1、肺癌免疫治疗进展,Future Outlook,Update of checkpoint Inhibitors in lung cancer therapy,Cancer Immunotherapy,1,2,3,Outline,Future Outlook,Update of checkpoint Inhibitors in lung cancer therapy,Cancer Immunotherapy,1,2,3,Outline,肿瘤免疫治疗攻克肿瘤的新希望,人类抗击肿瘤的历史肿瘤免疫治疗具有特异性和靶向性，一直为临床医师高度关注，近年进 步显著，使得免疫治疗成为更具期待的领域,靶向治疗,
2、进入21世纪，分子靶向 治疗如火如荼,e,Key events in the history of cancer immunotherapy,1890s 1st CA vaccine developed (coley),1973 discovery of the dendritic cell(steinman),1976 1st study with BCG in bladder CA,1978 Discovery of tumor specific mABs,1985 1st study with adoptive T-ce ll transfer in CA,1986 IFN(cytoki
3、ne) approved for CA,1990s Discovery of role of checkpoints in CA,1992 Il-2(Cytokine) approved for CA,1997 1st mAB approved for CA,2010 1st cellular immunotherapy approved for CA,2011 1st checkpoint inhibitor approved for CA,2014 2nd checkpoint inhibitor approved for CA,Enthusiasm phase 1976-1985,Ske
4、pticism phase 1986-1992,Renaissance phase 1997-,美国Science杂志:2013年六大值得关注的科学领域 单细胞测序 “普朗克”探测微波背景辐射 人类连接组计划 探索南极冰下世界 癌症免疫疗法 基础植物研究,Breakthrough of year 2013,Science. 2013 Dec 20;342(6165):1432-3,Immunity. 39(1)25 July 2013, Pages 110,Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle,CTLA-
5、4 and PD-1/PD-L1 checkpoint blockade for cancer treatment,CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment,Immune checkpoint blockade includes agents targeting the negative regulators CTLA-4 and PD-1CTLA-4 attenuates the early activation of naive and memory T cells in the lymph nodesAg
6、ents targeting CTLA-4 include ipilimumab and tremelimumabIn contrast, PD-1 modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2Agents targeting PD-1 include nivolumab and MK-3475Agents targeting PD-L1 include MPDL3280A and MEDI4736,Kyi C, et al.
7、FEBS Lett. 2014;588:368-376,Comparing CTLA-4 and PD-1,Crit Rev Oncol Hematol. 2014;89:140-165.,CTLA-4 and PD-1 have separate but complimentary roles in immune responses,Future Outlook,Update of checkpoint Inhibitors in lung cancer therapy,Cancer Immunotherapy,1,2,3,Outline,CTLA-4 Checkpoint Inhibito
8、r,Anti-CTLA-4 antibodies can induce clinical response in a broad variety of cancer,Adapted form Lebbe et al. ESMO 2008,Presented By Lawrence Fong at 2014 ASCO Annual Meeting,Bladder RenalEsophagealCNSColorectalGlioblastomaLeukemia Soft Tissue Sarcoma,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Ann Onco
9、l. 2013 Jan;24(1):75-83,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Ipilimumab in combination with PC as first-line therapy in stage IIIB/IV NSCLC,KaplanMeier plots for OS,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Deaths/patients 51/66 51/68 Median (95% CI), months 8.28 (6.80 to 12.39) 12.22 (9.26 to 14
10、.39) HR (95% CI) 0.87 (0.59 to 1.28) Log-rank P 0 .23,Control,Phased Ipi,Deaths/patients 51/66 51/70 Median (95% CI), months 8.28 (6.80 to 12.39) 9.69 (7.59 to 12.48) HR (95% CI) 0.99 (0.67 to 1.46) Log-rank P 0.48,Concurrent lpi,Control,Events/patients 61/66 58/70 Median (95% CI), mo 4.21(2.76 to 5
11、.32) 4.11 (2.76 to 5.32) HR (95% CI) 0.88 (0.61 to 1.27) Log-rank P .25,J Clin Oncol. 2012 Jun 10;30(17):2046-54,KaplanMeier plots for PFS per immune-related (ir) response criteria (irPFS) and modified WHO criteria (mWHO-PFS).,Events/patients 56/66 54/68 Median (95% CI), 4.63m(4.14 to 5.52) 5.68 (4.
12、76 to 7.79) HR (95% CI) 0.72 (0.50 to 1.06)Log-rank P .05,Control,Phased Ipi,Events/patients 56/66 55/70 Median (95% CI), 4.63m (4.14 to 5.52) 5.52 (4.17 to 6.74) HR (95% CI) 0.81 (0.55 to 1.17) Log-rank P .13,Control,Concurrent lpi,Events/patients 61/66 56/68 Median (95% CI),mo 4.21 (2.76 to 5.32)
13、5.13 (4.17 to 5.72) HR (95% CI) 0.69 (0.48 to 1.00)Log-rank P .02,Control,Phased Ipi,Control,Concurrent lpi,Adverse Events,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Follow-UP Every 12 wks For survival,SCREENING,INDUCTION,MAINTENANCE,FOLLOW-UP,CA184-104: phase III trial comparing the the efficacy of i
14、pilimumab (Ipi) with PC versusplacebo with PC in patients (pts) with stage IV/recurrent NSCLC of squamous histology,Tumor assessment Every 12 wks,J Clin Oncol 31, 2013 (suppl; abstr TPS8117),primary endpointOS secondary endpointsOS among pts who receive blinded therapy PFSbest overall response rate,
15、Tumor assessment Wks 7, 13, 19, 25,Exclusion Criteria: Brain Metastases Autoimmune diseases,PC Paclitaxel (175 mg/m2 , IV) +Carboplatin (AUC=6, IV),CA184-156: Phase III Trial Comparing the Efficacy of Ipi Plus Etoposide/Platinum Versus Etoposide/Platinum in Subjects With Newly Diagnosed ED-SCLC,J Cl
16、in Oncol 30, 2012 (suppl; abstr TPS7113),primary endpoint OS secondary endpointsOS among pts who receive blinded therapy immune-related and mWHO PFSbest overall response rateduration of response,Exclusion Criteria: Prior systemic therapy for lung cancer Symptomatic CNS metastases History of autoimmu
17、ne disease,Ipi Q3W 2 cycle,EP： etoposide (100 mg/m2, IV on Days 1-3 Q3W) +cisplatin (75 mg/m2, IV) or +carboplatin (AUC=5, IV) once Q3W Ipi: (10 mg/kg, IV, Q3W),Placebo Q3W 2cycle,A Phase III Study of Nivolumab in Combination with Yervoy in Patients with Advanced Non-Small Cell Lung Cancer,PD-1/PD-L
18、1 Checkpoint Inhibitors,PD-1 and PD-L1 antibodies in phase III development,Phase1 Nivolumab (anti-PD-1; BMS-936558, ONO-4538) multidose regimen,Eligibility:advcanced melanoma,NSCLC,RCC,CRC, or CRPC with PD after1-5 systemic therapies,Select Aes(1%) occuring in Pts with NSCLC treated with Nivolumab(N
19、=129),Drug-related pneumonitis(any grade) occurred in 8 NSCLC Pts(6%) VS 12 Pts(4%) in the overall study population -3Pts (2%) with NSCLC had grade pneumonitis,Efficacy of Nivolumab monotherapy in Pts treated with NSCLC,Nivolumab in combination with PT-DC in advanced NSCLC,Antonia SJ, et al. 2014 AS
20、CO Abstract 8113.,Results and Conclusions,治疗的前6周没有发生剂量限制毒性 3-4级治疗相关不良事件发生率为45% ORR：33-50% 1年OS：59-87%,Antonia SJ, et al. 2014 ASCO Abstract 8113.,Antonia SJ, et al. 2014 ASCO Abstract 8113.,Ongoing Nivolumab Clinical Trials in Patients With NSCLC,ClinicalTrials.gov. NCT02041533. 2. ClinicalTrials.go
21、v. NCT01642004. 3. ClinicalTrials.gov. NCT01673867. 4. ClinicalTrials.gov. NCT01721759. 5. ClinicalTrials.gov. NCT01968109. 6. ClinicalTrials.gov. NCT01714739. 7. ClinicalTrials.gov. NCT01454102.,Parts C to F: Additional MEL and NSCLC cohorts,MK3475(Pembrolizumab , Anti-PD-1): Phase I Trial Design,I
22、PI-N 10 q2w (n = 41),IPI-N 10 q3w (n = 24),Part A: Dose Escalation,IPI-N 2 q3w (n = 22),IPI-T 10 q2w (n = 16),IPI-T 10 q3w (n = 32),Part B: Metastatic or locally advanced, unresectable MEL,Ribas A et al. ASCO 2013. Abstract 9009.,KEYNOTE-001： NSCLC扩大队列研究设计 (N=307),*前11例患者随机分入2mg/kg q3w和10mg/kg q3w组，
23、剩余34例患者随机接受10mg/kg q2w和10mg/kg q3w组 *非随机队列的45例接受2mg/kg q3w的患者分析截止日期为2014年9月11日 数据截止日期：2014年3月3日 Garon EB, et al. 2014 ESMO Abstract LBA43.,主要终点：ORR (RECIST v1.1独立中心评估) 次要终点：免疫相关疗效标准(irRC)研究者评估 Pembrolizumab (MK3475) 治疗持续直至PD，不可接受的毒性或死亡,KEYNOTE-001：基线特征,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYN
24、OTE-001： 治疗暴露与治疗相关不良事件汇总,4例患者(1.5%)发生输注相关反应 发生率1%的其他潜在免疫调节不良事件为结肠炎和低钠血症,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001： 肿瘤大小自基线最大变化*(%) (RECIST v1.1，中心评估),*可评估患者为根据中心评估基线有可测量病灶且至少接受一次基线后肿瘤评估 Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：抗肿瘤活性 (RECIST v1.1，中心评估),a包括确认和未确认缓解；b数据截止日期为2
25、014年3月3日 Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001： 抗肿瘤活性 (irRC，研究者评估),a包括确认和未确认缓解；b数据截止日期为2014年9月11日 Garon EB, et al. 2014 ESMO Abstract LBA43.,额外45例接受2mg/kg q3w治疗的患者中，ORRa为20%(95%CI:10%-35%)b,KEYNOTE-001： 至缓解时间 & 缓解持续时间,a包括确认和未确认缓解 Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-00
26、1： 生存期评估：初治 vs. 复治,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001： 生存期评估：不同剂量,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001： PD-L1表达水平与缓解率,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001： 生存期评估：PD-L1表达,PD-L1强阳性：=50%的肿瘤细胞 PD-L1弱阳性：1-49%的肿瘤细胞 染色阴性为PD-L1无表达 Garon EB, et al. 2014
27、 ESMO Abstract LBA43.,PD-L1强阳性患者较弱阳性/阴性患者的PFS更长(HR=0.52; 95%CI:0.33-0.80) PD-L1强阳性患者较弱阳性/阴性患者的OS更长(HR=0.59; 95%CI:0.35-0.99),KEYNOTE-001： 总结与结论,在初治(ORR 26%)和复治(ORR 20%)晚期NSCLC患者中，所有剂量和方案都观察到很好的抗肿瘤活性 2mg/kg q3w剂量下，ORR为20%(irRC) 缓解持久 安全性及毒性可管理 PD-L1强表达与缓解率(37%)、PFS(HR=0.52)、OS(HR=0.59)的改善相关 在KEYNOTE-0
28、01研究额外入组的300例患者中将前瞻性验证PD-L1的截点,Garon EB, et al. 2014 ESMO Abstract LBA43.,4/49,PD-L1 Identifies Pts With NSCLC Most Likely to Benefit From MK-3475(Pembrolizumab, Anti-PD-1),Strong PD-L1 positive staining was considered 50% of tumor cells, and weak was defined as staining between 1% to 49% of positiv
29、ely staining tumor cells. Negative had no tumor staining for PD-L1.,Response Rate (%),3/42,7/46,15/41,25/129,Gandhi L, et al. AACR 2014. Abstract CT105. Reprinted with permission.,RR-RECIST 1.1,50,40,30,20,10,0,19,37,15,7,Total 1%-49% PD-L1 staining, 50% PD-L1 staining PD-L1 negative,Response Rate (
30、%),4/53,20/44,28/146,RR-irRC,50,40,30,20,10,0,19,46,8,8,n/N:,n/N:,Ongoing MK-3475(Pembrolizumab, Anti-PD-1) Clinical Trials in Patients With NSCLC,1. ClinicalTrials.gov. NCT02085070. 2. ClinicalTrials.gov. NCT02129556. 3. ClinicalTrials.gov. NCT01905657. 4. ClinicalTrials.gov. NCT02142738. 5. Clinic
31、alTrials.gov. NCT02039674.,Examples of PD-L1 NSCLC Sample IHC Staining*,PD-L1 Negative,PD-L1 Positive,*Clinical trial assay.,Gandhi L, et al. AACR 2014. Abstract CT105. Reprinted with permission.,Phase I Study of MPDL3280A (Anti-PDL-1) in NSCLC,MPDL3280A: antiPD-L1 antibody engineered for enhanced s
32、afety and efficacy Patients with metastatic solid tumors EGFR and KRAS status assessed at baseline Study design: MPDL3280A IV every 3 wks x 16 cycles ( 1 yr) Primary endpoint: safety Secondary endpoint: ORR by RECIST v1.1 Baseline demographics,*Safety evaluable patients (n = 85) with NSCLC. Data cut
33、off April 30, 2013. Systemic regimens administered in the metastatic, adjuvant or neoadjuvant setting. 3% of patients had no previous systemic regimens.,Horn L, et al. WCLC 2013. Abstract MO18. Reprinted with permission.,Duration of Treatment and Response,Wk,Histology IHC,NS IHC 0,S IHC 3,NS IHC 0,N
34、S IHC 1,NS IHC 0,S IHC 2,NS IHC 3,S IHC 3,NS IHC 3,NS IHC 0,NS IHC 3,NS IHC 1,*PD-LI status determined using proprietary Genentech Roche IHC. ORR includes investigator-assessed unconfirmed and confirmed (u/c) PR per RECIST 1.1. Patients first dosed at 1-20 mg/kg by October 1, 2012. Data cutoff April
35、 30, 2013.,MPDL3280A(Anti-PDL-1) in NSCLC: Best Response by PD-L1 Status and DOT/DOR,Horn L, et al. WCLC 2013. Abstract MO18. Reprinted with permission.,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,On study, on treatment On study, post treatment Treatment discontinued Ongoing response First response F
36、irst PD,*ORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by October 1, 2012. Data cutoff April 30, 2013.,Former/ Current Smokers,Never Smokers,Response by Smoking Status (ORR*),Smoking Status (NSCLC; n = 53),Pts With PR (%),EGFR Mutant,EGFR Status (NSCLC;
37、n = 53),Unknown,Response by EGFR Status (ORR*),Pts With PR (%),KRAS Status (NSCLC; n = 53),Response by KRAS Status (ORR*),Pts With PR (%),KRAS Mutant,Unknown,EGFR WT,EGFR Mutant,KRAS WT,KRAS Mutant,11/43,1/10,9/40,1/6,8/27,1/10,MPDL3280A (Anti-PDL-1)Phase Ia: Response by Smoking and Mutational Statu
38、s,Horn L, et al. WCLC 2013. Abstract MO18. Reprinted with permission.,50,40,30,20,10,0,50,40,30,20,10,0,50,40,30,20,10,0,Former/Current Smokers,Never Smokers,26%,10%,23%,17%,30%,10%,51%,30%,19%,76%,13%,11%,81%,19%,KRAS WT,EGFR WT,Majority of AEs were grade 1/2 and did not require intervention No MTD
39、 or dose-limiting toxicities No grade 3-5 pneumonitis observed Treatment-related death (cardio-respiratory arrest) in 1 patient with sinus thrombosis and large tumor mass invading the heart at baseline Immune-related grade 3.4 AEs: 1 patient with large-cell neuroendocrine NSCLC (diabetes mellitus, 1
40、%),MPDL3280A(Anti-PDL-1): Treatment-Related Adverse Events in Patients With NSCLC,*AEs occurring in 5% of patients. Grade 3/4 treatment-related AEs listed include treatment-related AEs for which the any grade occurrence was 5% of patients. Data cutoff April 30, 2013.,Horn L, et al. WCLC 2013. Abstra
41、ct MO18. Reprinted with permission.,Ongoing MPDL3280A(Anti-PDL-1) Clinical Trials in Patients With NSCLC,1. ClinicalTrials.gov. NCT02108652. 2. ClinicalTrials.gov. NCT01846416. 3. ClinicalTrials.gov. NCT01903993. 4. ClinicalTrials.gov. NCT01984242. 5. ClinicalTrials.gov. NCT02013219. 6. ClinicalTria
42、ls.gov. NCT01988896. 7. ClinicalTrials.gov. NCT01633970.,MED14736(Anti-PD-L1):Emerging promising clinical activity in select tumors,MED14736(Anti-PDL1) safety: No colitis, no high grade pneumonitis ,no drug-related deaths,Ongoing MEDI4736 (Anti-PDL-1)Clinical Trials in Patients With NSCLC,1. Clinica
43、lTrials.gov. NCT02087423. 2. ClinicalTrials.gov. NCT02125461. 3. ClinicalTrials.gov. NCT01975831. 4. ClinicalTrials.gov. NCT02000947. 5. ClinicalTrials.gov. NCT02088112. 6. ClinicalTrials.gov. NCT02118337.,NSCLC-other key PD-1/PD-L1 data presented at 2014 ASCO,Future Outlook,Update of checkpoint Inh
44、ibitors in lung cancer therapy,Cancer Immunotherapy,1,2,3,Outline,TumorChemo, Targeted, Hormone Therapy Rapid Activity, Tumor Shrinkage,Targeting tumor and tumor microenvironment,Targeting host immune system highly specific anti-tumor immunity memory: Durable response (cure?),Understanding of Tumor
45、Biology & ImmunologyEnables Rational Immuno-Combination,?,Effects of immunotherapy and targeted therapy on melanoma survival curves,Clin Cancer Res. 2012;18:336-341.,Combining Immunotherapy and Conventional Therapies,Yrs,Immunotherapy,Targeted Therapy,Survival,Combination,Controls/ Conventional Therapy,Clin Cancer Res. 2012;18:336-341.,Targeting tumor and tumor microenvironment,Targeting host immune system highly specific anti-tumor immunity memory: Durable response (cure?),TumorChemo, Targeted, Hormone Therapy Rapid Activity, Tumor Shrinkage,HOW?,THANK YOU ！ 谢谢！,
