2014黑色素瘤及胰腺癌治療進(jìn)展

1、黑色素瘤治療進(jìn)展,保守估計(jì)，美國每年約新增7.5萬人，中國每年新增2萬人,2010年晚期黑色素瘤治療情況,Vernon K Sondak. Discussion: Ipilimumab: The light at the end of the tunnel? 2010, ASCO plenary session,晚期黑色素瘤治療,2008ASCO 900例黑色素瘤肝轉(zhuǎn)移 手術(shù) VS 未手術(shù) 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,阻斷CTLA4/B7與阻斷 PD-1/PD-L1之區(qū)別,里程碑：Ipilimumab2013年全球銷售額高達(dá)5.77億美元,1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Robert C, et al. N Engl J Med. 2011;364:2517-252

3、6.,Ipi + gp100 Ipigp100,MedianOS, Mos,10.010.16.4,HR,0.680.66,P Value, .001.003,Ipi + D Placebo + D,MedianOS, Mos,11.29.1,HR,0.72,P Value, .001,Est 1, 2, 3-Yr Survival, %,47.3, 28.5, 20.836.3, 17.9, 12.2,Ipilimumab + gp100 vs gp1001,Ipilimumab vs Placebo2,OS (%),Mos,0,0,100,48,80,60,40,20,40,32,24,1

4、6,8,56,52,44,36,28,20,12,4,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余年來首個(gè)藥物證實(shí)改善晚期黑色素瘤總生存,Previously Treated Patients,Previously Untreated Patients,ODay S at al JCO 2010;28:18s (Abstract 4),免疫相關(guān)毒性irAE,E

5、volution of Response: Patient Example,Screening,Week 12 Initial increase in total tumour burden (mWHO PD),Week 16 Responding,Week 72 Durable 366:2443-2454. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 2. Hamid O, et al. N Engl J Med. 201

6、3;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 Trial,Melanoma expansion cohort of phase I KEYNOTE-001 study Ad

7、vanced, 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 q3w (n = 22),IPI Treated 10 mg/kg q2w (n = 16),IPI Treated 10 mg

8、/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. Copyright 2013 Massachusetts Medical Society. Reprinted with

9、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 Metastatic Melanoma Lesion After MK-3475 Treatment,Baseline: February

10、 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% incidence): ALT elevation, headache, hypothyroidism, decreased appet

11、ite, 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-L1,PD-L1+,P = .0007*,Kefford R, et al. ASCO 2014. Abstract 3005

12、.,*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 Expression,PD-L1 positivity: staining in 1% of tumor cells,PD-L1,P =

13、.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-L1 negative,Phase I Nivolumab Study: Long-term Follow-up in IP

14、I-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 PD-L1 analysis: positive if tumor membrane stained at any intens

15、ity (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),Nivolumab 0.3 mg/kg IV q2w (n = 18),Nivolumab 1 mg/kg IV q2w (n = 35)

16、,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 unique intervention All patients have 1 yr of follow-up,1Topalian S,

17、 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,Patient,Phase I Nivolumab Study in Advanced Melanoma: ORR by PD

18、-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: Expert Perspective,Longest follow-up of any PD-1 antibody study

19、 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 irAEs: 5%,Hodi FS, et al. ASCO 2014. Abstract 9002.,Phase I Stu

20、dy: 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 cycles,Maintenance Ipilimumab + Nivolumab q12w x 8 cycles,Patients

21、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 q2w (max 48 doses),Cohort 8,Cohorts 6, 7,Cohort 1, 2, 2a, 3,(n =

22、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 cohorts 22/94 (23%) patients discontinued treatment due to treatm

23、ent-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 Characteristics,34 pts maintain an ongoing response Patients can conti

24、nue 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) responded for 16 wks since end of therapy 89% (8/9) of pts in coho

25、rt 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 3Cohort 1,Nivo 1/IPI 3Cohort 2,Nivo 3/IPI 1Cohort 2a,Nivo 3/IP

26、I 3Cohort 3,Nivo 1/IPI 3Cohort 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 of Nivolumab + Ipilimumab in Melanoma: OS for Concurrent Tx,100,90,8

27、0,70,60,50,40,30,20,10,0,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 3Nivo 1/IPI 3 Nivo 3/IPI 1 Nivo 3/IPI 3 Concurrent,141716653,131716652,111615648,101515646,81515644,71413640,7144631,7132628,790319,740011,53008,23005,23005,22004,10001,10001,00000,Ni

28、vo 0.3 mg/kg + IPI 3 mg/kgNivo 1 mg/kg + IPI 3 mg/kgNivo 3 mg/kg + IPI 1 mg/kgNivo 3 mg/kg + IPI 3 mg/kgConcurrent cohort,Censored,2-yr OS: 50%,2-yr OS: 79%,2-yr OS: 88%,Concurrent Therapy With Ipilimumab and Nivolumab: Expert Perspective,42% ORR with 17% CRs and 82% in remission for all patients re

29、ceiving 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 associated with response Response in sequential patients associated with plasma ipilimumab levels prior to starting nivolumab Concurrent 2-yr

30、OS of 79% = impressive Benefit worth the toxicity?,輔助治療：高劑量干擾素1年方案,FDA 和EMA HDI - IIB,C和III期 (高?；颊撸? 20 MIU/m2 IV 5x /周，4周（誘導(dǎo)） 10 MIU/m2 SC 3x /周，48周 (維持),輔助治療：EORTC 18071: Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease,Eggermont A, et al. ASCO 2014. Abstract LBA9008.,Primary endpoint

31、: RFS per IRC (time to local, regional, distant metastasis, or death) Secondary endpoints: OS, DMFS, AE profile, health-related QoL,Patients with high-risk, completely 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

32、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, Australia),Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease: RFS,Eggermont A, et al. ASCO 2014. Abstract LBA9008.,*Stratified

33、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/kgPlacebo,60,0,12,24,36,48,Mos,Patients at Risk, nIpilimumabPlacebo,O234294,N475476,276260,205193,6762,54,00,Eggermont A, et al. ASCO 2014. Abstract LBA9008.,Even

34、ts/Patients,Ipilimumab,Placebo,HR (CI*)(Ipilimumab : Placebo),AJCC 2002 (CRF)Stage IIIAStage IIIBStage IIIC,Type of LN+ MicroscopicMacroscopic,Ulceration NoYesUnknown,Total,*95% CI for total, 99% CI elsewhere.Unstratified analysis.,34/9899/213101/164,36/88 121/207 137/181,83/210151/265,108/193186/28

35、3,116/257106/19712/21,131/244146/203 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 (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,Ipilimumabbetter,Placebobetter,Treatment effect P .01,Adj

36、. Ipilimumab vs Placebo for Resected Stage III Disease: RFS by Subgroup,Adjuvant Ipilimumab vs Placebo for Resected Stage III 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

37、 placebo to 26 mos with ipilimumab (HR: 0.75; P = .0013) Improvement seen for all stages, ulcerated primary or not, microscopic or macroscopic LN burden Grade 3/4 irAE rate: 42% Is the benefit worth the toxicity?,局部免疫治療：Oncolytic VirusT-vec,OPTiM: Talimogene Laherparepvec in Stage IIIB/IV Melanoma (

38、Phase III Study),Talimogene laherparepvec: an oncolytic immunotherapy comprising a HSV-1 virus backbone containing the gene 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

39、 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-Vec 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),ClinicalT. NCT00769704. Kaufman HL, et a

40、l. ASCO 2014. Abstract 9008a.,Randomized 2:1,*Initial dose 106 pfu/mL with 3 wks before subsequent dosing.,OPTiM Study 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

41、 2014. Abstract 9008a. Andtbacka RH, et al. ASCO 2013. Abstract LBA9008.,OPTiM Study of T-Vec in Stage IIIB/IV Melanoma: 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

42、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, nT-VecGM-CSF,295141,269124,230100,18783,15963,14552,12546,9536,6627,3615,165,20,00,T-Vec in Stage IIIB/IV Melanoma (OPTiM Study): Expert Perspective,T-Vec is an effective local intralesio

43、nal therapy with response rates at injected lesions of 64% 24-wk DRR endpoint met: 16% with T-Vec vs 2% 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 co

44、mbination with checkpoint protein inhibitors as an immune-priming agent,*Only patients who received both 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 baseli

45、ne: 538 Percentage change from baseline: 265,100,50,0,25,50,100,200,Percentage Change From Baseline,Patients (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:

46、 Max Change in Tumor Burden,T-Vec + IPI in Unresected Stage IIIB-IV Melanoma: Expert Perspective,18 patients 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 ear

47、ly results addressing the hypothesis that T-Vec may prime an immune response amplified by IPI,靶向治療：伊馬替尼、恩度、威羅菲尼、達(dá)拉菲尼、 達(dá)拉菲尼聯(lián)合曲美替尼,C-KIT突變患者格列衛(wèi)治療有效中國人約10.8%C-kit突變,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)

48、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 improve mPFS vs. Dacarbazine alone as the 1st line therapy Estimated 1- and 2-yr survival rates 1 yr: 26.7% vs. 56.3%， 2 yr: 12.7% vs.22.

49、6% Might be a new regimen for the untreated pts with advanced melanoma.,靶向BRAF 突變、MEK BRAF突變率：中國人：20.6%，西方：50%,威羅菲尼：BRIM3試驗(yàn) 腫瘤迅速縮小大于80% 迅速緩解癥狀 中位PFS7個(gè)月 與DTIC比較早期即有生存獲益,BREAK3：達(dá)拉非尼 Vs DTIC 達(dá)拉非尼 187 入組 150mgbid DTIC 63入組 1g/m2 PFS 達(dá)拉非尼 Vs DTIC 6.9m vs 2.7m 達(dá)拉非尼 OS大于18m MEK抑制劑：曲美替尼 177BRAF突變患者接受達(dá)拉非尼聯(lián)合

50、78既往未使用BRAF抑制劑 PFS 11m ORR63-76% 69既往使用BRAF抑制劑PFS3.6m ORR9-15%,Phase II Study: Combined BRAF and MEK Inhibition in BRAFV600-Positive Melanoma,Primary endpoints: cuSCC, PFS, ORR, DoR, safety Secondary endpoints: population PK parameters, OS,*Crossover to combination dabrafenib + trametinib 150/2 afte

51、r progression allowed.,Patients with metastatic melanoma, BRAFV600E/K mutations, ECOG PS 0-1, no previous BRAFi/MEKi (N = 162),Dabrafenib 150 mg BID* (n = 54),Dabrafenib 150 mg BIDTrametinib 2 mg QD (n = 54),Dabrafenib 150 mg BIDTrametinib 1 mg QD (n = 54),Flaherty KT, et al. N Engl J Med 2012;367:1

52、694-1703.,BRAF and MEK Inhibition in BRAFV600-Positive Melanoma: OS by Treatment Arm,Covariates significantly associated with OS Male vs female (HR: 0.45; P = .0472) LDH ULN vs ULN (HR: 0.19; P .0001) 3 vs 3 disease sites (HR: 0.23; P = .0007),Flaherty KT, et al. ASCO 2014. Abstract 9010.,III期臨床試驗(yàn)：C

53、OMBI-d: Dabrafenib + Trametinib as First-line Tx in BRAFV600E/K Melanoma,Primary endpoint: PFS Secondary endpoints include: OS, ORR, DoR, safety,Long GV, et al. ASCO 2014. Abstract 9011.,Patients with unresectable stage IIIC or IV cutaneous melanoma and BRAFV600E/K mutation (947 screened; N = 423),D

54、abrafenib 150 mg BID + Trametinib 2 mg QD (n = 211),Dabrafenib 150 mg BID + Placebo (n = 212),Stratified by LDH ( ULN vs ULN), and BRAF mutation (V600E vs V600K),Crossover not permitted,Dabrafenib + Trametinib as First-line Tx in BRAFV600E/K Melanoma (COMBI-d): PFS,Improved ORR with combination ther

55、apy (67% vs 51%),Long GV, et al. ASCO 2014. Abstract 9011.,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,Proportion Alive and Progression Free,Mos From Randomization,14,0,2,4,6,8,10,12,DabrafenibMed PFS: 8.8 mos6-mo PFS: 57%,Dabrafenib + TrametinibMed PFS: 9.3 mos6-mo PFS: 70%,HR 0.75 (95% CI: 0.57-0.99

56、;P = .035) Median follow-up: 9 mos,Dabrafenib + Trametinib as First-line Tx in BRAFV600E/K Melanoma (COMBI-d): OS,Long GV, et al. ASCO 2014. Abstract 9011.,*Not significant, did not cross stopping boundary for interim analysis (2-sided .00028).,Dabrafenib + Trametinib 6 month OS: 93% Died (events):

57、40 (19%),1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,2,4,6,8,10,12,14,Mos From Randomization,211 212,208 205,185 174,160 142,102 90,11 11,0 0,0 0,Pts at Risk, n Dabrafenib + trametinib Dabrafenib,Proportion Alive,16,18,20,199 190,44 41,2 0,Dabrafenib 6 month OS: 85% Died (events): 55 (26%),HR: 0.63

58、(95% CI: 0.42-0.94; P = .023*),Median follow-up: 9 mos,Dabrafenib + Trametinib in BRAFV600E/K Melanoma: Expert Perspective,Randomized phase II study (n = 162) Median OS: 25 mos in patients treated with dabrafenib 150 BID and trametinib 2 mg QD Pts who failed BRAFi who crossed over to dual therapy di

59、d worse with poor OS Females had worse outcomes than males Clinical factors associated with poor OS: LDH ULN and 3 disease sites,Randomized phase III study (N = 423) of dabrafenib alone vs dabrafenib plus trametinib PFS prolonged (HR: 0.75; P = .035) from 8.8 to 9.3 mos Despite crossover, OS prolonged 40 vs 55 deaths with short median follow-up of 9 mos Why the small