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Cáncer de pulmón

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Presentación realizada por la Dra. Dolores Isla del
Servicio de Oncología Médica del Hospital Clínico Universitario Lozano Blesa de Zaragoza, en el marco de la I Jornada de actualización e innovación en Oncología que tuvo lugar en el CIBA en enero de 2015.

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Cáncer de pulmón

  1. 1. Cáncer de Pulmón 2014 Dolores Isla Servicio de Oncología Médica Hospital Clínico Universitario Lozano Blesa de Zaragoza Zaragoza, 20 de Enero de 2015
  2. 2. CPNM Localizado
  3. 3. NEGATIVE
  4. 4. Shepherd F, ASCO 2014
  5. 5. CPNM Localmente avanzado
  6. 6. • Similar HR compared with the adjuvant approach, with an absolute 5-year OS improvement of 5%, for all stages: Stage I, 50% to 55%, Stage II, 30% to 35%, Stage III, 20% to 25% • More conclusive evidence in favour Adjuvant CT
  7. 7. CPNM Avanzado
  8. 8. Mutaciones mutuamente exclusivas
  9. 9. Kris M, JAMA 2014
  10. 10. CPNM Avanzado Mutación EGFR
  11. 11. Combined OS analysis: mutation categories Presented by: James Chih-Hsin Yang 1.0 0.8 0.6 0.4 0.2 0 EstimatedOSprobability 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) 1.0 0.8 0.6 0.4 0.2 0 EstimatedOSprobability Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0 119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0 Afatinib Chemo No of patients 183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0 93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0 Afatinib Chemo No of patients Del19 Afatinib n=236 Chemo n=119 Median, months 31.7 20.7 HR (95%CI), p-value 0.59 (0.45–0.77), p=0.0001 L858R Afatinib n=183 Chemo n=93 Median, months 22.1 26.9 HR (95%CI), p-value 1.25 (0.92–1.71), p=0.1600
  12. 12. Study Design Primary endpoint: PFS (RECIST v1.1, independent review) Secondary endpoints: OS, tumor response, QoL, safety Exploratory endpoint: biomarker assessment R Chemotherapy-naïve Stage IIIB/IV NSCLC or postoperative recurrence Non-squamous Activating EGFR mutations* Exon 19 deletion Exon 21 L858R PS 0–1 No brain metastasis E monotherapy Erlotinib 150mg qd (n = 75) EB combination Erlotinib 150mg qd + bevacizumab 15mg/kg q3w (n = 75) PD PD Stratification factors: sex, smoking status, clinical stage, EGFR mutation type 1:1 *T790M excluded Kato T, et al. J Clin Oncol. 2014;32(Suppl): Abstract 8005. Phase II
  13. 13. PFS by EGFR Mutation Type EB E Median, Months 18.0 10.3 HR 0.41 (95% CI: 0.24–0.72) EB E Number at risk 0 1.0 0 Number at risk EB E 1.0 0 0 Time, Months 4 8 122 6 10 14 18 22 2616 20 24 28 Time, Months 4 8 122 6 10 14 18 22 2616 20 24 28 0.2 0.4 0.6 0.8 PFSProbability PFSProbability 0.2 0.4 0.6 0.8 Exon 19 deletion Exon 21 L858R EB E Median, Months 13.9 7.1 HR 0.67 (95% CI: 0.38–1.18) EB E Median, Months HR 0.54 (95% CI: 0.36–0.79) P value* Primary Endpoint: PFS by Independent Review 0 0 1.0 Number at risk Time, Months 4 8 122 6 10 14 18 22 2616 20 24 28 0.2 0.4 0.6 0.8 PFSProbability 9.7 16.0 EB E *log-rank test, two-sided
  14. 14. AURA Study
  15. 15. Progression-freesurvivalby T790M(centraltest)status 0 6 12 18 24 30 36 42 Studyweek Probabilityofprogression-freesurvival T790M+(95%CI) T790M-(95%CI) Dots indicatecensoredobservations,shadedarearepresents95% CIs;progressioneventsthatdonotoccurwithin 14weeks of the lastevaluable assessment(orfirstdose)arecensored. Population: alldosedcentrally confirmedT790M+ andT790M-patients,N=170(115 T790M+,55T790M-;sixpatients forwhom startdateis not yet knownare notincluded) 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Patientsatrisk T790M+ T790M- 115 55 96 33 78 21 56 15 21 7 6 0 1 0 Responserate* inT790M+(centraltest) • ORR*=64%(69/107;95%Cl55%,73%)inpatientswith EGFRT790M+NSCLC • Overalldiseasecontrolrate(CR+PR+SD)=94%(101/107;95%CI88%,98%) 20mg 40mg 80mg 160mg 240mg N(107) 10 29 34 28 6 ORR 50% 62% 68% 64% 83% Bestpercentagechangefrombaselineintargetlesion:allevaluableT790M+patients,PartB *Includesconfirmedresponsesandresponsesawaitingconfirmation;#representsimputedvalues Population:alldosedcentrallyconfirmedT790M+patientswithabaselineRECISTassessmentandanevaluableresponse(CR/PR,SD,orPD), N=107(from120T790M+patients;13patientswithacurrentnon-evaluableresponsearenotincluded).D,discontinued;QD,oncedaily Bestpercentagechangefrom baselineintargetlesion: T790M+evaluablepatients,expansioncohortsonly(N=107) 40mgQD 80mgQD 160mgQD 240mgQD 20mgQD 40 20 -20 -40 -60 -80 -100 0 ## DD D D D D DD D DD D D DD D D D D D DD D
  16. 16. Toxicity: Hyperglycemia G3: 22%
  17. 17. Mok T, ESMO 2014
  18. 18. Mok T, ESMO 2014
  19. 19. EGFR TKIs beyond RECIST disease progression: ASPIRATION study Park K, ESMO 2014
  20. 20. CPNM Avanzado Translocación ALK/ROS1 Amplificación MET
  21. 21. Solomon B, NEJM 2014
  22. 22. PFS with crizotinib versus chemotherapy by independent radiologic review (full analysis population). PFS significantly longer on crizotinib than CT (10.9 vs 7.0 m; HR: 0.45; 95% CI: 0.35–0.60; P<0.0001). PROFILE 1014 PFS: 10.9 vs 7 m Solomon B, NEJM 2014
  23. 23. ORR: 74% vs. 45%; 95% CI: 20–39; P<0.0001), PROFILE 1014 COMENTARIO: •Tratamiento de 1º línea con crizotinib mejoria significativa de RR y PFS vs QT en CPNM no escamoso avanzado. •Tratamiento estándar en primera línea. Solomon B, NEJM 2014
  24. 24. • N= 130 patients • ORR: • 58% • 80 patients who had received crizotinib previously: 56% • PFS: 7 m.
  25. 25. • N= 130 patients • ORR: • 58% • 80 patients who had received crizotinib previously: 56% • PFS: 7 m. ONGOING PHASE III STUDIES 1st-LINE: •Crizotinib •QT
  26. 26. Alectinib: Crizotinib resistant NSCLC Phase I/II trial Gadgeel S, Lancet Oncol 2014 • N= 47 p. • ORR: • 55% of the 44 patients • 52% of the patients with CNS metastases • Doses: 900 mg twice-daily dose.
  27. 27. Alectinib: Crizotinib resistant NSCLC Phase I/II trial Gadgeel S, Lancet Oncol 2014 • N= 47 p. • ORR: • 55% of the 44 patients • 52% of the patients with CNS metastases • Doses: 900 mg twice-daily dose. ALEX Study: 1st-Line Phase III Study ALECTINIB vs CRIZOTINIB
  28. 28. Crizotinib and ROS1 + Shaw A, NEJM 2014
  29. 29. ASCO 2014
  30. 30. Kinase IC50 (nM) mean* Selectivity ratio Met 8 – ALK 40–60 5–8X ROS 55 7X RON 80 10X Axl 294 34X 322 37X Tie2 448 52X Abl 1,159 166X IRK 2,887 334X Lck 2,741 283X Sky >10,000 >1000X VEGFR2 >10,000 >1000X PDGFRβ >10,000 >1000X Crizotinib: selectiveCrizotinib: selective inhibitor ofinhibitor of ALK, MET and ROSALK, MET and ROS In archival tumor tissue, MET amplification was determined by FISH MET not amplified (not eligible) •MET/CEP7 ratio <1.8 MET amplified (intermediate MET level) •MET/CEP7 ratio >2.2– <5.0 MET amplified (high MET level) •MET/CEP7 ratio ≥5 MET amplified (low MET level) •MET/CEP7 ratio ≥1.8– ≤2.2
  31. 31. Smoking status, n (%) Never smoker Ex-smoker Smoker 1 (50) 1 (50) 0 1 (17) 4 (67) 1 (17) 0 6 (100) 0 2 (14) 11 (79) 1 (7) Low MET, n=2 Intermediate MET, n=6 High MET, n=6 Total, N=14 •Eficacia en pacientes con niveles de MET intermedios y altos. •Tamaño muestral insuficiente para extraer conclusiones.
  32. 32. CPNM Avanzado INMUNOTERAPIA
  33. 33. • Key results (cont.) - Strong PD-L1 tumour expression correlated with improved response, PFS and OS Conclusions - Pembrolizumab was effective in patients with treatment-naïve or previously treated advanced NSCLC - In particular, patients with strong PD-L1 tumour expression may benefit from this treatment LBA43: Antitumor activity of pembrolizumab (MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC) – Garon E et al Strong PD-L1 positivity defined as staining in ≥50% of tumour cells, and weak PD-L1 positivity as staining in 1–49% of tumour cells. Negative staining is no PD-L1 staining in tumour cells. Data cutoff: March 3, 2014. PFS (RECIST v1.1, Central Review) 0 8 16 24 32 40 48 100 80 60 40 20 0 Progression-freesurvival,% Time, weeks n at risk Strong Weak Negative 44 53 49 28 43 30 18 17 15 17 12 7 9 6 1 6 0 0 3 0 0 Overallsurvival,% Strong Weak Negative 0 2 4 6 8 10 100 80 60 40 20 0 Time, months 44 53 49 43 51 42 34 34 29 27 22 14 21 18 8 18 11 6 5 5 0 12 8 7 2 9 8 4 30 26 21 32 31 26 38 48 38 38 40 34 5 5 0 14 4 4 0 OS Garon et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA43
  34. 34. Rizvi, ASCO 2014
  35. 35. CPNM Avanzado NUEVOS FÁRMACOS
  36. 36. A randomized, multicenter, open-label, phase III study of gemcitabine- cisplatin (GC) chemotherapy plus NECITUMUMAB (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC). Abstract No:8008. Nick Thatcher*, Fred R. Hirsch, Alexander V. Luft, Aleksandra Szczesna, Tudor E. Ciuleanu, Wojciech Szafranski, Mircea Dediu, Rodryg Ramlau, Rinat K. Galiulin, Beatrix Bálint, György Losonczy, Andrzej Kazarnowicz, Keunchil Park, Christian Schumann, Martin Reck, Luis Paz-Ares, Henrik Depenbrock, Shivani Nanda, Anamarija Kruljac- Letunic, Mark A. Socinski Necitumumab: Ac anti EGFR Primary Objective: OS (HR 0.80); 545 pacients each arm
  37. 37. OS: 11.5m vs 9.9m PFS: 5.7 m vs 5.5m
  38. 38. LBA8011: NINTEDANIB (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double- blind phase III trial – Reck M et al R 1:1 PD PDKey patient inclusion criteria •Stage IIIB/IV or recurrent NSCLC •Failure after first-line chemotherapy •ECOG PS 0-1 (n=1,314) Placebo bid PO days 2-21 + docetaxel 75 mg/m2 IV day 1 q3w (n=659) Nintedanib 200 mg bid PO days 2-21 + docetaxel 75 mg/m2 IV day 1 q3w (n=655) Randomised, double-blind, placebo-controlled, Phase III study Objective: To evaluate nintedanib plus docetaxel in patients with stage IIIB/IV or recurrent NSCLC progressing after first-line chemotherapy Primary endpoint •PFS Secondary endpoints •OS in the total population •OS in adenocarcinoma Stratification • ECOG PS; prior bevacizumab; histology; brain metastases Reck M, Lancet Oncol 2014
  39. 39. Key efficacy data: PFS and OS • Key results – Patient characteristics were balanced between the two groups (~70% were <65 years of age; 73% male; ~50% had adenocarcinoma; ~25% were never smokers; ~95% had received prior platinum- based therapy) – Incidence of grade ≥3 AEs for nintedanib+docetaxel vs. placebo+docetaxel was 71.3% vs. 64.3% – Grade ≥3 AE occurring in ≥1% with nintedanib+docetaxel included: decreased neutrophils, ALT increased, diarrhoea, fatigue, dyspnoea, AST increased, pneumonia, asthenia, chest pain and appetite decreased Nintedanib+ docetaxel Placebo+ docetaxel HR (95% CI) p value PFS, months All patients Adenocarcinoma SCC 3.4 4.0 2.2 2.7 2.8 2.6 0.79 (0.68–0.92) 0.77 (0.62–0.96) 0.77 (0.62–0.96) 0.0019 0.0153 0.0200 OS, months All patients Adenocarcinoma SCC 10.1 12.6 8.6 9.1 10.3 8.7 0.94 (0.83–1.05) 0.83 (0.70–0.99) 1.01 (0.85–1.21) 0.2720 0.0359 0.8907 Reck M, Lancet Oncol 2014
  40. 40. Lancet 2014 • Phase III 2nd-Line Study • NSCLC: Squamous / Non- Squamous • N= 1253 p. • Primary Objective: OS: + • Toxicities were manageable +
  41. 41. ESMO 2014
  42. 42. LUX-Lung 8: PFS, independent review EstimatedPFSprobability 0 Time (months) 0.4 0.8 1.0 0.6 0.2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 No. of patients Afatinib 335 266 127 96 54 45 28 25 16 15 8 8 4 2 2 1 Erlotinib 334 256 112 72 43 34 15 12 6 5 0 0 0 0 0 0 Afatinib Erlotinib Total randomised, n (%) 335 (100) 334 (100) Patients progressed/died 202 (60) 212 (64) Median PFS, months 2.4 1.9 HR 0.82 95% CI (0.68–1.00) Log-rank p value 0.0427 CI, confidence interval; HR, hazard ratio
  43. 43. ¿Qué hemos aprendido en 2014? • Adyuvancia: – Erlotinib no mejora la SLP en p. EGFR + por FISH o IHQ. – EGFR-TKI en p. mutación EGFR + ¿? • Localmente avanzado: – QT neoadyuvante a Cirugía mejora un 5% la SG a 5 años. • Mutación de EGFR: – Afatinib mejora la OS frente a QT (pooled analysis) – Erlotinib + Bevacizumab mejoran PFS vs Erlotinib – Deleción exon 19 mejores resultados – Resistencia adquirida (T790M +): EGFR-TKI 3ª generación (AZD9291, CO-1686) son eficaces. – Tras PR a Gefitinib, continuar con Gefitinib + QT no mejora SG vs QT – Criterios RECIST pueden no ser útiles, EGFR-TKI pueden aportar beneficio en PR clinicamente no agresiva
  44. 44. ¿Qué hemos aprendido en 2014? • Translocación de ALK: – Crizotinib mejor SLP y RR que QT en 1ª línea – Ceritinib eficaz en pacientes previamente tratados y sin tratamiento previo, y activo en pacientes con M1 SNC (también Crizotinib) – Alectinib activo en p. pretratados, tb con afectación SNC • Traslocación ROS1: – Crizotinib es activo • Amplificación de MET: – Historia de tabaquismo – Crizotinib eficaz en p. con amplificación MET por FISH • Inmunoterapia: – Inh PD1/PL1: Activos en CPNM avanzado pretratados y 1ª línea – Mayor actividad en PD-L1 + – Por definir el mejor método para determinar PD-L1, cómo evaluar la eficacia,…
  45. 45. ¿Qué hemos aprendido en 2014? • Nuevos Fármacos: – Necitumumab mejora SG y SLP en 1ª línea – Nintedanib mejora SLP y SG en adenocarcinomas en 2ª línea – Ramucirumab mejora SG y SLP en 2ª línea – Afatinib en ca escamoso en 2ª línea mejora SLP respecto de Erlotinib (discretamente)

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