; IHC, 免疫組織化學; NSCLC, 非小細胞肺癌; ECOG PS, 東部腫瘤協作組 體能狀態; PO, 口服; PFS,

18、無進展生存期; IRC, 獨立評審委員會; CNS, 中樞神經系統; ORR, 客觀緩解率; DOR, 緩解時間; OS, 總生存期分層因素: ECOG PS (0/1 vs 2) 種族 (亞裔 vs 非亞裔) 腦轉移 (有 vs 無) N=286Alice Shaw, et al. ASCO 2017 Abstract No. LBA900813ALEX主要終點：研究者評估的PFSAlectinib PFS獲益顯著Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008進展風險53%0204060Alectinib100136912151821242

19、730克唑替尼1511321048465463516515213511310997816735153克唑替尼AlectinibNo. at Risk80無進展生存期 (%)天11.1 月月NR克唑替尼(N=151)Alectinib (N=152)事件數, n (%)102 (68)62 (41)中位PFS, 月(95% CI)11.1 (9.113.1) NR (17.7NR)HR (95% CI)P-值 (log-rank 檢驗)0.47 (0.340.65)P0.000114ALEX次要終點：IRC評估的PFSAlectinib PFS 顯著提高，超過25個月克唑替尼(N=151)Ale

20、ctinib (N=152)事件數(%)92 (61)63 (41)中位PFS, 月(95% CI)10.4 (7.714.6) 25.7 (19.9NR)HR (95% CI)P值 (log-rank 檢驗)0.50 (0.360.70)P0.0001020406010013691215182124273080無進展生存期 (%)天12892745746331241321121089583693515Alectinib克唑替尼1511522克唑替尼AlectinibNo. at Risk月10.4 月NRAlice Shaw, et al. ASCO 2017 Abstract No. LB

21、A9008進展風險50%15.3mo15ALEX PFS亞組分析：各亞組一致獲益Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008亞組整體年齡5050% Alectinib 耐藥突變對lorlatinib有效33Benjamin Solomon , 2016ASCO, abstract 9009克服耐藥：Lorlatinib34克服耐藥：Lorlatinib治療二代ALKi耐藥療效Efficacy in EXP3B (ALK+, Non-Crizotinib TKI CT)EXP3B (n=27)ORR, n/N (%) (95% CI)9/27

22、 (33)(16, 54) IC ORR, n/N (%) (95% CI)5/12 (42)(15, 72)Median DOR, mo(95% CI)NR(4.1, NR)DOR 6 mo, n/n (%)3/9 (33)Median PFS, mo (95% CI)5.5 (2.9, 9.0)12 patients (44%) had brain metastases at baseline.102030405060708090100706010030205040Intracraniala,b706010030205040102030405060708090100Best Change

23、From Baseline (%)Overalla,bOff treatment or PD occurred Complete response Partial response Stable diseaseProgressive disease (PD)Indeterminate Pooled Efficacy in EXP4 (ALK+, 2 ALK TKIs CT) and EXP5 (ALK+, 3 ALK TKIs CT)EXP4+5 (n=111)ORR, n/N (%) (95% CI)43/111 (39)(30, 49) IC ORR, n/N (%) (95% CI)40

24、/83 (48)(37, 59)Median DOR, mo (95% CI)NR(5.5, NR)DOR 6 mo, n/n (%)20/43 (47)Median PFS, mo (95% CI)6.9(5.4, 9.5)83 patients (75%) had brain metastases at baseline.706010030205040102030405060708090100Best Change From Baseline (%)Overalla,bOff treatment or PD occurred Complete response Partial response Stable diseaseProgressive disease (PD)In