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1、ALK陽(yáng)性晚期NSCLC治療進(jìn)展,NP-ALE-2017.10-004 Valid Until 2019.10,ALK陽(yáng)性晚期NSCLC治療進(jìn)展,ALK 陽(yáng)性NSCLC治療現(xiàn)狀A(yù)LK 陽(yáng)性NSCLC一線治療的突破ALK 陽(yáng)性患者整體治療策略,2016ALK+可見(jiàn)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(fā)展簡(jiǎn)史,2011Crizotinib, the first ALK inhibitor, approved,2014 (Jul)Alectinib approved in Japan,2013 (Jun)FDA granted Alectinib BTD

2、 for ALK+ NSCLC patients who have progressed on crizotinib,2007Japanese researchers identified ALK oncogene in NSCLC patients,2015 (Dec)Alectinib FDA approval for ALK-positive NSCLC progressing on/or intolerant to crizitinib,2016 (Sep)FDA granted Alecensa 2nd BTD for 1L ALK+ NSCLC,2017(Feb)Alectinib

3、 approved in EU,2017 (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.

4、 CA Cancer J Clin 2015; 8. Perez, et al. Lung Cancer; 9/Lancet. 2016 ;388(10048):1012-24.,2017 (May)Ceritinib FDA 1L approval,2014 (Apr)Certinib FDA approved for ALK-positive, crizotinib resistant NSCLC,ALK-TKIs,Crizotinib,Alectinib,Certinib,ALK基因重排,目前指南推薦的ALK抑制劑（NCCN，2017V9）,首個(gè)在頭對(duì)頭III期研究中證實(shí)優(yōu)于另一種TKI

5、藥物的靶向治療藥物,細(xì)胞信號(hào)激酶,ALK 陽(yáng)性NSCLC治療現(xiàn)狀Crizotinib,首個(gè)在國(guó)內(nèi)上市的針對(duì)ALK陽(yáng)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,克唑替尼一線治療后通常在1年內(nèi)出現(xiàn)疾病進(jìn)展（中位PFS 11個(gè)月）且不良事件發(fā)生率高,ALK 陽(yáng)性NSCLC治療現(xiàn)狀Ceritinib,1. Solomon et al., NEJM 2014;

6、371:216777; 2. Lu, et al. ASCO 2016; 3. Soria JC, et al. Lancet 2017;,Ceritinib,對(duì)比化療，而非克唑替尼,安全性差于化療的靶向藥物,ALK 陽(yáng)性NSCLC治療現(xiàn)狀腦轉(zhuǎn)移,1. Costa, et al. Clin Oncol 2011；2. Guerin, et al. J Med Econ 2015; 3. Johung, et al. J Clin Oncol 2015,ALK+ NSCLC患者診斷時(shí)大約30%具有CNS轉(zhuǎn)移超過(guò)40克唑替尼/Ceritinib治療患者以腦轉(zhuǎn)移作為首個(gè)進(jìn)展部位 46%接受克唑替尼治

7、療的患者1 42%接受Ceritinib治療的患者2,腦轉(zhuǎn)移嚴(yán)重影響患者生存及生活質(zhì)量,腦轉(zhuǎn)移患者預(yù)后更差,腦轉(zhuǎn)移患者癥狀加重,ALK陽(yáng)性晚期NSCLC治療進(jìn)展,ALK 陽(yáng)性NSCLC治療現(xiàn)狀A(yù)LK 陽(yáng)性NSCLC一線治療的突破ALK 陽(yáng)性患者整體治療策略,Alectinib in ALK+ NSCLC,CNS ORR 64% (95% CI (49.277.1)CNS mDOR 10.8 months (95% CI (7.614.1),1. Ou et al., JCO 2016;34:6618; 2. Shaw et al., Lancet Oncol 2016;17:23442; 3.

8、 Yang et al., WCLC 2016; 6. Gadgeel et al., JCO 2016;34:407985,Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008,Alectinib vs crizotinib：J-ALEX,首個(gè)頭對(duì)頭比較Alectinib與Crizotinib一線治療晚期ALK陽(yáng)性NSCLC的III期臨床研究,首要終點(diǎn)：獨(dú)立評(píng)審（IRF）評(píng)估的PFS次要終點(diǎn)：OS、ORR、DOR、至緩解時(shí)間、CNS PFS、HRQOL、安全性、PK,J-ALEX：Alectinib顯著延長(zhǎng)PFS,主要終點(diǎn)：IRF評(píng)估的PFS,1

9、5.7mo,進(jìn)展風(fēng)險(xiǎn)62%,Y. Takiguchi, et al. ASCO 2017 Abstract No. 9064.,IRF, 獨(dú)立評(píng)審委員會(huì),J-ALEX：Alectinib具有更好的安全性,Nokihara, et al. ASCO 2016,Alectinib vs Crizotinib：ALEX,關(guān)鍵入選標(biāo)準(zhǔn)晚期或轉(zhuǎn)移性ALK+ NSCLCALK+ 中心實(shí)驗(yàn)室IHC檢測(cè)初治ECOG PS 02可測(cè)量病灶允許無(wú)癥狀腦轉(zhuǎn)移,Alectinib600 mg BID PO,克唑替尼250 mg BID PO,研究終點(diǎn)主要PFS (RECIST 1.1), 研究者評(píng)估次要PFS （IR

10、C評(píng)估）至CNS進(jìn)展時(shí)間ORR, DOROS安全性和耐受性患者報(bào)告的結(jié)局,隨機(jī),方案不允許交叉,ALK, 間變性淋巴瘤激酶; IHC, 免疫組織化學(xué); NSCLC, 非小細(xì)胞肺癌; ECOG PS, 東部腫瘤協(xié)作組 體能狀態(tài); PO, 口服; PFS, 無(wú)進(jìn)展生存期; IRC, 獨(dú)立評(píng)審委員會(huì); CNS, 中樞神經(jīng)系統(tǒng); ORR, 客觀緩解率; DOR, 緩解時(shí)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(zhuǎn)移 (有 vs 無(wú)),N=286,Alice Shaw, et al. ASCO 2017 Abstract No. LBA90

11、08,ALEX主要終點(diǎn)：研究者評(píng)估的PFSAlectinib PFS獲益顯著,Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008,進(jìn)展風(fēng)險(xiǎn)53%,ALEX次要終點(diǎn)：IRC評(píng)估的PFSAlectinib PFS 顯著提高，超過(guò)25個(gè)月,0,20,40,60,100,1,3,6,9,12,15,18,21,24,27,30,80,無(wú)進(jìn)展生存期 (%),天,128,92,74,57,46,33,12,4,132,112,108,95,83,69,35,15,Alectinib,克唑替尼,151,152,2,克唑替尼,Alectinib,No. at R

12、isk,月,10.4 月,NR,Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008,進(jìn)展風(fēng)險(xiǎn)50%,15.3mo,ALEX PFS亞組分析：各亞組一致獲益,Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008,ALEX次要終點(diǎn)：客觀緩解率與OS,OS尚不成熟：30個(gè)月OS超過(guò)70,Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008,*研究者評(píng)估,AF-001JP：Alectinib長(zhǎng)期隨訪結(jié)果,AF-001JP：Alectinib治療未經(jīng)TKIs治療的A

13、LK+ NSCLC的I/II期研究,*NR: Not reached to median,PFS by IRC,OS,Makoto Nishio, et al. WCLC 2017 Abstract No. OA05.08,Alectinib治療腦轉(zhuǎn)移患者的獨(dú)特優(yōu)勢(shì),克唑替尼是P-gp底物，ceritinib是P-gp和BCRP底物57,與克唑替尼和Ceritinib不同，Alectinib不是P-gp底物，因此具有高的 腦血漿 比14,克唑替尼治療顱內(nèi)失敗主要原因在于其藥代動(dòng)力學(xué),克唑替尼/ceritinib被泵出血腦屏障,克唑替尼和ceritinib的CNS暴露可能不足以控制腦部病灶，CN

14、S可能成為腫瘤生長(zhǎng)的避難場(chǎng)所8,9,1. Kodama, et al. Cancer Chemother Pharmacol 2014 2. Misra, et al. J Pharm Pharmaceut Sci 2003 3. Crizotinib US PI 2015; 4. Ceritinib US PI 2015 5. Tang, et al. Int J Cancer 2014 6. Kort, et al. Pharmacol Res 2015; 7. Katayama, et al. EBioMedicine 2016 8. Dagogo-Jack and Shaw. Ann

15、Oncol 2016; 9. Rusthoven and Doebele. J Clin Oncol 2016,J-ALEX：無(wú)論基線是否伴腦轉(zhuǎn)移，Alectinib均顯著獲益,至腦轉(zhuǎn)移進(jìn)展時(shí)間（IRF評(píng)估）,基線伴有腦轉(zhuǎn)移,基線不伴有腦轉(zhuǎn)移,IRF, 獨(dú)立評(píng)審委員會(huì),基線伴有腦轉(zhuǎn)移,基線不伴有腦轉(zhuǎn)移,PFS（IRF評(píng)估）,Y. Takiguchi, et al. ASCO 2017 Abstract No. 9064.,ALEX：無(wú)論基線是否伴腦轉(zhuǎn)移，Alectinib均顯著改善PFS,ESMO 2017 Abstract No. 1298O,ALEX：Alectinib 有效預(yù)防腦轉(zhuǎn)移發(fā)生

16、,Alectinib用于一線，腦轉(zhuǎn)移作為首個(gè)復(fù)發(fā)部位的比例顯著降低Alectinib顯著降低12個(gè)月累積CNS進(jìn)展發(fā)生率（CIR），無(wú)論基線是否存在腦轉(zhuǎn)移（顱內(nèi)進(jìn)展風(fēng)險(xiǎn)分別降低82及86）對(duì)于基線無(wú)腦轉(zhuǎn)移患者，12個(gè)月CIR僅為4.6,患者在基線時(shí)無(wú)腦轉(zhuǎn)移,患者在基線時(shí)有腦轉(zhuǎn)移,ESMO 2017 Abstract No. 1298O,ALEX: Alectinib安全性優(yōu)于克唑替尼,Alice Shaw, et al. ASCO 2017 Abstract No. LBA9008,AE, 不良事件; ALT, 谷丙轉(zhuǎn)氨酶; AST, 谷草轉(zhuǎn)氨酶,治療組間10的不良事件,不同ALK抑制劑安全性比較,發(fā)生率 (%),便秘,惡心,腹瀉,Alectinib,Alectinib,Alectinib,克唑替尼,克唑替尼,克唑替尼,Ceritinib,Ceritinib,Ceritinib,35,44,19,11,74,69,9,58,60,Alectinib,克唑替尼,Ceritinib,嘔吐,6,73,85,注：以上為一線治療III期研究結(jié)果,Kim, et al. WCLC 2016; Lu