肺癌免疫治療進展ppt課件(1)

1、肺癌免疫治療進展,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,Outli

2、ne,腫瘤免疫治療—攻克腫瘤的新希望,人類抗擊腫瘤的歷史腫瘤免疫治療具有特異性和靶向性，一直為臨床醫(yī)師高度關注，近年進步顯著，使得免疫治療成為更具期待的領域,靶向治療,進入21世紀，分子靶向治療如火如荼,,,e,Key events in the history of cancer immunotherapy,,1890s 1st CA vaccine developed(coley),1973 discove

3、ry 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 IFNα(cytokine) approved for CA,1990s Discove

4、ry 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 in

5、hibitor approved for CA,,,,,,,,,,,,,Enthusiasm phase1976-1985,Skepticism phase1986-1992,Renaissance phase1997-,美國《Science》雜志:2013年六大值得關注的科學領域單細胞測序“普朗克”探測微波背景輻射人類連接組計劃探索南極冰下世界癌癥免疫療法基礎植物研究,Breakthrough of year 2

6、013,Science. 2013 Dec 20;342(6165):1432-3,Immunity. 39(1)25 July 2013, Pages 1–10,Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle,CTLA-4 and PD-1/PD-L1 checkpoint blockade for cancer treatment,CTLA-4 a

7、nd PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment,Immune checkpoint blockade includes agents targeting the negative regulators CTLA-4 and PD-1 CTLA-4 attenuates the early activation of naive and memory T cells

8、 in the lymph nodes Agents targeting CTLA-4 include ipilimumab and tremelimumab In contrast, PD-1 modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2

9、 Agents targeting PD-1 include nivolumab and MK-3475 Agents targeting PD-L1 include MPDL3280A and MEDI4736,Kyi C, et al. FEBS Lett. 2014;588:368-376,Comparing CTLA-4 and PD-1,Crit Rev Oncol Hematol. 2014;89:140-165.

10、,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 Inhibitor,Anti-CTLA

11、-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 Renal Esophageal CNS

12、 Colorectal Glioblastoma LeukemiaSoft Tissue Sarcoma,,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Ann Oncol. 2013 Jan;24(1):75-83,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Ipilimumab in combination with PC

13、as first-line therapy in stage IIIB/IV NSCLC,Kaplan–Meier plots for OS,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Deaths/patients 51/66 51/68Median (95% CI), months 8.28

14、(6.80 to 12.39) 12.22 (9.26 to 14.39)HR (95% CI) 0.87 (0.59 to 1.28)Log-rank P 0 .23,C

15、ontrol,Phased Ipi,Deaths/patients 51/66 51/70Median (95% CI), months 8.28 (6.80 to 12.39) 9.69 (7.59 to 12.48)HR (95% CI)

16、 0.99 (0.67 to 1.46)Log-rank P 0.48,Concurrent lpi,Control,Events/patients 61/66 58/7

17、0Median (95% CI), mo 4.21(2.76 to 5.32) 4.11 (2.76 to 5.32)HR (95% CI) 0.88 (0.61 to 1.27)Log-rank P .25,J Clin

18、Oncol. 2012 Jun 10;30(17):2046-54,Kaplan–Meier plots for PFS per immune-related (ir) response criteria (irPFS) and modified WHO criteria (mWHO-PFS).,Events/patients 56/66 54/68Median

19、(95% CI), 4.63m(4.14 to 5.52) 5.68 (4.76 to 7.79)HR (95% CI) 0.72 (0.50 to 1.06) Log-rank P .05,Control,Phased Ipi,E

20、vents/patients 56/66 55/70Median (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

21、 .13,Control,Concurrent lpi,Events/patients 61/66 56/68Median (95% CI),mo 4.21 (2.76 to 5.32) 5.13 (4.17 to 5.72)HR (95% CI)

22、 0.69 (0.48 to 1.00) Log-rank P .02,Control,Phased Ipi,Control,Concurrent lpi,Adverse Events,J Clin Oncol. 2012

23、Jun 10;30(17):2046-54,Follow-UPEvery 12 wksFor survival,SCREENING,INDUCTION,MAINTENANCE,FOLLOW-UP,CA184-104: phase III trial comparing the the efficacy of ipilimumab (Ipi) with PC versus placebo with PC in patients (p

24、ts) with stage IV/recurrent NSCLC of squamous histology,Tumor assessmentEvery 12 wks,J Clin Oncol 31, 2013 (suppl; abstr TPS8117),primary endpoint OSsecondary endpoints OS among pts who receive blinded therapy

25、 PFS best overall response rate,Tumor assessmentWks 7, 13, 19, 25,Exclusion Criteria:Brain MetastasesAutoimmune diseases,PC Paclitaxel (175 mg/m2 , IV)+Carboplatin (AUC=6, IV),CA184-156: Phase III Trial Co

26、mparing the Efficacy of Ipi Plus Etoposide/Platinum Versus Etoposide/Platinum in Subjects With Newly Diagnosed ED-SCLC,J Clin Oncol 30, 2012 (suppl; abstr TPS7113),primary endpoint OSsecondary endpoints OS amo

27、ng pts who receive blinded therapy immune-related and mWHO PFS best overall response rate duration of response,Exclusion Criteria:Prior systemic therapy for lung cancerSymptomatic CNS metastasesHistory

28、of autoimmune disease,Ipi Q3W 2 cycle,EP：etoposide (100 mg/m^2, IV on Days 1-3 Q3W) +cisplatin (75 mg/m^2, IV) or +carboplatin (AUC=5, IV) once Q3WIpi: (10 mg/kg, IV, Q3W),PlaceboQ3W 2cycle,,,A Phase III Study of

29、Nivolumab in Combination with Yervoy in Patients with Advanced Non-Small Cell Lung Cancer,,,,PD-1/PD-L1 Checkpoint Inhibitors,PD-1 and PD-L1 antibodies in phase III development,Phase1 Nivolumab (anti-PD-1; BMS-936558, ON

30、O-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=129),Drug-related pneumonitis(an

31、y grade) occurred in 8 NSCLC Pts(6%) VS 12 Pts(4%) in the overall study population -3Pts (2%) with NSCLC had grade ¾ pneumonitis,Efficacy of Nivolumab monotherapy in Pts treated with NSCLC,Nivolumab in combinati

32、on with PT-DC in advanced NSCLC,Antonia SJ, et al. 2014 ASCO Abstract 8113.,Results and Conclusions,治療的前6周沒有發(fā)生劑量限制毒性3-4級治療相關不良事件發(fā)生率為45%ORR：33-50%1年OS：59-87%,Antonia SJ, et al. 2014 ASCO Abstract 8113.,Antonia SJ, et

33、al. 2014 ASCO Abstract 8113.,Ongoing Nivolumab Clinical Trials in Patients With NSCLC,ClinicalTrials.gov. NCT02041533. 2. ClinicalTrials.gov. NCT01642004. 3. ClinicalTrials.gov. NCT01673867. 4. ClinicalTrials.gov. NCT0

34、1721759. 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 Desi

35、gn,IPI-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

36、2013. Abstract 9009.,,KEYNOTE-001：NSCLC擴大隊列研究設計 (N=307),*前11例患者隨機分入2mg/kg q3w和10mg/kg q3w組，剩余34例患者隨機接受10mg/kg q2w和10mg/kg q3w組****非隨機隊列的45例接受2mg/kg q3w的患者分析截止日期為2014年9月11日數據截止日期：2014年3月3日Garon EB, et al. 2014 ESMO Ab

37、stract LBA43.,主要終點：ORR (RECIST v1.1[獨立中心評估])次要終點：免疫相關療效標準(irRC)[研究者評估]Pembrolizumab (MK3475) 治療持續(xù)直至PD，不可接受的毒性或死亡,KEYNOTE-001：基線特征,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：治療暴露與治療相關不良事件匯總,4例患者(1.5%)發(fā)生輸注相關

38、反應發(fā)生率<1%的其他潛在免疫調節(jié)不良事件為結腸炎和低鈉血癥,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：腫瘤大小自基線最大變化*(%)(RECIST v1.1，中心評估),*可評估患者為根據中心評估基線有可測量病灶且至少接受一次基線后腫瘤評估Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：抗腫

39、瘤活性(RECIST v1.1，中心評估),a包括確認和未確認緩解；b數據截止日期為2014年3月3日Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：抗腫瘤活性 (irRC，研究者評估),a包括確認和未確認緩解；b數據截止日期為2014年9月11日Garon EB, et al. 2014 ESMO Abstract LBA43.,額外45例接受2mg/kg q3w治

40、療的患者中，ORRa為20%(95%CI:10%-35%)b,KEYNOTE-001：至緩解時間 & 緩解持續(xù)時間,a包括確認和未確認緩解Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：生存期評估：初治 vs. 復治,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：生存期評估：不同劑量,Garon

41、EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：PD-L1表達水平與緩解率,Garon EB, et al. 2014 ESMO Abstract LBA43.,KEYNOTE-001：生存期評估：PD-L1表達,PD-L1強陽性：>=50%的腫瘤細胞PD-L1弱陽性：1-49%的腫瘤細胞染色陰性為PD-L1無表達Garon EB, et al. 2014 ESMO Ab

42、stract LBA43.,PD-L1強陽性患者較弱陽性/陰性患者的PFS更長(HR=0.52; 95%CI:0.33-0.80)PD-L1強陽性患者較弱陽性/陰性患者的OS更長(HR=0.59; 95%CI:0.35-0.99),KEYNOTE-001：總結與結論,在初治(ORR 26%)和復治(ORR 20%)晚期NSCLC患者中，所有劑量和方案都觀察到很好的抗腫瘤活性2mg/kg q3w劑量下，ORR為20%(irRC)緩

43、解持久安全性及毒性可管理PD-L1強表達與緩解率(37%)、PFS(HR=0.52)、OS(HR=0.59)的改善相關在KEYNOTE-001研究額外入組的300例患者中將前瞻性驗證PD-L1的截點,Garon EB, et al. 2014 ESMO Abstract LBA43.,,4/49,,,,,PD-L1 Identifies Pts With NSCLC Most Likely to Benefit From MK-3

44、475(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 positively staining tumor cells. Negative had no tumor staining for

45、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,Total1%-49% PD-L1 staining,≥ 50% PD-L1 staining PD-L1 nega

46、tive,,,,,,,,Response Rate (%),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. Clinic

47、alTrials.gov. NCT02129556. 3. ClinicalTrials.gov. NCT01905657. 4. ClinicalTrials.gov. NCT02142738. 5. ClinicalTrials.gov. NCT02039674.,Examples of PD-L1 NSCLC Sample IHC Staining*,PD-L1 Negative,PD-L1 Positive,*Clinica

48、l trial assay.,Gandhi L, et al. AACR 2014. Abstract CT105. Reprinted with permission.,Phase I Study of MPDL3280A(Anti-PDL-1) in NSCLC,MPDL3280A: anti–PD-L1 antibody engineered for enhanced safety and efficacyPatients w

49、ith metastatic solid tumorsEGFR and KRAS status assessed at baselineStudy design: MPDL3280A IV every 3 wks x 16 cycles (≈ 1 yr) Primary endpoint: safetySecondary endpoint: ORR by RECIST v1.1Baseline demographics,*Sa

50、fety evaluable patients (n = 85) with NSCLC. Data cutoff 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

51、. WCLC 2013. Abstract MO18. Reprinted with permission.,Duration of Treatment and Response,Wk,Histology IHC,NS IHC 0,S IHC 3,NS IHC 0,NS IHC 1,NS IHC 0,S IHC 2,NS IHC 3,S IHC 3

52、,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 fir

53、st dosed at 1-20 mg/kg by October 1, 2012. Data cutoff April 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.,,,,,,,,

54、,,,,,,,,,,,,,,,,,,,,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,On study, on treatmentOn study, post treatmentTreatment discontinuedOngoing responseFirst responseFirst PD,,,,,,,,*ORR includes investigator-assessed u/

55、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

56、(%),EGFR Mutant,EGFR Status (NSCLC; 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 W

57、T,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 Status,Horn L, et al. WCLC 2013. Abstract MO18. Reprinted with permission.,50,40,30,20,10,0,50,40,30,20,10,0

58、,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 interventionNo MTD or dose-

59、limiting toxicitiesNo grade 3-5 pneumonitis observedTreatment-related death (cardio-respiratory arrest) in 1 patient with sinus thrombosis and large tumor mass invading the heart at baselineImmune-related grade 3.4 AE

60、s: 1 patient with large-cell neuroendocrine NSCLC (diabetes mellitus, 1%),MPDL3280A(Anti-PDL-1): Treatment-Related Adverse Events in Patients With NSCLC,*AEs occurring in ≥ 5% of patients. ?Grade 3/4 treatment-related A

61、Es 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. Abstract MO18. Reprinted with permission.,Ongoing MPDL3280A(Anti-PD

62、L-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. NCT0201

63、3219. 6. ClinicalTrials.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 pneumoniti

64、s ,no drug-related deaths,Ongoing MEDI4736 (Anti-PDL-1)Clinical Trials in Patients With NSCLC,1. ClinicalTrials.gov. NCT02087423. 2. ClinicalTrials.gov. NCT02125461. 3. ClinicalTrials.gov. NCT01975831. 4. ClinicalTrial

65、s.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 Inhibitors in lung cancer therap

66、y,Cancer Immunotherapy,1,2,3,Outline,Tumor Chemo, Targeted, Hormone Therapy Rapid Activity, Tumor Shrinkage,Targeting tumor and tumor microenvironment,Targeting host immune system ? highly specific anti-tumor immunit

67、y ? memory: Durable response (cure?),Understanding of Tumor Biology & Immunology Enables Rational Immuno-Combination,,?,Effects of immunotherapy and targeted therapy on melanoma survival curves,Clin Cancer Res. 20

68、12;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 t