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1、黑色素瘤治疗进展,保守估计，美国每年约新增7.5万人，中国每年新增2万人,2010年晚期黑色素瘤治疗情况,Vernon K Sondak. Discussion: Ipilimumab: The light at the end of the tunnel? 2010, ASCO plenary session,晚期黑色素瘤治疗,2008ASCO 900例黑色素瘤肝转移 手术 VS 未手术 OS 29m VS 7m 5年OS 33% VS 5%,Ribas A. N Engl J Med. 2012;366:2517-2519. Copyright 2012 Massachusetts Med
2、ical Society. Reprinted with permission from Massachusetts Medical Society.,CTLA-4 and PD-1/L1 Checkpoint Blockade for Cancer Treatment,阻断CTLA4/B7 与阻断 PD-1/PD-L1之区别,里程碑：Ipilimumab 2013年全球销售额高达5.77亿美元,1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Robert C, et al. N Engl J Med. 2011;364:2517-2
3、526.,Ipi + gp100 Ipi gp100,Median OS, Mos,10.0 10.1 6.4,HR,0.68 0.66,P Value, .001 .003,Ipi + D Placebo + D,Median OS, Mos,11.2 9.1,HR,0.72,P Value, .001,Est 1, 2, 3-Yr Survival, %,47.3, 28.5, 20.8 36.3, 17.9, 12.2,Ipilimumab + gp100 vs gp1001,Ipilimumab vs Placebo2,OS (%),Mos,0,0,100,48,80,60,40,20
4、,40,32,24,16,8,56,52,44,36,28,20,12,4,Patients Survival (%),Mos,0,0,100,80,60,40,20,32,20,48,28,16,4,44,40,8,12,24,36,Ipilimumab + dacarbazine,Placebo + dacarbazine,Ipilimumab：30余年来首个药物证实改善晚期黑色素瘤总生存,Previously Treated Patients,Previously Untreated Patients,ODay S at al JCO 2010;28:18s (Abstract 4),免
5、疫相关毒性irAE,Evolution of Response: Patient Example,Screening,Week 12 Initial increase in total tumour burden (mWHO PD),Week 16 Responding,Week 72 Durable & ongoing response without signs of IRAEs,Courtesy of K. Harmankaya,抗PD-1抗体 Keytruda (pembrolizumab,MK3475) 9月4日美国FDA批准 Opdivo（nivolumab）日本已经上市,Nivo
6、lumab Activity (ORR)1 Melanoma: 28% NSCLC: 18% RCC: 27%,MK-3475 Activity (ORR)2 Melanoma: 38% Highest dose: 52% (assessed by RECIST 1.1 with confirmation by ICR),1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Mass
7、achusetts Medical Society. 2. Hamid O, et al. N Engl J Med. 2013;369:134-144.,Activity of Anti-PD-1 Agents in Solid Tumors,81% of pts with response still on treatment at time of analysis (median followup: 11 mos),Patient with metastatic melanoma,Pembrolizumab (MK-3475) in Advanced Melanoma: Phase I
8、Trial,Melanoma expansion cohort of phase I KEYNOTE-001 study Advanced, unresectable disease with ECOG PS 0-1 Ipilimumab-treated patients must have PD with resolution of related AEs,Ribas A, et al. ASCO 2014. LBA9000.,IPI Naive 10 mg/kg q2w (n = 41),IPI Naive 10 mg/kg q3w (n = 24),IPI Naive 2 mg/kg q
9、3w (n = 22),IPI Treated 10 mg/kg q2w (n = 16),IPI Treated 10 mg/kg q3w (n = 32),IPI Refractory 10 vs 2 mg/kg q3w (n = 173),IPI Nave 10 vs 2 mg/kg q3w (n = 103),Nonrandomized cohorts (n = 135),Randomized cohorts (n = 276),Baseline January 2012,April 2012,Hamid O, et al. N Engl J Med. 2013;369:134-144
10、. Copyright 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.,54-yr-old male with desmoplastic melanoma after progressing on ipilimumab,Clinical Activity of MK-3475 in a Patient With Metastatic Desmoplastic Melanoma,CTL Infiltrates in Regressing Metast
11、atic Melanoma Lesion After MK-3475 Treatment,Baseline: February 29, 2012,August 20, 2012,Ribas A, et al. ASCO 2013. Abstract 9009.,Pembrolizumab (MK-3475) in Advanced Melanoma: AEs 10% Incidence,Similar safety profiles in ipilimumab-naive and ipilimumab-treated patients Other grade 3/4 AE ( 1% incid
12、ence): ALT elevation, headache, hypothyroidism, decreased appetite, dyspnea,Ribas A, et al. ASCO 2014. Abstract LBA9000.,40,49,13,Pembrolizumab (MK-3475) in Advanced Melanoma: Response by PD-L1 Expression,PD-L1 positivity: staining in 1% of tumor cells 125 patients evaluable for PD-L1 expression,PD-
13、L1,PD-L1+,P = .0007*,Kefford R, et al. ASCO 2014. Abstract 3005.,*1-sided P values calculated by logistic regression, adjusting for dose/schedule.,Unselected (n = 113),PD-L1+ (n = 83),PD-L1 (n = 30),0,10,20,30,40,50,60,70,ORR (%),Pembrolizumab (MK-3475) in Advanced Melanoma: Survival by PD-L1 Expres
14、sion,PD-L1 positivity: staining in 1% of tumor cells,PD-L1,P = .0051,P = .3165,Overall Survival,Progression-Free Survival,Kefford R, et al. ASCO 2014. Abstract 3005.,80,60,40,20,0,0,20,40,60,80,100,PFS (%),Wks,PD-L1 positive PD-L1 negative,80,60,40,20,0,0,20,40,60,80,100,OS (%),Wks,PD-L1 positive PD
15、-L1 negative,Phase I Nivolumab Study: Long-term Follow-up in IPI-Naive Pts With Melanoma,Primary endpoints: safety, tolerability Secondary endpoints: preliminary efficacy, dose-response relationships Study amended to collect OS data Subgroup analysis of response by key patient features Exploratory P
16、D-L1 analysis: positive if tumor membrane stained at any intensity (cut-off: 1% or 5% expression),Hodi FS, et al. ASCO 2014. Abstract 9002.,Patients with advanced melanoma, ECOG PS 0-2, 1-5 lines of previous systemic therapy (N = 107) Treatment max:96 weeks,Nivolumab 0.1 mg/kg IV q2w (n = 17),Nivolu
17、mab 0.3 mg/kg IV q2w (n = 18),Nivolumab 1 mg/kg IV q2w (n = 35),Nivolumab 3 mg/kg IV q2w (n = 17),Nivolumab 10 mg/kg IV q2w (n = 20),Phase I Nivolumab Study in Advanced Melanoma: Select AEs,Select AE: associated with potential immunologic etiologies that require more frequent monitoring and/or uniqu
18、e intervention All patients have 1 yr of follow-up,1Topalian S, et al. J Clin Oncol. 2014 ;32:1020-30,Topalian S, et al. J Clin Oncol. 2014;32:1020-1030. Hodi FS, et al. ASCO 2014. Abstract 9002.,-100,-50,0,50,100,150,200,Maximum % Response in Baseline Target Lesions,1% cutoff,Positive,PD-L1 status,
19、Patient,Phase I Nivolumab Study in Advanced Melanoma: ORR by PD-L1 Expression,Tumor tissue collection retrospective; 41 samples,Hodi FS, et al. ASCO 2014. Abstract 9002.,Negative,-100,-50,0,50,100,150,200,5% cutoff,Positive,PD-L1 status,Patient,Negative,Phase I Nivolumab Study in Advanced Melanoma:
20、Expert Perspective,Longest follow-up of any PD-1 antibody study Response duration 64% beyond 24 wks Median DoR of 22.9 mos Survival outcomes 2-yr OS: 48%; 3-yr OS: 41% Median OS: 20.3 mos at 3 mg/kg dose for phase II/III studies Median PFS: 9.7 mos at 3 mg/kg dose for phase II/III studies Grade 3/4
21、irAEs: 5%,Hodi FS, et al. ASCO 2014. Abstract 9002.,Phase I Study: Nivolumab + Ipilimumab in Stage III/IV Melanoma,Concurrent therapy study design Sequenced therapy study design,Patients with stage III/IV melanoma with 3 previous therapies,Induction Ipilimumab q3w x 4 cycles + Nivolumab q3w x 8 cycl
22、es,Maintenance Ipilimumab + Nivolumab q12w x 8 cycles,Patients with stage III/IV melanoma with 3 previous doses of ipilimumab (n = 33),Nivolumab (1 or 3 mg/kg) q2w until progression,Wolchok JD, et al. N Engl J Med. 2013;369:122-133. Sznol M, et al. ASCO 2014. LBA9003,Maintenance Nivolumab 3 mg/kg q2
23、w (max 48 doses),Cohort 8,Cohorts 6, 7,Cohort 1, 2, 2a, 3,(n = 53),(n = 41),Induction Ipilimumab 1 mg/kg q3w x 4 cycles + Nivolumab 3 mg/kg q3w x 4 cycles,Phase I Study of Nivolumab + Ipilimumab in Advanced Melanoma: Safety,No new safety signals with 22 mos of follow-up for the initial concurrent co
24、horts 22/94 (23%) patients discontinued treatment due to treatment-related adverse events 1/94 drug-related death in trial; fatal multiorgan failure (as a result of colitis) in cohort 8,Sznol M, et al. ASCO 2014. Abstract LBA9003.,Phase I Study of Nivolumab + Ipilimumab in Melanoma: Response Charact
25、eristics,34 pts maintain an ongoing response Patients can continue to respond following treatment discontinuation Median follow-up of 22 mos and 7 mos for cohorts 2 and 8, respectively For 7 responding pts in cohort 2 who discontinued therapy for reasons other than disease progression, 86% (6/7) res
26、ponded for 16 wks since end of therapy 89% (8/9) of pts in cohort 2 remained in response and 94% (16/17) of cohort 8 remained in response at the time of analysis,Sznol M, et al. ASCO 2014. Abstract LBA9003.,0,4,8,12,16,20,24,28,130,0,10,20,30,40,50,60,70,80,90,100,110,120,Wks,Mos,Cohort,Nivo 0.3/IPI
27、 3 Cohort 1,Nivo 1/IPI 3 Cohort 2,Nivo 3/IPI 1 Cohort 2a,Nivo 3/IPI 3 Cohort 3,Nivo 1/IPI 3 Cohort 8,Time to and duration of response while on treatment,Response duration following treatment discontinuation,Time to response,Ongoing response,Sznol M, et al. ASCO 2014. Abstract LBA9003.,Phase I Study
28、of Nivolumab + Ipilimumab in Melanoma: OS for Concurrent Tx,100,90,80,70,60,50,40,30,20,10,0,Survival (%),48,0,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,Mos,Pts at Risk, n Nivo 0.3/IPI 3 Nivo 1/IPI 3 Nivo 3/IPI 1 Nivo 3/IPI 3 Concurrent,14 17 16 6 53,13 17 16 6 52,11 16 15 6 48,10 15 15 6 46,8 15 15
29、 6 44,7 14 13 6 40,7 14 4 6 31,7 13 2 6 28,7 9 0 3 19,7 4 0 0 11,5 3 0 0 8,2 3 0 0 5,2 3 0 0 5,2 2 0 0 4,1 0 0 0 1,1 0 0 0 1,0 0 0 0 0,Nivo 0.3 mg/kg + IPI 3 mg/kg Nivo 1 mg/kg + IPI 3 mg/kg Nivo 3 mg/kg + IPI 1 mg/kg Nivo 3 mg/kg + IPI 3 mg/kg Concurrent cohort,Censored,2-yr OS: 50%,2-yr OS: 79%,2-
30、yr OS: 88%,Concurrent Therapy With Ipilimumab and Nivolumab: Expert Perspective,42% ORR with 17% CRs and 82% in remission for all patients receiving concurrent treatment 62% rate of grade 3/4 irAEs at optimal doses: LFTs, lipase, amylase, rash, colitis BRAF status, PD-L1 tumor staining not clearly a
31、ssociated with response Response in sequential patients associated with plasma ipilimumab levels prior to starting nivolumab Concurrent 2-yr OS of 79% = impressive Benefit worth the toxicity?,辅助治疗：高剂量干扰素1年方案,FDA 和EMA HDI - IIB,C和III期 (高危患者）: 20 MIU/m2 IV 5x /周，4周（诱导） 10 MIU/m2 SC 3x /周，48周 (维持),辅助治疗
32、：EORTC 18071: Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease,Eggermont A, et al. ASCO 2014. Abstract LBA9008.,Primary endpoint: RFS per IRC (time to local, regional, distant metastasis, or death) Secondary endpoints: OS, DMFS, AE profile, health-related QoL,Patients with high-risk, co
33、mpletely resected stage III melanoma and ECOG PS 0/1 (N = 951),Ipilimumab 10 mg/kg q3w x 4 then q12w for up to 3 yrs (n = 475),Placebo q3w x 4 then q12w for up to 3 yrs (n = 476),Stratified by stage (IIIa vs IIIb vs IIIc with 1-3 positive LN vs IIIc with 4 positive LN), region (North America, Europe
34、, Australia),Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease: RFS,Eggermont A, et al. ASCO 2014. Abstract LBA9008.,*Stratified by stage. Data are not yet mature.,100,80,60,40,20,0,Patients Alive Without Relapse (%),Median: 26.1 mos,Median: 17.1 mos,Ipilimumab 10 mg/kg Placebo,60,0,12,2
35、4,36,48,Mos,Patients at Risk, n Ipilimumab Placebo,O 234 294,N 475 476,276 260,205 193,67 62,5 4,0 0,Eggermont A, et al. ASCO 2014. Abstract LBA9008.,Events/Patients,Ipilimumab,Placebo,HR (CI*) (Ipilimumab : Placebo),AJCC 2002 (CRF) Stage IIIA Stage IIIB Stage IIIC,Type of LN+ Microscopic Macroscopi
36、c,Ulceration No Yes Unknown,Total,*95% CI for total, 99% CI elsewhere. Unstratified analysis.,34/98 99/213 101/164,36/88 121/207 137/181,83/210 151/265,108/193 186/283,116/257 106/197 12/21,131/244 146/203 17/29,234/475 (49.3%),294/476 (61.8%),0.76 (0.64-0.91),0.84 (0.61-1.17) 0.67 (0.48-0.93) 1.08
37、(0.40-2.87),0.68 (0.47-0.99) 0.83 (0.63-1.10),0.91 (0.49-1.68) 0.77 (0.54-1.08) 0.73 (0.52-1.02),0.25,0.5,1.0,2.0,4.0,Ipilimumab better,Placebo better,Treatment effect P .01,Adj. Ipilimumab vs Placebo for Resected Stage III Disease: RFS by Subgroup,Adjuvant Ipilimumab vs Placebo for Resected Stage I
38、II Disease: irAEs,Eggermont A, et al. ASCO 2014. LBA9008.,Adjuvant Ipilimumab in Stage III Melanoma: Expert Perspective,Median RFS in resected stage IIIa-c melanoma: 17 mos with placebo to 26 mos with ipilimumab (HR: 0.75; P = .0013) Improvement seen for all stages, ulcerated primary or not, microsc
39、opic or macroscopic LN burden Grade 3/4 irAE rate: 42% Is the benefit worth the toxicity?,局部免疫治疗：Oncolytic Virus T-vec,OPTiM: Talimogene Laherparepvec in Stage IIIB/IV Melanoma (Phase III Study),Talimogene laherparepvec: an oncolytic immunotherapy comprising a HSV-1 virus backbone containing the gen
40、e for GM-CSF, a potent immune stimulator Primary endpoint: durable response rate (CR or PR for 6 mos) Secondary endpoints: OS, ORR, TTF, safety,Patients with stage IIIb, IIIc, or IV unresectable melanoma, ECOG PS 0-1 (N = 436),Every 2 wks for up to 2 yrs,Up to 3 yrs of follow-up after treatment,T-Ve
41、c up to 4 mL (108 pfu/mL per injection) intralesionally q2w* (n = 295),GM-CSF 125 g/m2 SC daily for 2 wks, then 2 wks off (n = 141),ClinicalTrials.gov. NCT00769704. Kaufman HL, et al. ASCO 2014. Abstract 9008a.,Randomized 2:1,*Initial dose 106 pfu/mL with 3 wks before subsequent dosing.,OPTiM Study
42、of T-Vec in Stage IIIB/IV Melanoma: Response (ITT Population),DRR: 16.3% with T-Vec vs 2.1% with GM-CSF (P .0001) Responses in both local and distant lesions,Kaufman HL, et al. ASCO 2014. Abstract 9008a. Andtbacka RH, et al. ASCO 2013. Abstract LBA9008.,OPTiM Study of T-Vec in Stage IIIB/IV Melanoma
43、: OS,Events/N (%),Median (95% CI),in Mos,T-Vec,189/295 (64),23.3 (19.5-29.6),GM-CSF,101/141 (72),18.9 (16.0-23.7),HR: 0.79 (95% CI: 0.62-1.00; unadjusted log-rank P = .051),Kaufman HL, et al. ASCO 2014. Abstract 9008a.,100,80,60,40,20,0,OS (%),60,0,10,15,20,5,25,30,35,40,45,50,55,Pts at Risk, n T-Ve
44、c GM-CSF,295 141,269 124,230 100,187 83,159 63,145 52,125 46,95 36,66 27,36 15,16 5,2 0,0 0,T-Vec in Stage IIIB/IV Melanoma (OPTiM Study): Expert Perspective,T-Vec is an effective local intralesional therapy with response rates at injected lesions of 64% 24-wk DRR endpoint met: 16% with T-Vec vs 2%
45、with GM-CSF (P .0001) Toxicities were minimal OS: borderline significant improvement with T-Vec (HR: 0.79; P = .051) T-Vec has locoregional activity and modest systemic effects, well suited for combination with checkpoint protein inhibitors as an immune-priming agent,*Only patients who received both
46、 T-Vec and IPI. CR, CRu, and PD included. 1 patient with PD not shown in the plot because tumor burden could not be accurately calculated (missing postbaseline data). Percentage change from baseline: 538 Percentage change from baseline: 265,100,50,0,25,50,100,200,Percentage Change From Baseline,Pati
47、ents (N=17),Stage IV M1c (n=4),Stage IV M1b (n=5),Stage IV M1a (n=4),Stage IIIc (n=3),Stage IIIb (n=1),Puzanov I, et al. ASCO 2014. Abstract 9029.,T-Vec + IPI in Unresected Stage IIIB-IV Melanoma: Max Change in Tumor Burden,T-Vec + IPI in Unresected Stage IIIB-IV Melanoma: Expert Perspective,18 pati
48、ents treated with T-Vec plus IPI ORR: 56% (4 CR, 6 PR) plus 3 SD Only 3 grade 3/4 irAEs from IPI Melan-Atargeting T cells increased in the peripheral blood after combination therapy Impressive early results addressing the hypothesis that T-Vec may prime an immune response amplified by IPI,靶向治疗： 伊马替尼
49、、恩度、威罗菲尼、达拉菲尼、 达拉菲尼联合曲美替尼,C-KIT突变患者格列卫治疗有效 中国人约10.8%C-kit突变,501 patients screened. 43 pts treated and evaluated Response: (23.3%) 10 PR and 13 SD. No response in 15 dose escalation (600-800 mg/day) pts The median PFS: 3.5m (15 weeks) The OS: 14m (60 weeks), 1-year OS 51%,Guo, et al. J Clin Oncol. 2011,恩度+DTIC vs DTIC,恩度+DTIC vs DTIC,Endostar plus Dacarbazine improv