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Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente

Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente. Manuel Cobo Dols Oncologia Médica H Regional Universitario Málaga. IBIMA 12-4-2018. EGFR TKIs versus Chemotherapy. Ongoing Study: erlotinib + bevacizumab vs. erlotinib as first-line treatment.

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Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente

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  1. Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente Manuel Cobo Dols Oncologia Médica H Regional Universitario Málaga. IBIMA 12-4-2018

  2. EGFR TKIs versus Chemotherapy

  3. Ongoing Study: erlotinib + bevacizumabvs.erlotinibas first-line treatment BEVERLY (NCT02633189) Italy NEJ026(UMIN000017069) Japan ARTEMIS(NCT02759614) China Study No. ACCRU RC1126 (NCT01532089) USA Study Design • Phases III • Erlotinib+Bec vs • Erlotinib • EGFR Mut (+) • Phases III • Erlotinib+Bec vs • Erlotinib • EGFR Mut (+) • Phases III • Erlotinib+Bec vs • Erlotinib • EGFR Mut (+) • Phases III • Erlotinib+Bec vs • Erlotinib • EGFR Mut (+) Status Recruiting Recruiting Recruiting Recruiting Primary Endpoint PFS PFS PFS PFS 1 2 Secondary Endpoints OS QoL ORR OS QoL ORR OS ORR Safety OS ORR Safety 2012–2017 Study Period 2015–2018 2016–2019 2015 – 2018

  4. IMPRESS. In exploratory analysis of T790M negative, there may be PFS benefit to continuation of EGFR TKI Soria JC, et al. Lancet Oncol. 2015;16:990-998.

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

  6. Girard N. Future oncol 2017

  7. 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 plasma: 63% RR, 10m PFS T790M+ in tumor: 62% RR, 10m PFS 40 patients T790M- tumor and plasma Oxnard et al, JCO, 2016

  8. Immunotherapy in EGFR-Mutant NSCLC CheckMate 057 1.0 4.0 0.25 0.5 2.0 Nivolumab Docetaxel KEYNOTE-010* 1.0 10 0.1 Docetaxel Pembrolizumab OAK 0.2 1.0 2 Docetaxel Atezolizumab *Data for the pembrolizumab doses were pooled. References in slidenotes.

  9. 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) Osimertinib 18.9 (15.2, 21.4) 0.8 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 0 3 6 9 12 15 18 21 24 27 Time from randomization, months No. at risk Osimertinib 279 262 233 210 178 139 71 26 4 0 SoC 277 239 197 152 107 78 37 10 2 0 Ramalingam S et al. Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR

  10. PFS* across subgroups 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, 0.72) 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) Favours osimertinib Favours SoC 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)¶ 0.1 0.2 0.3 0.4 0.6 0.8 1.0 2.0 10.0 FLAURA data cut-off: 12 June 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; 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 analysisCNS, 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

  11. Objective response rate* Duration of response 1.0 Median DoR, months (95% CI) 17.2 (13.8, 22.0) 8.5 (7.3, 9.8) Osimertinib SoC 0.9 0.8 0.7 0.6 0.5 Probability of remaining in response 223 210 205 180 181 136 160 95 128 69 82 39 40 17 14 4 0 1 0 0 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 risk Osimertinib SoC 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.

  12. 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 <0.0015 was required for statistical significance at current maturity (95%CI 0.45, 0.88) p=0.0068‡ Osimertinib Not reached 0.2 SoC Not reached 0.0 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 0 SoC 277 263 252 237 218 200 126 64 24 1 0 Ramalingam S et al. Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR

  13. Girard N. Future oncol 2017

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

  15. Afatinib in NSCLC Pts With Uncommom EGFR Mutations *Consists of pts 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). Yang JC, et al. Lancet Oncol. 2015;16:830-838.

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

  17. 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

  18. PFS benefit in AURA3 patients with CNS metastases at baseline With CNS metastases Without CNS metastases Median PFS, months (95% CI) 10.8 (8.3, 12.5) 5.6 (4.2, 6.8) Osimertinib (n=186) Platinum-pemetrexed (n=89) 1.0 1.0 Osimertinib (n=93) Platinum-pemetrexed (n=51) Median PFS, months (95% CI) 8.5 (6.8, 12.3) 4.2 (4.1, 5.4) 0.8 0.8 HR 0.32(95% CI 0.21, 0.49) HR 0.40(95% CI 0.29, 0.55) 0.6 0.6 Probability ofprogression-free survival Probability ofprogression-free survival 0.4 0.4 0.2 0.2 0 0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 Months Months No. at risk Osimertinib Platinum-pemetrexed 93 51 80 32 46 9 27 4 14 2 4 0 0 0 186 89 160 61 116 35 61 13 36 5 9 1 0 0 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. Mok et al. NEJM 2017

  19. FLAURA: CNS response*: CNS evaluable for response set SoC (n=19) Osimertinib (n=22)# R 20 20 R R R R R R R R R R R R R R R 0 0 -20 -20 Progressive disease Not evaluable Best change from baseline in target lesion size (%) Best change from baseline in target lesion size (%) Stable disease -40 -40 Stable disease Partial response Partial response -60 -60 Complete response -80 -80 -100 -100 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): mdx729.007 Osimertinib aun no aprobado en 1º línea de CPNM avanzado con mutación EGFR

  20. Osimertinib (N=61) 1.0 Median CNS PFS, months (95% CI) NC (16.5, NC) 13.9(8.3, NC) Flaura. CNS PFS: CNS FULL ANALYSIS SET. Osimertinib is the recomendation in pts with SNC metastases SoC (N=67) 0.8 0.6 HR 0.48(95% CI 0.26, 0.86) p=0.014 Probability of progression-free survival 0.4 0.2 0.0 0 3 6 9 12 15 18 21 24 27 Time from randomisation (months) 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 <0.0015 was required for statistical significance at current maturityCI, 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): mdx729.007 Osimertinib aun no aprobado en 1º línea de CPNM avanzado con mutación EGFR

  21. Sequential cronograma 15-30% no possible 2º line First line Second line Third and sucessive lines 25-30% T790M notdetected: Not Possiblebiopsy. Liquidbiopsy false negative Osi T790M + Osi T790M + Osi T790M + Osi T790M + Firstgeneration TKI ErlotinibOrgefitinib 9-10 m 9-10 m 9-10 m 9-10 m 9-10 m QT T790M - QT T790M - QT T790M - QT T790M - 5,5 m 5,5 m 5,5 m 5,5 m Secondgeneration TKI Afatinib 11-13 m Afatin Secondgeneration TKI Dacometinib 14,7 m Dacomet TKI + angiangiogenic Erlotinib + bevacizumab 16 m erl + bev 10 m erl + bev E + B T790M - ultsens 16 m erl + bev E + B T790M + ultsens Osi + Gefit T790M + C797S trans 9-10 m 18,9 m osimertinib Thirdgeneration TKI Osimertinib QT T790M + C797S Cis QT No Mutat QT No Mutat QT No Mutat QT No Mutat QT No Mutat QT No Mutat Inmunoth ? Inmunoth ? sequential TKI sequential TKI sequential TKI Inmunoth ? Nazartinib? Inmunoth ? Inmunoth ? sequential TKI Inmunoth ? Inmunoth ? Inmunoth ? Inmunoth ? Inmunoth ? Inmunoth ? ????????????? 2-4 m 2-4 m 2-4 m 2-4 m 5,5 m ? m 5,5 m ? m ? m 5,5 m ? m 5,5 m ? m ? m ? m ? m ? m 5,5 m ? m ? m ? m 5,5 m 5,5 m Osimert T790M - ultsens ????????????? Osimert T790M + ultsens Chemoterapy 5,5-6 m

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

  23. Sequential cronograma 15-30% no possible 2º line First line Second line Third and sucessive lines 25-35% T790M notdetected: Not Possiblebiopsy. Liquidbiopsy false negative Firstgeneration TKI ErlotinibOrgefitinib 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 ? Secondgeneration TKI Afatinib 11-13 m Afatin Secondgeneration TKI Dacometinib 14,7 m Dacomet TKI + angiangiogenic Erlotinib + bevacizumab 16 m erl + bev 10 m erl + bev E + B T790M - ultsens 16 m erl + bev E + B T790M + ultsens 18,9 m osimertinib Thirdgeneration TKI Osimertinib ????????????? Osimert T790M - ultsens ????????????? Osimert T790M + ultsens Chemoterapy 5,5-6 m

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

  25. 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 Data cut-off (LL3 &6: 25 March 2016; LL7: 05 December 2016) Discontinued afatinib at time of analysis 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 Other† 1st-gen TKI monotherapy* Any subs systemic treatment Single-agent CT Platinum-based CT Any-line treatment 277 (50%) 181 (33%) 186 (34%) 121(22%) 394 (71%) Second-line treatment 252 (46%) 39 (7%) 49 (9%) 54 (10%) 394 (71%) Third-line treatment 48 (9%) 104 (19%) 75 (14%) 38 (7%) 265 (48%) • *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 30(5%) 27(5%) 50(9%) 49(9%) 156 (28%) Sequist L et al., ESMO 2017 poster #1349

  26. 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 Not all tumor cells shed DNA to blood Non-Shedding DNAs Shedding DNAs Tumor Heterogeneity Liquid Biopsy Tissue Biopsy Presented by : James Chih-Hsin Yang, MD, PhD. National Taiwan University

  27. Mechanisms of Acquired Resistance to Osimertinib: Driver Mutation, Potential Targeted Therapy Option BRAF V600E  BRAF inhibitor • C797S/T790M cis (most frequent)3:  no treatment option L781Q  notreatmentoption unknowndriver notreatmentoption • C797S/T790M trans2:  combinationof TKIs • C797S/T790M wt: Retained sensitivity to 1st and 2nd -gen TKIs11 Investigationalcompounds Unknowndriver Rechallenge with 3rd gen TKI might be beneficial Unknowndriver notreatmentoption Lost T790M:48% 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: 228-231 10 .Piotrowska Z et al., ASCO 2017 11. Ercan D. et al., Can Res 2015, 21:3913-3923 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 al., Lung Cancer, 2017 4. Ho, C-C et al., JTO . 12 (3): 567-572, 2017 5. Bersanelli M et al. J Thorac Oncol. 2016;11:e121-123.

  28. PotentialStrategies at Osimertinibresistance: First, Second Generation TKI EGFRm NSCLC Sensitive EGFR mut, T790M Sensitive EGFR mut Third Generation Osimertinib Resistance: Re-biopsy 20% Allelic disposition Most frequent Sensitive EGFRm T790M +C797S+ Trans 29% Sensitive EGFRm T790M +C797S + Cis Sensitive EGFRm T790M - C797S+ Resistant to TKIs_Chemo Sensitive to 1-2G TKIs Sensitive to 1G + 3G TKI Adapted form Niederst et al. CCR 2015. Preclinical data Courtesy N. Reguart

  29. Frequency of co-occurring mutations in C797S+ samples 51/61 (84%) pts had at least one bona fide resistance mechanism co-occurring with C797S 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? Genomic landscape of EGFR C797S in lung cancer ctDNA, Presented by Zofia Piotrowska 9/12 Piotrowska Z. IASLC 2017 Tokio

  30. 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

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

  32. 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

  33. 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

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