Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente Manuel Cobo Dols Oncologia Médica H Regional Universitario Málaga. IBIMA.

Presentación del tema: "Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente Manuel Cobo Dols Oncologia Médica H Regional Universitario Málaga. IBIMA."— Transcripción de la presentación:

1 Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente
Manuel Cobo Dols Oncologia Médica H Regional Universitario Málaga. IBIMA

2

3 EGFR TKIs versus Chemotherapy

4

5

6

7

8

9

10

11

12 Events/N Median PFS (95%CI) 12m PFS (95%CI) All 57/109 13.8 m ( ) 56.7% ( ) T790M+ 15/37 16.0 m (13.1-NE) 72.4% ( ) T790M- 42/72 10.5 m ( ) 49.4% ( )

13 Ongoing Study: erlotinib + bevacizumab vs
Ongoing Study: erlotinib + bevacizumab vs. erlotinib as first-line treatment Study Design Recruiting Secondary Endpoints Period Primary Endpoint 1 2 ACCRU RC1126 (NCT ) USA Phases III Erlotinib+Bec vs Erlotinib EGFR Mut (+) PFS OS ORR Safety 2012–2017 BEVERLY (NCT ) Italy 2015 – 2018 QoL NEJ026 (UMIN ) Japan 2015–2018 ARTEMIS (NCT ) China 2016–2019 Status No.

14

15

16 IMPRESS. In exploratory analysis of T790M negative, there may be PFS benefit to continuation of EGFR TKI Soria JC, et al. Lancet Oncol. 2015;16:

17 Osimertinib (8-10m) EGFRdel 19 Erlotinib, Gefitinib, Afatinib (8-12m)
PD: rebiopsy T790M Osimertinib (8-10m) EGFRdel 19 L858R Other Initial biopsy also: liquid biopsy Mok et al., Phase III (Aura 3) (Osimertinib vs. CT) mPFS 10.1 vs. 4.4 m NEJM 2016

18

19 Girard N. Future oncol 2017

20 40 patients T790M- tumor and plasma
Plasma EGFR T790M Plasma from AURA trial sent for BEAMing Paired tumor and plasma available for 216 patients 47 T790M+ in tumor, not plasma 18 T790M+ in plasma, not tumor 111 T790M+ in tumor and plasma T790M+ in tumor: 62% RR, 10m PFS T790M+ in plasma: 63% RR, 10m PFS 40 patients T790M- tumor and plasma Oxnard et al, JCO, 2016

21

22 Immunotherapy in EGFR-Mutant NSCLC
CheckMate 057 Pts, n Unstratified HR (95% CI) 82 1.18 ( ) 340 0.66 ( ) 160 0.74 ( ) Mutant Not detected Not reported 0.25 0.5 1.0 2.0 4.0 KEYNOTE-010* Nivolumab Docetaxel Events/Pts, n/N HR (95% CI) 46/86 0.88 ( ) 447/875 0.66 ( ) Mutant Wild type 0.1 1.0 10 NSCLC, non-small-cell lung cancer. References 1. Borghaei H, et al. N Engl J Med. 2015;373: 2. Herbst RS, et al. Lancet. 2016;387: 3. Rittmeyer A, et al. Lancet. 2017;389: Pembrolizumab Docetaxel OAK Pts, n (%) HR (95% CI) 85 (10) 1.24 ( ) 628 (74) 0.69 ( ) Mutant Wild type 0.2 1.0 2 Atezolizumab Docetaxel *Data for the pembrolizumab doses were pooled. References in slidenotes.

23

24 LBA2_PR: Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA) PFS Key results 1.0 Median PFS, months (95%CI) 0.8 Osimertinib 18.9 (15.2, 21.4) SoC 10.2 (9.6, 11.1) 0.6 HR 0.46 Probability of progression-free survival (95%CI 0.37, 0.57) p<0.0001 0.4 0.2 0.0 3 6 9 12 15 18 21 24 27 No. at risk Time from randomization, months Osimertinib 279 262 233 210 178 139 71 26 4 SoC 277 239 197 152 107 78 37 10 2 Ramalingam S et al. Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR

25 PFS* across subgroups Favours osimertinib Favours SoC
Hazard ratio (95% confidence interval) 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, 0.72) 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) (0.34, 0.54) NC (NC, NC) Subgroup Overall (n=556) Log Rank (primary) Cox PH Sex Male (n=206) Female (n=350) Age at screening <65 (n=298) ≥65 (n=258) Race Asian (n=347) Non-Asian (n=209) Smoking history Yes (n=199) No (n=357) CNS metastases Yes (n=116) No (n=440) WHO performance status 0 (n=228) 1 (n=327) EGFR mutation at randomisation# Exon 19 deletion (n=349) L858R (n=207) EGFR mutation by ctDNAǂ Positive (n=359) Negative (n=124) Centrally confirmed EGFR mutation§ Positive (n=500) Negative (n=6)¶ Figure , Table References Ramalingam SS, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care EGFR-TKI as first-line therapy in patients with EGFRm advanced NSCLC: FLAURA.[ Oral presentation]. European Society for Medical Oncology Conference, Madrid, Spain, September 8-12, 2017. 0.1 0.2 0.3 0.4 0.6 0.8 1.0 2.0 10.0 FLAURA data cut-off: 12 June 2017 Hazard 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; ǂResult missing for 36 patients in the osimertinib arm and 37 patients in the SoC arm; §Result missing for 21 patients in the osimertinib arm and 29 patients in the SoC arm; ¶Subgroup categories with less than 20 events were excluded from the analysis CNS, central nervous system; ctDNA, circulating tumour DNA; EGFR, epidermal growth factor receptor; PFS, progression-free survival; SoC, standard-of-care; WHO, World Health Organization. Ramalingam et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain. PFS hazard ratio and 95% confidence interval

26 Objective response rate*
Duration of response Osimertinib (n=279) SoC (n=277) ORR (95% CI) 80% (75, 85) 76% (70, 81) Odds ratio# (95% CI) 1.28 (0.85, 1.93); p=0.2335 Complete responseǂ, n (%) Partial responseǂ, n (%) Stable disease ≥6 weeks, n (%) Progression, n (%) Not evaluable, n (%) 7 (3) 216 (77) 47 (17) 3 (1) 6 (2) 4 (1) 206 (74) 46 (17) 14 (5) 7 (3) Estimated remaining in response§, (95% CI) 12 months 18 months 64% (58, 71) 49% (41, 56) 37% (31, 44) 19% (13, 26) 1.0 Median DoR, months (95% CI) 17.2 (13.8, 22.0) 8.5 (7.3, 9.8) Osimertinib 0.9 SoC 0.8 0.7 0.6 Probability of remaining in response 0.5 0.4 0.3 0.2 Table , Table , Table References Ramalingam SS, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care EGFR-TKI as first-line therapy in patients with EGFRm advanced NSCLC: FLAURA.[ Oral presentation]. European Society for Medical Oncology Conference, Madrid, Spain, September 8-12, 2017. 0.1 0.0 3 6 9 12 15 18 21 24 27 Time from first response (months) No. at risk Osimertinib SoC 223 210 205 180 181 136 160 95 128 69 82 39 40 17 14 4 1 FLAURA data cut-off: 12 June 2017 Tick 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); ǂResponse did not require confirmation; §Calculated using Kaplan-Meier approach CI, 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.

27 LBA2_PR: Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA) OS interim analysis Key results (cont.) 1.0 0.8 0.6 Probability of overall survival 0.4 Median overall survival HR 0.63 ‡A p-value of < was required for statistical significance at current maturity Osimertinib (95%CI 0.45, 0.88) p=0.0068‡ 0.2 Not reached SoC Not reached 0.0 3 6 9 12 15 18 21 24 27 30 Time from randomization, months No. at risk Osimertinib 279 276 269 253 243 232 154 87 29 4 SoC 277 263 252 237 218 200 126 64 24 1 Ramalingam S et al. Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR

28

29 Girard N. Future oncol 2017

30 Posibilidad antiangiogénicos?
Decisión de tratamiento en primera línea. Factores a tener en cuenta Paciente Tumor Edad Sintomática /asintomático PS Carga tumoral Comorbilidad Localización / Nº mts Posibilidad antiangiogénicos? Cercanía domicilo a hospital Mts SNC Apoyo familiar Subtipo mutación

31

32 Afatinib in NSCLC Pts With Uncommom EGFR Mutations
Outcome Afatinib Group 1 (n = 38)* Afatinib Group 2 (n = 14)†‡ Group 3 (n = 23)‡ Chemotherapy Group (n = 25)§ ORR, % (95% CI) 71.1 ( ) 14.3 ( ) 8.7 ( ) 24 ( ) Median DOR, mos (95% CI) 11.1 ( ) 8.2 ( ) 7.1 ( ) -- Disease control, % (95% CI) 84.2 ( ) 64.3 ( ) 65.2 ( ) Median PFS, mos (95% CI) 10.7 ( ) 2.9 ( ) 2.7 ( ) ( ) Median OS, mos (95% CI) 19.4 ( ) 14.9 ( ) 9.2 ( ) 30.2 ( ) *Consists of pts with all point mutations or duplications in exons †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). Cohort n Uncommon Mutations Group 1 38 Point mutations or duplications in exons (L861Q, G719S, G719A, G719C, S768I, rare others) alone or in combination with each other Group 2 14 De novo T790M mutations in exon 20 alone or in combination with other mutations Group 3 23 Exon 20 insertions DOR, duration of response; NSCLC, non-small-cell lung cancer. Yang JC, et al. Lancet Oncol. 2015;16:

33 Pacientes con PS 2 ó mayor
Juan O. Therapeutic Advances in Medical Oncology 2017

34 Pacientes unfit- ancianos dependientes/polimedicados
Pacientes unfit, suelen ser 30% de los casos Ensayos con afatinib, dacometinib o osimertinib, no han reclutado pts PS 2 El resto de estudios, con erlotinib y gefitinib la proporción de pts PS 2 fue pequeña (excepto en el EURTAC con erlotinib se reclutaron 14% de pts con PS 2)[Rosell et al. Lancet Oncol 2012]. .- Pacientes PS 2: lo más recomendado gefitinib y erlotinib. Más datos Afatinib y dacometinib son más tóxicos Sólo un estudio prospectivo fase II con gefitinib que reclutó 30 pts con mutación de EGFR, inelegible para quimioterapia. 22 pts de ellos tenían PS ⩾ 3, y 68% de ellos, el PS regresó a PS 1 en el curso de 1 mes, con una RG del &%% PFS 6,5 meses y SG de 18,8 meses Tener en cuenta el tipo de comorbilidad (Ej. Problemas intestinales crónicos, TKIs 2º generación menos recomendados. Hepática: más toxicidad con gefitinib, etc) Erlotinib y gefitinib tienen más interacción farmacológica. gefitinib y erlotinib tienen un potencial importante de interacción con otros fármacos. Se comportan como inductores o inhibidores de enzimas relacionadas con los citocromos Juan O. Therapeutic Advances in Medical Oncology 2017

35 PFS benefit in AURA3 patients with CNS metastases at baseline
Without CNS metastases Population: intent-to-treat Progression-free survival defined as time from randomisation until date of objective disease progression or death. Progression included deaths in the absence of RECIST progression. Tick marks indicate censored data. CNS metastases determined programmatically from baseline data of CNS lesion site, medical history, and/or surgery, and/or radiotherapy. Probability of progression-free survival 1.0 0.8 0.6 0.4 0.2 No. at risk Osimertinib Platinum-pemetrexed 3 6 9 12 15 18 93 51 80 32 46 27 4 14 2 Months Osimertinib (n=93) Platinum-pemetrexed (n=51) Median PFS, months (95% CI) 8.5 (6.8, 12.3) 4.2 (4.1, 5.4) HR 0.32 (95% CI 0.21, 0.49) 186 89 160 61 116 35 13 36 5 1 Osimertinib (n=186) Platinum-pemetrexed (n=89) 10.8 (8.3, 12.5) 5.6 (4.2, 6.8) HR 0.40 (95% CI 0.29, 0.55) Mok et al. NEJM 2017

36 FLAURA: CNS response*: CNS evaluable for response set
Osimertinib (n=22)# SoC (n=19) R 20 20 R R R R R R R R R R R R R R R -20 -20 Best change from baseline in target lesion size (%) -40 Best change from baseline in target lesion size (%) -40 -60 -60 Stable disease Partial response Progressive disease -80 Not evaluable Stable disease Partial response Complete response -80 -100 -100 Figure , Table R Prior brain radiotherapy R Prior brain radiotherapy Median best percentage change from baseline in CNS target lesion size: -45% (range -100% to +20%) Median best percentage change from baseline in CNS target lesion size: -64% (range -100% to +20%) Presented by J Vansteenkiste at ESMO Asia 2017, 17–19 November 2017, Singapore Proferred Paper Session 1, Abstract LBA5. Ann Oncol 2017;28 (suppl_10): mdx Osimertinib aun no aprobado en 1º línea de CPNM avanzado con mutación EGFR

37 Flaura. CNS PFS: CNS FULL ANALYSIS SET
Flaura. CNS PFS: CNS FULL ANALYSIS SET. Osimertinib is the recomendation in pts with SNC metastases Median CNS PFS, months (95% CI) NC (16.5, NC) 13.9 (8.3, NC) 0.2 0.4 0.6 0.8 1.0 0.0 3 6 9 12 15 18 21 24 27 Time from randomisation (months) Probability of progression-free survival Osimertinib (N=61) SoC (N=67) Osimertinib (n=61) SoC (n=67) Median follow-up for CNS PFS, months 12.4 7.0 Total number of events (CNS progression or death), % 30 45 Pts with CNS progression other than death, %* 20 39 Progression in new CNS lesions, % 12 HR (95% CI 0.26, 0.86) p=0.014 Table 34 CSR; Figure 17; Table 35 No. at risk Osimertinib SoC CNS PFS was nominally statistically significant CNS PFS analysis was third in the hierarchical 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 *Progression 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 < was required for statistical significance at current maturity CI, confidence interval; CNS, central nervous system; HR, hazard ratio; NC, not calculable; PFS, progression-free survival; SoC, standard-of-care FLAURA data cut-off: 12 June 2017 Presented by J Vansteenkiste at ESMO Asia 2017, 17–19 November 2017, Singapore Proferred Paper Session 1, Abstract LBA5. Ann Oncol 2017;28 (suppl_10): mdx Osimertinib aun no aprobado en 1º línea de CPNM avanzado con mutación EGFR

38 Sequential cronograma
15-30% no possible 2º line First line Second line Third and sucessive lines 25-30% T790M not detected: Not Possible biopsy. Liquid biopsy false negative First generation TKI Erlotinib Or gefitinib Osi T790M + QT T790M - 9-10 m 5,5 m QT No Mutat 5,5 m Inmunoth ? ? m 9-10 m Inmunoth ? ? m sequential TKI 2-4 m Osi T790M + QT T790M - 9-10 m 5,5 m QT No Mutat 5,5 m Inmunoth ? ? m Second generation TKI Afatinib 11-13 m Afatin Inmunoth ? ? m sequential TKI 2-4 m Second generation TKI Dacometinib Osi T790M + QT T790M - 9-10 m 5,5 m QT No Mutat 5,5 m Inmunoth ? ? m 14,7 m Dacomet Inmunoth ? ? m sequential TKI 2-4 m Inmunoth ? ? m TKI + angiangiogenic Erlotinib + bevacizumab 16 m erl + bev Osi T790M + QT T790M - 9-10 m 5,5 m QT No Mutat 5,5 m Inmunoth ? ? m sequential TKI 2-4 m E + B T790M - ultsens 10 m erl + bev 16 m erl + bev E + B T790M + ultsens Osi + Gefit T790M + C797S trans QT No Mutat 5,5 m Inmunoth ? ? m 9-10 m Third generation TKI Osimertinib 18,9 m osimertinib QT T790M + C797S Cis ????????????? Osimert T790M - ultsens ????????????? Inmunoth ? ? m Nazartinib? ? m 5,5 m Osimert T790M + ultsens QT No Mutat 5,5 m Inmunoth ? ? m Chemoterapy 5,5-6 m

39 CRITICAL QUESTION. When appoved, Osimertinib for all patients in first line EGFR mut, OR sequence has sense in a subgroup of patients?

40 Which is the more recomendable treatment in first line EGFR mut ???
Sequential cronograma 15-30% no possible 2º line First line Second line Third and sucessive lines 25-35% T790M not detected: Not Possible biopsy. Liquid biopsy false negative First generation TKI Erlotinib Or gefitinib 9-10 m Which 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 ? Second generation TKI Afatinib 11-13 m Afatin Second generation TKI Dacometinib 14,7 m Dacomet TKI + angiangiogenic Erlotinib + bevacizumab 16 m erl + bev E + B T790M - ultsens 10 m erl + bev 16 m erl + bev E + B T790M + ultsens Third generation TKI Osimertinib 18,9 m osimertinib ????????????? Osimert T790M - ultsens ????????????? Osimert T790M + ultsens Chemoterapy 5,5-6 m

41 Osimertinib: up to first?
.- Add median survivals: WRONG This is not biological real. It is play 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 Osimertinib: up to first? Presented By Sanjay Popat at 2017 ASCO Annual Meeting

42 Subsequent therapies post-afatinib among patients with EGFRM+ NSCLC in LUX-Lung 3, 6 and 7
Patients with common EGFR mutations randomised to afatinib n=579 Discontinued afatinib at time of analysis Data cut-off (LL3 &6: 25 March 2016; LL7: 05 December 2016) n=553 29 % of patients not Received subsequent therapy for differenten reasons: This patients loose the chance to received 2º line therapy against T790M mut 1st-gen TKI monotherapy* Other† Any subs systemic treatment Platinum- based CT Single- agent CT Any-line treatment 394 (71%) 277 (50%) 181 (33%) 186 (34%) 121 (22%) Second-line treatment 394 (71%) 252 (46%) 39 (7%) 49 (9%) 54 (10%) A retrospective analysis of subsequent therapy outcomes in patients with common EGFR mutations in LL3, 6 and 7 was conducted Data had been prospectively collected as study follow-up information -Platinum-based CT post-afatinib treatment was received predominantly in the second line, whereas single-agent CT was received mostly in the third line -Time on first-generation EGFR TKI monotherapy post-afatinib was longest in the second-line setting -There was no relevant difference in treatment duration across Del19 and L858R EGFR mutational subgroups for patients randomised to afatinib who received subsequent therapies Third-line treatment 265 (48%) 48 (9%) 104 (19%) 75 (14%) 38 (7%) *Erlotinib, gefitinib and icotinib; †Includes: platinum- based, single-agent and other CT combination therapies; osimertinib, afatinib, HM61713 and rociletinib monotherapies; erlotinib-, gefitinib-, icotinib- and afatinib-containing combinations; immune checkpoint inhibitors; and ‘other’ therapies Fourth-line treatment 156 (28%) 27 (5%) 50 (9%) 49 (9%) 30 (5%) Sequist L et al., ESMO poster #1349

43 Not always Liquid biopsy detect T790M. 67-75% false negative
All EGFRmut contain actEGFRmut But only some contain resistant T790M These patients loose chance to received Osimertinib in second line Vessels, Tissue Barriers Non-Shedding DNAs Not all tumor cells shed DNA to blood Shedding DNAs During phase 2, antitumor activity was evaluated according to Simon’s 2-stage design: if 9 or more of 24 patients experienced a desired response in the first stage, then 39 additional patients would be enrolled. If 25 or more of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects. Antitumor activity was assessed using RECIST v1.1 Tumor Heterogeneity Tissue Biopsy Liquid Biopsy Presented by : James Chih-Hsin Yang, MD, PhD. National Taiwan University

44 Mechanisms of Acquired Resistance to Osimertinib: Driver Mutation, Potential Targeted Therapy Option
BRAF V600E  BRAF inhibitor L781Q  no treatment option C797S/T790M cis (most frequent)3:  no treatment option unknown driver  no treatment option C797S/T790M trans2:  combination of TKIs C797S/T790M wt: Retained sensitivity to 1st and 2nd -gen TKIs11 Investigational compounds Only 3rd gen TKI-naïve patients from Piotrovska et al were considered Unknown driver  Rechallenge with 3rd gen TKI might be beneficial Lost T790M:48% Unknown driver  no treatment option 1.Thress KS, et al. Nat Med. 2015;21: 2.Niederst MJ, et al. Clin Cancer Res. 2015;21:   3.Hidaka N et al., Lung Cancer, 2017 4. Ho, C-C et al., JTO (3): , 2017 5. Bersanelli M et al. J Thorac Oncol. 2016;11:e 6. Kim TM, et al. J Thorac Oncol. 2015;10:  7. Planchard D et al. Annals of Onc 2015;26:  8. Li L et al. Oncotarget 9. Ou S-HI et al. Lung Cancer 2017: 10 .Piotrowska Z et al., ASCO 2017 11. Ercan D. et al., Can Res 2015, 21:

45 Potential Strategies at Osimertinib resistance:
First, Second Generation TKI EGFRm NSCLC Sensitive EGFR mut Sensitive EGFR mut, T790M Third Generation Osimertinib Resistance: Re-biopsy 20% Allelic disposition Sensitive EGFRm T790M - C797S+ Sensitive EGFRm T790M + C797S+ Trans Sensitive EGFRm T790M + C797S + Cis Most frequent 29% Sensitive to 1-2G TKIs Sensitive to 1G + 3G TKI Resistant to TKIs_Chemo Adapted form Niederst et al. CCR Preclinical data Courtesy N. Reguart

46 Frequency of co-occurring mutations in C797S+ samples
Alteration Patients (%) EGFR amplification 29 (48%) MET amplification 10 (16%) BRAF V600E (with/without BRAF amplification) 3 (5%) PIK3CA mutation (with/without PIK3CA amplification) 9 (15%) PIK3CA amplification alone 2 (3%) BRAF amplification alone CCNE1 amplification KRAS amplification, mutation or both 5 (8%) MYC amplification 6 (10%) Fusions (EML4-ALK, NCOA4-RET, CCDC6-RET, STRN-ALK, TPM3-NTRK1, LMNA-NTRK1) Adjacent EGFR mutations (L792, F795, G796, L798, Q791, P794) 8 (13%) Frequency of co-occurring mutations in C797S+ samples 51/61 (84%) pts had at least one bona fide resistance mechanism co-occurring with C797S Genomic landscape of EGFR C797S in lung cancer ctDNA, Presented by Zofia Piotrowska The question: Although 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? 9/12 Piotrowska Z. IASLC 2017 Tokio

47 Start of 1-2º generation TKI
T790M before treatment may be detected by ultrasensitive methods both in solid or liquid biopsy: Probably this would be the population with more benefit to osimertinib from the first line T790M clone Start of 3º generation TKI .- 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 drug 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 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. Rosenbloom et al. / Biochimica et Biophysica Acta 1867 (2017) 69–83

48 Future + Bevacizumab? AFATINIB or Dacomitinib?
Azuma K, et al. JTO Remon J, et al. Clin Lung Cancer 2017

49 3.- Erlotinib + bevacizumab 4.- Dacometinib + Durvalumab
En una paciente con 48 años, mujer. Adenocarcinoma pulmón avanzado. Mutación EGFR con deleción exón 19, cuál sería el tratamiento menos recomendable si estuvieran todas las opciones disponibles? 1.- Gefitinib 2.- Afatinib 3.- Erlotinib + bevacizumab 4.- Dacometinib + Durvalumab 5.- Osimertinib

50 Paciente varón, 73 años. No fumador Adenoca pulmón avanzado
Paciente varón, 73 años. No fumador Adenoca pulmón avanzado. Metátasis pulmón, higado. 2 comorbilidades. Mutación exón 21. Tratado con gefitinib. Remisión Parcial. Tras 1 ños, se demuestra progresión en Lesión cerebral única y crecimiento discreto de 1 lesión pulmonar. Cuál sería la mejor forma de proceder?. 1.- Realización de biopsia líquida para detectar mutación T790M. En caso de ser positiva, tratamiento con osimertinib. En caso de ser negativa: tratamiento con quimioterapia. 2.- Realización de biopsia líquida para detectar mutación T790M. En caso de ser positiva, tratamiento con osimertinib. En caso de ser negativa, intentar hacer Biopsia de la lesión tumoral. Si sigue siendo negativa: tratamiento con quimioterapia. 3.- Realización de biopsia líquida para detectar mutación T790M. En caso de ser positiva, tratamiento con osimertinib. En caso de ser negativa, intentar hacer Biopsia de la lesión tumoral. Si sigue siendo negativa: Trat local con radioterapia estereotáxica lesión cerebral y de lesión pulmonar única y seguir con gefitinib. 4.- Tratamiento con osimertinib en cualquier caso 5.- Realización de biopsia líquida para detectar mutación T790M. En caso de ser positiva, tratamiento con terapia local sobre lesión cerebral y pulmonar única y seguir con gefitinib