El tratamiento actual de primera línea en CPNCP. EGFR mutado: balance entre eficacia/perfil de tolerancia Manuel Dómine Servicio de Oncología Médica.

Transcripción

1 El tratamiento actual de primera línea en CPNCP. EGFR mutado: balance entre eficacia/perfil de tolerancia Manuel Dómine Servicio de Oncología Médica. Hospital Universitario Fundación Jiménez Díaz Instituto de Investigación Sanitaria- Fundación Jiménez Díaz (IIS-FJD).

2 17,664 patients with NSCLC A genetic alteration was recorded in about 50% of the analyses Presence of a genetic alteration compared with absence of a genetic alteration was associated with improved: first-line progressionfree survival (10 0 months [95% CI ] vs 7 1 months [ ]; p<0 0001) overall survival (16 5 months [ ] vs 11 8 months [ ]; p<0 0001)

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4 Estudios Randomizados TKIs Vs Quimioterapia en pacientes con mutaciones EGFR (TKIs 1ª generación) Gefitinib Estudio/ Fase Ramas de tratamiento Nºpacientes (región) RR ( (%) p m SLP (meses) HR p Supervivencia SM (meses) HR p IPASS 1 2 /III Gefitinib vs Carbo-taxol 261 Asia 71.2 vs 47.3 p< vs p< vs p= First-SIGNAL 3 /III Gefitinib vs Cis-gem 96 Corea 84.6 vs 37.5 p= vs p= vs p=0.428 WJTOC /III Gefitinib vs Cis-docetaxel 177 Japón 62.1 vs 32.2 p< vs p< vs p= NEJ /III Gefitinib vs Carbo-taxol 230 Japón 73.7 vs 30.7 p< vs p< vs p=0.483 RR: tasa de respuestas, mslp: mediana de Supervivencia libre de progresión, SM: Supervivencia Mediana NR: no reportado

5 Estudios Randomizados TKIs Vs Quimioterapia en pacientes con mutaciones EGFR (TKIs 1ª generación) Erlotinib Estudio/ Fase Ramas de tratamiento Nºpacientes (región) RR ( (%) p m SLP (meses) HR p Supervivencia SM (meses) HR p OPTIMAL 8 9 /III Erlotinib vs carbo-gem 154 China 83 vs 36 p< vs p< vs p = EURTAC 10 /III Erlotinib vs cis-docetaxel 174 Europa 58 vs 15 p< vs p< vs p=0.87 ENSURE 11 /III Erlotinib vs cis-gem 148 Asia 62.7 vs 33.6 p< vs p< vs p=0.607 RR: tasa de respuestas, mslp: mediana de Supervivencia libre de progresión, SM: Supervivencia Mediana NR: no reportado

6 Estudios Randomizados TKIs Vs Quimioterapia en pacientes con mutaciones EGFR (TKIs 2ª generación) (Afatinib) Estudio/ Fase Ramas de tratamiento Nºpacientes (región) RR ( (%) p m SLP (meses) HR p Supervivencia SM (meses) HR p LUX-LUNG 3/III Afatinib vs Cis-pem 345 Global 345 Global 11.1 vs p= vs p=0.39 LUX-LUNG 6 /III Afatinib vs Cis-gem 364 China 67 vs 23 p< vs p< vs p=061 RR: tasa de respuestas, mslp: mediana de Supervivencia libre de progresión, SM: Supervivencia Mediana NR: no reportado

7 Estimated OS probability Estimated OS probability Del19 and L858R Subgroups Combined OS analysis of LUX-lung 3 and LUX- lung 6 * Del19 L858R Del19 L858R Afatinib (n=236) Chemo (n=119) Afatinib (n=183) Chemo (n=93) Median, months Median, months HR (95% CI) P value 0.59 ( ) P= HR (95% CI) P value 1.25 ( ) P= Afatinib Chemotherapy Time of overall survival (months) Afatinib Chemotherapy Time of overall survival (months) No. of patients: No. of patients: Afatinib Chemotherapy Afatinib Chemotherapy *Yang et al. Lancet Oncology 2015

8 LUX-LUNG 7 STUDY DESIGN Patients (N=319) Stage IIIB/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumour tissue* No prior treatment for advanced/metastatic disease ECOG PS 0/1 1:1 Afatinib 40 mg QD Stratified by Mutation type (Del19/L858R) Brain metastases (present/absent) Gefitinib 250 mg QD Co-primary endpoints: PFS (independent review) TTF OS Secondary endpoints: ORR Time to response Duration of response Tumour shrinkage HRQoL Treatment beyond progression allowed if deemed beneficial by investigator RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter Primary PFS analysis conducted after ~250 events; primary OS analysis conducted after ~213 events and 32-mo follow-up All statistical testing at two-sided 5% alpha level with no adjustment for multiplicity

9 Estimated PFS probability PFS by Independent Review Afatinib Gefitinib Median, mo HR (95% CI) P-value 0.73 ( ) Afatinib Gefitinib %* 18% % Time of progression free survival (months) No. at risk: Afatinib Gefitinib % Park K et al. Lancet Oncol. 2016;17(5):577-89; * P= P=0.0184

10 Estimated PFS probability Estimated PFS probability PFS by Mutation Type (Independent Review) Del19 L858R 1.0 Afatinib (n=93) Gefitinib (n=93) 1.0 Afatinib (n=67) Gefitinib (n=66) Median, mo Median, mo HR (95% CI), P-value 0.76 ( ) HR (95% CI), P-value 0.71 ( ) Afatinib Gefitinib 0.6 Afatinib Gefitinib Time of progression-free survival (months) No. at risk: Afatinib Gefitinib Time of progression-free survival (months) No. at risk: Afatinib Gefitinib Park K et al. Lancet Oncol. 2016;17(5):577-89

11 Estimated Overall Survival Probability Overall Survival (71% Maturity; April 2016) % # Afatinib Gefitinib Events Median, mo HR (95% CI) P-value 0.86 ( ) Afatinib Gefitinib 51% 48% $ 40% Time to Death (months) No. at risk: Afatinib Gefitinib Paz-Ares L et al. Ann Oncol, 2017 epub ahead of print * # P=0.0756; $ P=

12 Os by EGFR mutation subtype. (Update Dec. 2016) Del19 L858R OS trends with afatinib were consistent across mutational (Del19, 30.7 months; L858R, 25.0 months) subgroups Corral J et al., ELCC 2017; #93PD

13 Drug-Related AEs ( 20, updated) Afatinib (n=160) Gefitinib (n=159) All Gr Grade 3* All Gr Grade 3* Any AE, n (%) 156 (97.5) 50 (31.3) 153 (96.2) 31 (19.5) Diarrhoea 144 (90.0) 21 (13.1) 97 (61.0) 2 (1.3) Rash/Acne 142 (88.8) 15 (9.4) 129 (81.1) 5 (3.1) Stomatitis 103 (64.4) 7 (4.4) 38 (23.9) 0 Paronychia 90 (56.3) 3 (1.9) 28 (17.6) 1 (0.6) Dry skin 52 (32.5) 0 59 (37.1) 0 Pruritus 37 (23.1) 0 36 (22.6) 0 Fatigue 33 (20.6) 9 (5.6) 23 (14.5) 0 ALT increased 15 (9.4) 0 38 (23.9) 13 (8.2) AST increased 10 (6.3) 0 33 (20.8) 4 (2.5) Low rates of treatment discontinuation due to drug-related AEs were observed in each arm (6,3% each) Paz-Ares L et al Paz-Ares L et al. Ann Oncol, 2017

14 Estimated PFS probability Estimated PFS probability Estimated PFS Probability Median PFS was similar in patients who had dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily LUX-Lung LUX-Lung 6 <40 mg in first 6 months 40 mg in first 6 months Time (months) Time (months) LUX-Lung Time of progression-free survival (months) Yang J et al. J Clin Oncol 33, 2015 (suppl; abstr 8073); Schuler M et al., ELCC 2016, #138PD; Hirsh V JCO 34, 2016 (suppl; abstr 9046

15 Phase III trial ARCHER 1050 Dacomitinib vs Gefitinib for the First-Line Treatment of Advanced NSCLC Mok T, et al. ASCO Abstract LBA9007.

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17 AE Occurring in 15% in Either Arm, % Dacomitinib (n = 227) Gefitinib (n = 224) Any Gr 1 Gr 2 Gr 3 Any Gr 1 Gr 2 Gr 3 Diarrhea* Paronychia Dermatitis acneiform Stomatitis Decreased appetite Dry skin Weight decrease Alopecia Cough Pruritis ALT increase Outcome Serious AE, n (%) Any Treatment related Causing discontinuation Causing death Dacomitinib (n = 227) 62 (27.3) 21 (9.3) 22 (9.7) 2 (0.9)* Gefitinib (n = 224) 50 (22.3) 10 (4.5) 15 (6.7) 1 (0.4) Median time to dose reduction, mos (range) 2.8 ( ) 3.3 ( ) Median duration of dose reduction, mos (range) 11.3 ( ) 5.2 ( ) Reduced dose given, n (%) 30 mg/day 15 mg/day ARCHER 1050: Serious AE and Dose Modification *Gr 5 diarrhea, n = 1. Otherwise, no listed AE with severity above grade 3 in either arm. 87 (38.3) 63 (27.8) Pts requiring dose reduction, n (%) 150 (66.1) 18 (8.0) NA

18 PFS probability JO25567: erlotinib vs erlotinib + bevacizumab PFS by independent review in all patients (primary endpoint) Avastin + Tarceva Tarceva HR=0.54 ( ) Log-rank p< Number at risk Time (months) A+T T Seto, et al. Lancet Oncol, 2014

19 JO25567: PFS by EGFR mutation type Seto, et al. Lancet Oncol, 2014

20 JO25567: AEs in >20% of patients Seto, et al. Lancet Oncol 2014

21 First line EGFR m+ Erlotinib + BVZ BELIEF Phase II trial Ph II BELIEF (2015 ECC) 1 st Line: erlotinib + BVZ n=109 EGFRm+ (Del 19, L858R) 37 pts T790m+ pretreatment SLP 1a: 72.4% SLPm 16m TRO: 70.3% 72 pts T790m- pretreatment SLP 1a: 49.4% SLPm: 10.5m TRO: 79.2% Rosell R, et al. Lancet Respir Med. 2017;5:

22 FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC Soria et al. NEJM 2017; November 18, 2017DOI: /NEJMoa

23 FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC Soria et al. NEJM 2017; November 18, 2017DOI: /NEJMoa

24 FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC Soria et al. NEJM 2017; November 18, 2017DOI: /NEJMoa

25 FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC Soria et al. NEJM 2017; November 18, 2017DOI: /NEJMoa

26 Probability of progression-free survival Osimertinib in first line increase PFS because target clones with T790M from the beginning OR RELAPSE THE APARITION OF T790M AS THE FIRST RESISTANCE MECHANISM? 1.0 Median PFS, months (95% CI) 0.8 Osimertinib SoC 18.9 (15.2, 21.4) 10.2 (9.6, 11.1) # Pre-existing T-790M IN 34-35% of patients. Rosell Lancet Respiratory 2017, Rosell CCR HR 0.46 (95% CI 0.37, 0.57) p< No. at risk Osimertinib SoC Time from randomisation (months)

27 All causality AE in 15% of patients, % FLAURA: Phase III TRIAL Adverse Events Osimertinib (n=279) SoC (n=277) Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4 Diarrhoea 161 (58) 6 (2) (57) 6 (2) 0 Dry skin 88 (32) 1 (<1) 0 90 (32) 3 (1) 0 Paronychia 81 (29) 1 (<1) 0 80 (29) 2 (1) 0 Stomatitis 80 (29) 1 (<1) 1 (<1) 56 (20) 1 (<1) 0 Dermatitis acneiform 71 (25) (48) 13 (5) 0 Decreased appetite 56 (20) 7 (3) 0 51 (18) 5 (2) 0 Pruritus 48 (17) 1 (<1) 0 43 (16) 0 0 Cough 46 (16) (15) 1 (<1) 0 Constipation 42 (15) (13) 0 0 AST increased 26 (9) 2 (1) 0 68 (25) 12 (4) 0 ALT increased 18 (6) 1 (<1) 0 75 (27) 21 (8) 4 (1) Soria et al. NEJM 2017; November 18, 2017DOI: /NEJMoa

28 AEs Randomized Trials EGFR TKIs Trials Adverse Events Gefitinib ARCHER Erlotinib JO25567 Afatinib LL7 Dacomitinib ARCHER Osimertinib FLAURA Erlo + BVZ JO25567 Any/Grade 3 Any/Grade 3 Any/Grade 3 Any/Grade 3 Any/Grade 3 Any/Grade 3 Diarrhoea 55.8/0.9 78/1 90/ /8.4 58/2 81/1 Dry skin 17/0 75/3 52/0 27.8/1.3 32/<1 76/3 Paronychia 20.1/1.3 65/4 56.3/ /7.5 29/<1 75/3 Stomatitis 17.9/0.4 60/3 64.4/ /3.5 29/<2 63/1 Dermatitis acneiform 28.6/0 99/ / / /0 99/25 Decreased appetite 24.6/0.4 32/1 17/0 30.8/3.1 20/3 35/1 Pruritus 13.8/1.3 42/0 23.1/0 19.8/0.4 17/<1 45/1 AST/ALT increased 39.3/8.5 51/18 16/0 19.4/0.9 18/1 44/8 Hypertension - 13/ /60 Haemorrhagic Event - 29/ /3 Proteinuria - 4/ /8 AEs causing discontinuation %

29 IPASS First Signal WJTOG NEJ002 OPTIMAL EURTAC ENSURE LUX - LUNG 3 LUX - LUNG 6 LUX - LUNG 7 ARCHER 1050 J BELIEF FLAURA First Line Trials with TKIs EGFR + Progression Free survival (months) Gefitinib Erlotinib Afatinib Dacomitinib Erlo + Bvz Osimertinib

30 PFS comparison second vs third gen TKIs LL7 ARCHER FLAURA 35.8%

31 Efficacy of Afatinib in Uncommon mutations

32 V in s G S V H d u p P R H in s A H D d e l in s G Y N in s H H D in s Y H Y D in s G S d u p S V D P in s D N P A d u p A S V S I M a x im u m R e s p o n s e fro m B a s e lin e Poziotinib in exon 20 inertions EGFR Exon 20 insertions have a sterically hindered binding pocket EGFR T790M EGFR D770insSVD Robichaux et al WCLC 2016 Preliminary results: poziotinib induces partial response in 73% of patients with EGFR Exon 20 mutations -11 EGFR exon 20 patients with baseline and follow up scans at 2 m (longest on treatment=6 months). -Activity: 8/11 PR observed; 2 patients have had additional follow up scans confirming PR. -duration of response not yet evaluable; only one patient with PD thus far. -Evidence of CNS activity in patient with CNS metastasis and another with LMD -additional patient treated on compassionate use IND (CIND) also had PR S A,P Poziotinib Prior Therapy: P = AP32788 S= ASP 8273 E = Erlotiniib A = Afatinib E,A -Toxicities: significant EGFR-related toxicities include rash, diarrhea, paronychia, mucositis consistent with those previously described. -55% underwent dose reduction to 12mg thus far -6 0 Abstract ID 10369, Elamin et al. Elamin et al. IASLC 2017 Ab 10369

33 Targeted treatments are evaluated in resistance to 3 rd gen inhibitor Initial biopsy also: liquid biopsy PD: rebiopsy also: liquid biopsy PD: rebiopsy also: liquid biopsy EGFRde l 19 L858R Erlotinib, Gefitinib, Afatinib (10m) T790M Osimertinib (10m) EGFR C797S EGFR G724S Osimertinib (20m) hl MET amp. clinical trials HER2 amp. KRAS mut Chemotherapy Thress et al, NEJM 2015, Ortiz-Cuaran et al, CCR 2016, Fassunke et al, in prep.

34 OS in patients treated with a subsequent 3rd-generation EGFR TKI 20% / 17% who discontinued afatinib / gefitinib received 3 rd gen TKIs (osimertinib, olmutinib and rociletinib) Corral J et al., ELCC 2017; #93PD

35 Cuál es la secuencia óptima para EGFR mutados? 1ª generación TKI (10 meses) Osimertinib en T790M (10 meses) OS 27 meses QT (5 meses) OS 22 meses 2ª generación TKI (14-16 meses) Osimertinib en T790M (10 meses) QT (5 meses) OS 27 meses OS? Erlotinib + BVZ (16 meses) QT (5 meses) Osimertinib en T790M (10 meses) OS? OS? Osimertinib (19 meses) QT (5 meses) OS? 35

36 CONCLUSIONES Osimertinib es el fármaco más eficaz en términos de SLP Osimertinib es el que presenta mejor perfil de tolerancia Debe ser nuestra primera opcíón de tratamiento en todos los pacientes? Si en pacientes con metastasis cerebrales Si en pacientes con mutaciones de T790M de novo En pacientes con mutaciones no comunes (18-21 (L861Q, G719S, G719A, G719C, S768I, y otras), afatinib ha mostrado una eficacia alta y podría ser la primera opción. En el resto de pacientes los tratamientos secuenciales con TKIs de 1ª y 2ª generación seguido de orsimetinib en T790M + pueden obtener SLP comparables a osimetinib en 1ª línea. Inserciones 20: Pociotinib La secuencia óptima todavia es incierta y todavía está pendiente de los resultados de supervivencia de los estudios AURA y FLAURA Pendientes de resultados de estudios de combinaciones con antiangiogénicos e inmmunoterapia