1、Cncer de pulmn no microctico EGFR mutado: Optimizacin del manejo del paciente,Manuel Cobo DolsOncologia Mdica H Regional Universitario Mlaga. IBIMA12-4-2018,EGFR TKIs versus Chemotherapy,Ongoing Study: erlotinib + bevacizumab vs. erlotinib as first-line treatment,IMPRESS. In exploratory analysis of
2、T790M negative, there may be PFS benefit to continuation of EGFR TKI,Soria JC, et al. Lancet Oncol. 2015;16:990-998.,Mok et al., Phase III (Aura 3) (Osimertinib vs. CT) mPFS 10.1 vs. 4.4 m NEJM 2016,Girard N. Future oncol 2017,Plasma EGFR T790M,Plasma from AURA trial sent for BEAMingPaired tumor and
3、 plasma available for 216 patients,Oxnard et al, JCO, 2016,18 T790M+ in plasma, not tumor,111 T790M+ in tumor and plasma,47 T790M+ in tumor, not plasma,40 patients T790M- tumor and plasma,T790M+ in tumor:62% RR, 10m PFS,T790M+ in plasma:63% RR, 10m PFS,Immunotherapy in EGFR-Mutant NSCLC,*Data for th
4、e pembrolizumab doses were pooled.,CheckMate 057,KEYNOTE-010*,OAK,Nivolumab,Docetaxel,Pembrolizumab,Docetaxel,Atezolizumab,Docetaxel,References in slidenotes.,1.0,0.5,2.0,0.25,4.0,1.0,0.1,10,1.0,0.2,2,LBA2_PR: Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC
5、(FLAURA),Key results,Ramalingam S et al. Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR,Median PFS, months (95%CI),18.9 (15.2, 21.4),10.2 (9.6, 11.1),HR 0.46,(95%CI 0.37, 0.57)p0.0001,Osimertinib,SoC,PFS,1.0,0.6,0.4,0.2,0.0,0,3,6,9,12,15,18,21,24,27,0.8,Probability of progression-free survival,Time from r
6、andomization, months,No. at risk,Osimertinib,SoC,279,262,233,210,178,139,0,71,26,4,277,239,197,152,107,78,37,10,2,0,Favours SoC,SubgroupOverall (n=556)Log Rank (primary)Cox PHSex Male (n=206) Female (n=350)Age at screening65 (n=298)65 (n=258)RaceAsian (n=347)Non-Asian (n=209)Smoking history Yes (n=1
7、99)No (n=357)CNS metastasesYes (n=116)No (n=440)WHO performance status0 (n=228)1 (n=327)EGFR mutation at randomisation#Exon 19 deletion (n=349) L858R (n=207)EGFR mutation by ctDNAPositive (n=359)Negative (n=124)Centrally confirmed EGFR mutationPositive (n=500)Negative (n=6),FLAURA data cut-off: 12 J
8、une 2017Hazard ratio 1 implies a lower risk of progression on osimertinib 80 mg. Size of circle is proportional to the number of events*By Investigator assessment; #Local or central test; Result missing for 36 patients in the osimertinib arm and 37 patients in the SoC arm; Result missing for 21 pati
9、ents in the osimertinib arm and 29 patients in the SoC arm; Subgroup categories with less than 20 events were excluded from the analysisCNS, central nervous system; ctDNA, circulating tumour DNA; EGFR, epidermal growth factor receptor; PFS, progression-free survival; SoC, standard-of-care; WHO, Worl
10、d Health Organization. Ramalingam et al. Presented at :ESMO Congress Sep 8-12, 2017; Madrid, Spain.,PFS* across subgroups,0.1,0.2,0.3,0.4,0.6,0.8,Hazard ratio (95% confidence interval)0.46 (0.37, 0.57)0.46 (0.37, 0.57)0.58 (0.41, 0.82)0.40 (0.30, 0.52)0.44 (0.33, 0.58)0.49 (0.35, 0.67)0.55 (0.42, 0.
11、72)0.34 (0.23, 0.48) 0.48 (0.34, 0.68)0.45 (0.34, 0.59)0.47 (0.30, 0.74)0.46 (0.36, 0.59)0.39 (0.27, 0.56)0.50 (0.38, 0.66) 0.43 (0.32, 0.56)0.51 (0.36, 0.71)0.44 (0.34, 0.57)0.48 (0.28, 0.80)0.43 (0.34, 0.54)NC (NC, NC),2.0,PFS hazard ratio and 95% confidence interval,1.0,Favours osimertinib,10.0,2
12、5,Objective response rate*,FLAURA data cut-off: 12 June 2017Tick marks indicate censored data *By investigator assessment #Analysis performed using a logistic regression stratified by race (Asian versus Non-Asian) and mutation type (Exon 19 deletion versus L858R); Response did not require confirmati
13、on; Calculated using Kaplan-Meier approachCI, confidence interval; DoR, duration of response; ORR, objective response rate; SoC, standard-of-care. Ramalinagm et al. Presented at :ESMO Congress Sep 8-12, 2017; Madrid, Spain.,Duration of response,Median DoR, months (95% CI) 17.2 (13.8, 22.0) 8.5 (7.3,
14、 9.8),Probability of remaining in response,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,3,6,9,12,15,18,21,24,27,Time from first response (months),No. at riskOsimertinibSoC,Osimertinib,SoC,26,Key results (cont.),Ramalingam S et al. Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR,No. at risk,Osimertinib,SoC
15、,279,276,269,253,243,232,0,154,87,4,277,263,252,237,218,200,126,64,1,0,29,24,OS interim analysis,1.0,0.6,0.4,0.2,0.0,0,3,6,9,12,15,18,21,24,27,0.8,30,Probability of overall survival,Time from randomization, months,HR 0.63,(95%CI 0.45, 0.88)p=0.0068,A p-value of 0.0015 was required forstatistical sig
16、nificance at current maturity,Median overall survival,Not reached,Osimertinib,SoC,Not reached,LBA2_PR: Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA),Girard N. Future oncol 2017,Paciente,Tumor,Edad,PS,Comorbilidad,Cercana domicilo a hospital,Apoyo
17、familiar,Sintomtica /asintomtico,Carga tumoral,Localizacin / N mtsPosibilidad antiangiognicos?,Mts SNC,Subtipo mutacin,Decisin de tratamiento en primera lnea. Factores a tener en cuenta,Afatinib in NSCLC Pts With Uncommom EGFR Mutations,Yang JC, et al. Lancet Oncol. 2015;16:830-838.,*Consists of pts
18、 with all point mutations or duplications in exons 18-21. Consists of pts with de novo T790M mutations. Consists of pts with exon 20 insertions. Consists of pts with mutations falling into groups 1/2/3 (n = 18/3/2).,Pacientes con PS 2 mayor,Juan O. Therapeutic Advances in Medical Oncology 2017,Pacie
19、ntes unfit, suelen ser 30% de los casos Ensayos con afatinib, dacometinib o osimertinib, no han reclutado pts PS 2El resto de estudios, con erlotinib y gefitinib la proporcin de pts PS 2 fue pequea (excepto en el EURTAC con erlotinib se reclutaron 14% de pts con PS 2)Rosell et al. Lancet Oncol 2012.
20、- Pacientes PS 2: lo ms recomendado gefitinib y erlotinib. Ms datosAfatinib y dacometinib son ms txicosSlo un estudio prospectivo fase II con gefitinib que reclut 30 pts con mutacin de EGFR, inelegible para quimioterapia. 22 pts de ellos tenan PS 3, y 68% de ellos, el PS regres a PS 1 en el curso de
21、 1 mes, con una RG del &% PFS 6,5 meses y SG de 18,8 mesesTener en cuenta el tipo de comorbilidad (Ej. Problemas intestinales crnicos, TKIs 2 generacin menos recomendados. Heptica: ms toxicidad con gefitinib, etc)Erlotinib y gefitinib tienen ms interaccin farmacolgica. gefitinib y erlotinib tienen u
22、n potencial importante de interaccin con otros frmacos. Se comportan como inductores o inhibidores de enzimas relacionadas con los citocromos,Juan O. Therapeutic Advances in Medical Oncology 2017,Pacientes unfit- ancianos dependientes/polimedicados,PFS benefit in AURA3 patients with CNS metastases a
23、t baseline,Mok et al. NEJM 2017,Osimertinib (n=22)#,SoC (n=19),Median best percentage change from baseline in CNS target lesion size: -64% (range -100% to +20%),Median best percentage change from baseline in CNS target lesion size: -45% (range -100% to +20%),Best change from baseline in target lesio
24、n size (%),-100,-80,-60,-40,-20,0,20,-100,-80,-60,-40,-20,0,20,Best change from baseline in target lesion size (%),FLAURA: CNS RESPONSE*: CNS EVALUABLE FOR RESPONSE SET,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R Prior brain radiotherapy,R Prior brain radiotherapy,36,Presented by J Vansteenkiste at ESMO Asia
25、2017, 1719 November 2017, Singapore Proferred Paper Session 1, Abstract LBA5. Ann Oncol 2017;28 (suppl_10): mdx729.007,Osimertinib aun no aprobado en 1 lnea de CPNM avanzado con mutacin EGFR,Flaura. CNS PFS: CNS FULL ANALYSIS SET. Osimertinib is the recomendation in pts with SNC metastases,*Progress
26、ion events that did not occur within 2 scheduled visits (plus visit window) of the last evaluable assessment (or randomisation) were censored and therefore excluded in the number of events; #A p-value of 0.0015 was required for statistical significance at current maturityCI, confidence interval; CNS
27、, central nervous system; HR, hazard ratio; NC, not calculable; PFS, progression-free survival; SoC, standard-of-careFLAURA data cut-off: 12 June 2017,Median CNS PFS, months (95% CI) NC (16.5, NC) 13.9 (8.3, NC),CNS PFS was nominally statistically significantCNS PFS analysis was third in the hierarc
28、hical statistical testing strategy and, as OS did not reach formal statistical significance (HR 0.63 95% CI 0.45, 0.88; p=0.0068),# CNS PFS could not be formally tested for statistical significance,No. at riskOsimertinibSoC,Presented by J Vansteenkiste at ESMO Asia 2017, 1719 November 2017, Singapor
29、e Proferred Paper Session 1, Abstract LBA5. Ann Oncol 2017;28 (suppl_10): mdx729.007,Osimertinib aun no aprobado en 1 lnea de CPNM avanzado con mutacin EGFR,First line,Second line,Third and sucessive lines,First generation TKIErlotinib Or gefitinib,Second generation TKIAfatinib,TKI + angiangiogenicE
30、rlotinib + bevacizumab,Third generation TKIOsimertinib,Chemoterapy,9-10 m,15-30% no possible 2 line,11-13 m Afatin,Second generation TKIDacometinib,14,7 m Dacomet,16 m erl + bev,E + B T790M - ultsens,10 m erl + bev,E + B T790M + ultsens,16 m erl + bev,18,9 m osimertinib,Osimert T790M - ultsens,Osime
31、rt T790M + ultsens,?,?,5,5-6 m,25-30% T790M not detected: NotPossible biopsy. Liquid biopsy false negative,Osi + GefitT790M + C797Strans,9-10 m,QTT790M + C797SCis,5,5 m,Sequential cronograma,CRITICAL QUESTION.When appoved, Osimertinib for all patients in first line EGFR mut, OR sequence has sense in
32、 a subgroup of patients?,First line,Second line,Third and sucessive lines,First generation TKIErlotinib Or gefitinib,Second generation TKIAfatinib,TKI + angiangiogenicErlotinib + bevacizumab,Third generation TKIOsimertinib,Chemoterapy,9-10 m,15-30% no possible 2 line,11-13 m Afatin,Second generation
33、 TKIDacometinib,14,7 m Dacomet,16 m erl + bev,E + B T790M - ultsens,10 m erl + bev,E + B T790M + ultsens,16 m erl + bev,18,9 m osimertinib,Osimert T790M - ultsens,Osimert T790M + ultsens,?,?,5,5-6 m,25-35% T790M not detected: NotPossible biopsy. Liquid biopsy false negative,Sequential cronograma,Whi
34、ch is the more recomendable treatment in first line EGFR mut ?Is based on PFS or is based in the overall survival of the complete potential sequence ?,Osimertinib: up to first?,Presented By Sanjay Popat at 2017 ASCO Annual Meeting,.- Add median survivals: WRONGThis is not biological real. It is play
35、 with numbers,.- “Osimertinib first line: no other target therapies in sucessive lines. Best, use sequence: WRONG. If the treatment is clearly benefit, this must be the first line,Subsequent therapies post-afatinib among patients with EGFRM+ NSCLC in LUX-Lung 3, 6 and 7,Single-agent CT,Other,1st-gen
36、 TKI monotherapy*,Any subs systemic treatment,Platinum-based CT,Second-line treatment,394(71%),252(46%),39(7%),49(9%),54(10%),Third-line treatment,265(48%),48(9%),104(19%),75(14%),38(7%),Fourth-line treatment,156(28%),27(5%),50(9%),49(9%),30(5%),Any-line treatment,394(71%),277(50%),181(33%),186(34%)
37、,Discontinued afatinib at time of analysis,Patients with common EGFR mutations randomised to afatinib,n=579,n=553,121(22%),*Erlotinib, gefitinib and icotinib; Includes: platinum-based, single-agent and other CT combination therapies; osimertinib, afatinib, HM61713 and rociletinib monotherapies; erlo
38、tinib-, gefitinib-, icotinib- and afatinib-containing combinations; immune checkpoint inhibitors; and other therapies,Sequist L et al., ESMO 2017 poster #1349,Data cut-off (LL3 LL7: 05 December 2016),29 % of patients notReceived subsequent therapy for differenten reasons:This patients loose the chan
39、ce to received 2 line therapy againstT790M mut,Non-Shedding DNAs,Shedding DNAs,Vessels, Tissue Barriers,TissueBiopsy,LiquidBiopsy,Tumor Heterogeneity,All EGFRmut contain actEGFRmutBut only some contain resistant T790M,Not all tumor cells shed DNA to blood,Presented by : James Chih-Hsin Yang, MD, PhD
40、. National Taiwan University,Not always Liquid biopsy detect T790M. 67-75% false negative,These patients loose chance to received Osimertinib in second line,L781Q no treatment option,1.Thress KS, et al. Nat Med. 2015;21:560-562. 2.Niederst MJ, et al. Clin Cancer Res. 2015;21:3924-3933.3.Hidaka N et
41、al., Lung Cancer, 2017 4. Ho, C-C et al., JTO . 12 (3): 567-572, 20175. Bersanelli M et al. J Thorac Oncol. 2016;11:e121-123.,6. Kim TM, et al. J Thorac Oncol. 2015;10:1736-1744.7. Planchard D et al. Annals of Onc 2015;26:2073-2078.8. Li L et al. Oncotarget. 2017.9. Ou S-HI et al. Lung Cancer 2017:
42、228-23110 .Piotrowska Z et al., ASCO 201711. Ercan D. et al., Can Res 2015, 21:3913-3923,Unknown driver no treatment option,Unknown driver Rechallenge with 3rd gen TKI might be beneficial,Investigational compounds,unknown driver no treatment option,BRAF V600E BRAF inhibitor,C797S/T790M cis (most fre
43、quent)3: no treatment option,C797S/T790M trans2: combination of TKIsC797S/T790M wt: Retained sensitivity to 1st and 2nd -gen TKIs11,Mechanisms of Acquired Resistance to Osimertinib: Driver Mutation, Potential Targeted Therapy Option,Lost T790M:48%,Potential Strategies at Osimertinib resistance:,Adap
44、ted form Niederst et al. CCR 2015. Preclinical data,EGFRmNSCLC,Sensitive EGFR mut,First, Second Generation TKI,Third Generation Osimertinib Resistance: Re-biopsy,Sensitive EGFR mut, T790M,Sensitive to 1-2G TKIs,Sensitive to 1G + 3G TKI,Resistant toTKIs_Chemo,29%,Most frequent,20%,Allelic disposition
45、,Courtesy N. Reguart,9/12,Genomic landscape of EGFR C797S in lung cancer ctDNA, Presented by Zofia Piotrowska,Frequency of co-occurring mutations in C797S+ samples,51/61 (84%) pts had at least one bona fide resistance mechanism co-occurring with C797S,Piotrowska Z. IASLC 2017 Tokio,The question: Alt
46、hough osimertinib in first line increase PFS because target clones with T790M from the beguining OR RELAPSE THE APARITION OF T790M AS THE FIRST RESISTANCE MECHANISM, could induce more agressive fenotypes in the progession and short the overall survival in many patients?,Rosenbloom et al. / Biochimic
47、a et Biophysica Acta 1867 (2017) 6983,.- Competition between sensitive and resistant strains. The fitness landscape of drug-resistant strains, as well as the timing of drug resistance mutations, can determine the outcome of therapy. Sometimes the two subclones have equal fitness in the absence of dr
48、ug OR sometimes the resistant subclone pays a fitness “cost” and is less fit than the sensitive clone .- C: The drug resistance mutation occurs early, allowing the resistant clone to grow to a large size by the time therapy begins. As a result, the slight decrease in tumor size caused by therapy may
49、 go undetected, and the tumor may be deemed intrinsically resistant to therapy. D: The drug resistance mutation occurs late, and the resistant clone is small at the time of treatment. Substantial time may pass before the tumor regrows. The tumor is deemed to acquire resistance during therapy, .- E Drug resistance mutations occur multiple times before therapy, but cannot grow substantially due to the fitness cost. If a resistance mutation occurs near the time that treatment begins, elimination of drug-sensitive cells releases the resistant subclone from competition, allowing it to grow.,
