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Il trattamento di prima linea nel paziente con mutazione EGFR Vanesa Gregorc

Il trattamento di prima linea nel paziente con mutazione EGFR Vanesa Gregorc Thoracic Oncology and Melanoma area coordinator IRCCS Ospedale San Raffaele Milano. Who should be tested for EGFR mutations?. Non-squamous NSCLC NSCLC NOS Adenosquamous NSCLC Squamous cell carcinoma if

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Il trattamento di prima linea nel paziente con mutazione EGFR Vanesa Gregorc

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  1. Il trattamento di prima linea nel paziente con mutazione EGFR Vanesa Gregorc Thoracic Oncology and Melanoma area coordinator IRCCS Ospedale San Raffaele Milano

  2. Who should be tested for EGFR mutations? • Non-squamous NSCLC • NSCLC NOS • Adenosquamous NSCLC • Squamous cell carcinoma if • Low smoking exposure • Young age

  3. Smoking exposure and EGFR mutations Pack-year %EGFR+ 30-51 0-15 >=16 0-10 Pham et al, JCO 2006

  4. Lung Cancer Consortium Mutation - 16 US cancer centers - Test 10 driver mutations in 1000 lung adenocarcinomas At half of LCMC sites, multiplexed testing for all mutations is now routine practice in their pathology departments (ASCO 2011)

  5. EGFR mutations Sequist et al, JCO 2007

  6. Test EGFR su DNA circolante Douillard et al, Br J Cancer 2013

  7. Quale EGFR-TKI in EGFR mutati? Indicazioni AIFA Gefitinib Indicato in qualunque linea in EGFR mutati Erlotinib Indicato in I linea negli EGFR mutati; II-III linea indipendentemente da EGFR Afatinib Indicato in I linea negli EGFR mutati

  8. 1st line: EGFR-TKIs vs CT *Primary endpoint

  9. PFS with TKIs better for del19 than L858R Del19 HR: 0.24 L858R HR: 0.48 p for interaction < 0.001 Lee et al. JCO 2015 MTE12: Therapy for Driver Mutation Positive Advanced NSCLC – Federico Cappuzzo

  10. PFS

  11. Lancet Oncology, Feb 2015

  12. LUX-Lung 3: OS in Common Mutations and Del19 in Asian and Whole Population Common Mutations Del19 PFS in overall population PFS in overall population 1.0 1.0 0.8 0.8 0.6 0.6 Estimated OS probability Estimated OS probability 0.4 0.4 0.2 0.2 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Time (months) Time (months) No. of patients No. of patients Afatinib 203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0 104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0 149 148 141 135 126 121 106 98 91 81 77 67 47 41 29 9 1 0 75 70 66 61 57 51 45 42 40 37 31 27 20 17 10 5 1 0 Afatinib 112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0 57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0 82 81 78 75 70 68 59 56 52 45 43 37 27 24 18 6 1 0 41 40 37 33 31 26 22 20 18 17 15 11 7 5 1 1 0 0 Cis/Pem Pem/Cis Afatinib Afatinib Cis/Pem Cis/Pem Sequist et al. CMSTO 2014. Oral presentation. Abstract 3341.

  13. HR for OS in del19 Kato T et al., ISPOR 2015; PCN40

  14. HR for OS in L858R Crossover from CT to TKI 75% 53% 52% 95% 76% Adapted from West, ASCO 2014

  15. HR for OS in L858R Kato T et al., ISPOR 2015; PCN40

  16. Outcome in caso di mutazioni non comuni Yang et al, WCLC 2013

  17. Survey (n = 562, 10 countries):first-line choice in EGFR mutated Spicer et al, ELCC 2015

  18. OPEN Questions: EGFR-TKI and OBD vs MTD, side effects, dosage, drug interaction, drug reductions

  19. Fatigue: Afatinib: 10-17% Gefitinib: 10-39% Erlotinib: 5-57% Stomatitis: Erlonib: 13% Gefitinib: 9-40% Afatinib: 50-72% Anorexia: Afatinib: 10-20% Gefitinib: 14-44% Erlotinib: 31% Vomiting: Erlonib: 1% Afatinib: 9-17% Gefitinib: 12-19% Transaminitis: Erlotinib: 6% Afatinib: 11% Gefitinib: 40-60% Diarrhoea: Erlonib: 25-57% Gefitinib: 34-54% Afatinib: 88-95% Skin Rash: Gefitinib: 49-85% Erlotinib: 73-79% Afatinib: 80-89% Paronichia: Erlonib: 4% Gefitinib: 13-32% Afatinib: 32-56% Modified from Landi L , Expert Opin Pharmacother 2014

  20. Afatinib Plasma Levels in Patients Who Dose Reduced and Those Who Remained on Afatinib 40 mg • Dose reduction was more likely in patients with higher plasma concentrations • Geometric mean plasma concentrations • 24.4 ng/mL after dose reduction to 30 mg ≥4 days previously (n=38) • 23.7 ng/mL in patients who remained on 40 mg (n=126) : patients who remained on 40 mg until C3V1 (n=126); , patients who dose reduced to 30 mg before C3V1 (n=38; only 10 of these patients had valid trough concentrations on 40 mg afatinib at C2V1 [the rest had either no PK sampling due to dose interruption, were already on 30 mg afatinib or were excluded due to invalid sampling]) Yang et al. ASCO 2015 #8073 Individual data with median and 25th/75th percentiles 10th/90th percentiles Datapoints outside percentiles 140 120 100 80 Trough plasma concentrations (ng/mL) 60 40 20 0 40 mg(n=122) 40 mg(n=10) 40 mg(n=126) 30 mg(n=38) C2V1 (Day 22) C3V1 (Day 43)

  21. PFS in Patients Who Had or Had Not Dose Reductions Within the First 6 Months <40 mg in first 6 months Median PFS was similar in patients who had afatinib dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily ≥40 mg in first 6 months PFS in overall population No. at risk <40 mg in first 6 months 105 87 75 58 41 26 15 6 2 0 ≥40 mg for first 6 months 124 93 76 62 36 24 16 4 1 0 CI, confidence interval; HR, hazard ratio Yang et al. ASCO 2015 #8073 1.0 0.8 0.6 Estimated PFS probability 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 Time (months)

  22. Pharmacokinetic parameters for EGFR TKI Afatinib è indicato  nel trattamento di pazienti adulti naïve agli inibitori tirosinchinasici del recettore del fattore di crescita dell’epidermide (EGFR-TKI) con carcinoma polmonare non a piccole cellule (NSCLC) localmente avanzato o metastatico con mutazione(i) attivante(i) l’EGFR. Adapted from S. Peters et al. Cancer Treatments review 40(2014) 917-926

  23. OPEN Questions: Direct comparisons?

  24. LUX Lung 7: phase IIb trial of afatinib vs gefitinib • Patients with • Advanced lung adenocarcinoma • Documented common EGFR mutations (del19 or L858R) • First line (no prior treatment) • N = 264 Randomization Gefitinib 250 mg Afatinib 40 mg Primary endpoint: PFS and disease control rate at 12 months ClinicalTrials.gov. NCT01466660.

  25. ARCHER 1050: phase III trial of dacomitinib vs gefitinib • Patients with • Advanced NSCLC • Documented common EGFR mutations (del19 or L858R ± T790M) • First line (no prior treatment) • N = 440 Randomization Gefitinib 250 mg Dacomitinib 45 mg Primary endpoint: PFS ClinicalTrials.gov. NCT01774721

  26. OPEN Questions: EGFR-TKIS clinical strategy?

  27. Del19/L858R: first line TKI and post progression treatment PFS (months) T790M+ (60%) 8-9 9-11 Gefitinib, erlotinib AZD9291, Rociletinib ? 10-13 Afatinib ?

  28. Del19/L858R: first line TKI and post progression treatment PFS (months) ? AZD9291, Rociletinib ? Randomized trials of 3rd vs 1st generation TKI in 1L are ongoing

  29. OPEN Questions: T790M in TKI-naïve patients

  30. EURTAC: PFS according to T790M and treatment T790M detected in 65.2% of patient 9.7 months 6.0 months Costa et al. Clinical Cancer Research 2014

  31. T790M in TKI-naïve patients • 20 T790M TKI-naïve patients (2% of EGFR-mutant tumors) • 16/20 concurrent L858R • 4/20 concurrent exon 19 deletion Yu et al. Ann Oncol 2014

  32. PFS under TKIs inT790M+ patients Yu et al. Ann Oncol 2014

  33. IrreversibleTKIs and T790M: small therapeuticwindow T790M 100x Wt T790M 10x Relative IC50 Wt Wt T790M 1x EGFRm EGFRm EGFRm Gefitinib Erlotinib Ideal T790M inhibitor Afatinib Dacomitinib Adapted from Oxnard

  34. OPEN Questions: EGFR-TKIS resistance EGFR-Tkis & future?

  35. EGFR mutations are early events 100 No of mutations PTEN MAP3K19 TP53 EGFR ARID1B TP53 EGFR TP53 EGFR TP53 EGFR Private Shared Trunk 50 EGFR EGFR EGFR EGFR A014 L858R A001 L858R A006 Ex 19 del A021 L858R A017 L858R A022 Ex 20 ins A028 L858R A027 Ex 19 del Tan, WLCC 2015

  36. Infiammation+/-IMMS angiogenesis ETOP 2-11 BELIEF | 18th ECCO – 40th ESMO European Cancer Congress, September 2015

  37. Future perspectives Need for a deepened understanding of mechanisms of primary resistance to TKIs in EGFR mutated patients • Mutation-basedmechanisms: • De novo T790M • PIK3CA mutations (2%) • PTEN loss (5%) • Microenvironment mediated cancer progression: • Angiogenesis: VEGFR, FGFR (nintedanib, ramucirumab) • Paracrine signalling: HGF (ficlatuzumab) • Immune escape: PD-1/PDL-1 (immunotherapy)

  38. Erlotinib +/- ramucirumab

  39. Ongoing studies RELAY (NCT02411448) Erlotinib in Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC

  40. PROSE study: VeriStrat proteomic algorithm as a prognostic and predictive test • Good classification group had no significant OS difference between treatment arms: • HR Erl vs CT 1.06 [95% CI 0.77–1.46], p=0.714. • Poor classification group had significantly shorter OS on erlotinib than on chemotherapy: • HR Erl vs CT 1.72 [95% CI 1.08–2.74], p=0.022. VeriStrat proteomic classifier is prognostic for OS and PFS • OS: HR Poor vs Good 2.50 [95% CI 1.88–3.31]; p<0.0001 • PFS: HR Poor vs Good 1.75 [95% CI 1.34–2.29]; p<0.0001 Gregorc et al. Lancet Oncol.2014 Jun;15(7):713-21

  41. Phase II study of Ficlatuzumab+Gefitinib vs Gefitinib+placebo VeriStrat retrospective analysis Good Poor Mok et al. Ann Oncol. 2012;23(Suppl 9):ix391:Abstract 1198P Mok et al. Ann Oncol, 25 (Suppl. 4) (2014), pp. 58–84 (Abstract 205P)

  42. Erlotinib +/- Ficlatuzumab

  43. Ongoing studies RELAY (NCT02411448) Erlotinib in Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC FOCAL(NCT02318368) Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib in Subjects with PreviouslyUntreatedMetastatic, EGFR-mutated NSCLC and BDX004 Positive Label

  44. AZD9291 +/- MEDI4736

  45. Ongoing studies RELAY (NCT02411448) Erlotinib in Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC FOCAL(NCT02318368) Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib in Subjects with PreviouslyUntreatedMetastatic, EGFR-mutated NSCLC and BDX004 Positive Label CAURAL (NCT02454933) Phase III Study of AZD9291 in Combination with MEDI4736 (anti PD-L1 mAb)versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic EGFR T790M positive NSCLC who have received Prior EGFR TKIs

  46. -Drug interaction -Patient compliance (ECOG PS, age, education..) -Liver function Afatinib Gefitinib/Erlotinib EGFR-mutant NSCLC Del 19 L858R Gefitinib/Erlotinib/Afatinib Or CT followed by EGFR-TKis Afatinib/Erlotinib/Gefitinib Uncommon EGFRm

  47. www.lucenetwork.it Database Center Net Database NSCLC Navigator Database Clinical Trial ongoing Forum di discussione Link a siti utili alessandro.urbani@programmaergo.com

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