TKI en primera línea EGFR mutado:importancia del equilibrio eficacia tolerabilidad Dra Pilar Lianes Barragan Consorcio Sanitario del Maresme (Barcelona)
Indice Epidemiología TKI en primera línea Eficacia por tipo de mutación Qué TKI elegir? Toxicidad
EGFR Mutations Cause Lung Cancer ELREA del19 Somatic mutations discovered in 2004 Associated with response to TKIS 1,2,3 Found in 30-40% of Asians 4 Found in 10-15 % of Caucasians More frequent in adenocarcinomas Found more commonly in never or light smokers 5 Del19 and L858R mutations make up 85% of all activating mutations Around 50% of patients relapsing on 1 st generation EGFR-TKI display an EGFR T790M containing mutation 1. Lynch NEJM 2004; 2. Paez Science 2004; 3. Pao PNAS 2004; 4. Shigematsu JNCI 2005; 5. Pham JCO 2006 3
EGFR mutated NSCLC is a distinct disease : oncogene addiction
FINDING THE MUTATION
TKI vs QT en 1ª línea EGFR TKIs are more efficacious than chemo - PFS - RR - OS?
Probability of progression-free survival Probability of progression-free survival Progression-free survival in EGFR mutation positive and negative patients EGFR mutation positive EGFR mutation negative 1.0 Gefitinib (n=132) Carboplatin / paclitaxel (n=129) 1.0 Gefitinib (n=91) Carboplatin / paclitaxel (n=85) 0.8 0.6 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) 0.8 0.6 HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib, 88 (96.7%) No. events C / P, 70 (82.4%) 0.4 0.4 0.2 0.2 t risk : efitinib C / P 0.0 0 4 8 12 16 20 24 Months 132 108 71 31 11 3 0 129 103 37 7 2 1 0 0.0 0 4 8 12 16 20 24 Months 91 21 4 2 1 0 0 85 58 14 1 0 0 0 Treatment by subgroup interaction test, p<0.0001 ITT population Cox analysis with covariates Ipass study-mok et al NEJM 361:947 2009
EURTAC Trial: Erlotinib v Chemo Rosell et al., Lancet Oncol 2012
Phase III trials in EGFR + Author Study Agent N (EGF R mut +) RR Median PFS (mo) PFS HR OS (mo) OS HR Mok et al IPASS Gefitinib 261 71.2% vs 47.3% 9.8 vs 6.4 0.48 (0.36-0.64) 21.6 vs 21.9 1.00 (0.76-1.33) Han et al First- SIGNAL Gefitinib 42 84.6% vs 37.5% 8.0 vs 6.3 0.54 (0.27-1.1) 27.2 vs 25.6 1.04 (0.50-2.18) Mitsudomi et al WJTOG 3405 Gefitinib 172 62.1% vs 32.2% 9.2 vs 6.3 0.49 (0.34-0.71) 30.9 vs NR 1.25 (0.88-1.78) Maemond o et al NEJGSG00 2 Gefitinib 230 73.7% vs 30.7% 10.8 vs 5.4 0.30 (0.22-0.41) 30.5 vs 23.6 0.89 (0.63-1.24) Zhou et al OPTIMAL Erlotinib 154 83% vs 36% 13.7 vs 4.6 0.16 (0.10-0.26) Rosell et al EURTAC Erlotinib 174 58% vs 15% 9.7 vs 5.2 0.47 (0.28-0.78) 22.7 vs 28.9 1.04 (0.69-1.58) 19.3 vs 19.5 0.93 (0.64-1.35) Sequist et al LUX-Lung 3 Afatinib 345 56% vs 23% 13.6 vs 6.9 0.47 (0.34 0.65) 31.6 vs 28.2 0.78 (0.58 1.06) Wu et al LUX-Lung 6 Afatinib 364 67% vs 23% 11.0 vs 5.6 0.28 (0.20 0.39) 23.6 vs 23.5 0.83 (0.62 1.09) Mok TS, et al. N Engl J Med. 2009;361(10):947-957. Han J-Y, et al. J Clin Oncol. 2012; 30:1122-1128. Mitsudomi T, et al. Lancet Oncol. 2010;11(2):121-128. Maemondo M, et al. N Engl J Med. 2010;362(25):2380-2388. Zhou C, et al. Lancet Oncol. 2011;12(8):735-742. Zhou C, et al. J Clin Oncol. 2012;30(suppl): abstract 7520. Rosell R, et al. Lancet Oncol. 2012;13: 239-246. Sequist LV, et al. J Clin Oncol. 2013;31(27):3327-3334. Wu YL, et al. Lancet Oncol. 2014;15(2):213-222
Estimated OS probability Estimated OS probability LUX-Lung 3 and 6 Exploratory Combined OS Analysis: Del19 and L858R Subgroups Del19 L858R 1.0 1.0 0.8 0.6 Afatinib Chemotherapy 0.8 0.6 Afatinib Chemotherapy 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 No. at risk: Afatinib 40 236 230 223 217 202 192 173 160 145 131 117 Time 90 of overall 50 survival 38 (months) 22 6 1 0 Chemotherapy 119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. at risk: Afatinib 40 183 181 167 154 141 128 111 91 80 70 64 51 Time of overall 27 survival 20 (months) 11 3 0 0 Chemotherapy 93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0 Afatinib (n=236) Del19 Chemo (n=119) Afatinib (n=183) L858R Chemo (n=93) Median, months 31.7 20.7 22.1 26.9 HR (95% CI), P-value 0.59 (0.45-0.77), P=0.0001 1.25 (0.92-1.71), P=0.1600 Yang J et al. Lancet Oncol 2015
Son todas la mutaciones iguales?
1202O: Clinical and biological characteristics of non-small cell lung cancer (NSCLC) harbouring EGFR mutation: Results of the nationwide programme of the French Cooperative Thoracic Intergroup (IFCT) Leduc C, et al Key results (cont.) Wild-type Exon 18 Exon 19 Exon 20 Exon 21 p-value OS, months [95%CI] 11.8 [10.1, 13.3] (n=1270) 14.2 [12.4, NR] (n=44) 27.0 [23.4, 29.1] (n=555) 16.0 [8.1, 19.1] (n=50) 21.3 [18.5, 27.8] (n=439) <0.001 PFS (first-line EGFR TKI), months [95%CI] 7.2 [6.3, 7.9] (n=1243) 12.4 [5.8, NR] (n=44) 16.3 [13.9, 18.0] (n=560) 6.4 [2.9, 9.0] (n=48) 13.7 [11.6, 16.1] (n=442) <0.0001 DCR (TKI), % 21 (n=14) 78 (n=9) 82 (n=235) 20 (n=5) 81 (n=201) <0.0001 Median OS improved for exon 19 deletions vs. L858 mutations (26.5 vs. 21.3 months, p=0.045); deletion length had no impact on OS For exon 21, median OS was longer for L858R compared with L861Q, other substitutions or wild-type (22.4 vs. 14.1 vs. 14.9 vs. 11.8, respectively; p<0.0001) For mutations further classified as common, rare or complex, DCR was 82%, 77% and 54.5%, respectively, under first-line EGFR-TKI therapy (p=0.05) No difference in DCR under EGFR-TKI therapy was observed according to mutation type for exon 19 or 21 Conclusions Distinct clinical characteristics were observed for common and uncommon EGFR mutations Patients with common exon 19 mutations tended to have better outcomes Leduc et al. Ann Oncol 2016; 27 (suppl 6): abstr 1202O
Mutaciones poco frecuentes
Mutation categories in LUX-Lung 3&6 LUX-Lung 3: Sequist et al. J Clin Oncol. 2013;31:3327; LUX-Lung 6: Wu et al. Lancet Oncol. 2014;15:213;
LUX-Lung program: Activity of Afatinib in patients with Specific Uncommon EGFRM+ Largest prospective dataset (n=75) from LUX-lung 2, 3 and 6 Activity was observed in other mutations (exon 18 [G719X], 20 [S768I], and 21 [L861Q]) that are known to be less responsive to reversible EGFR TKIs Median PFS, mo (range) Median OS, mo (range) De Novo T790M (n=14) 2.9 (0.3 13. 8) 14.9 (1.5-30.5) Exon 20 Insertions (n=23) 2.7 (0.4-11.9) 9.4 (0.4-32.2 a ) Other (n=38) 10.7 (0.0 a -35.8 a ) 18.6 (0.0 a -51.3 a ) EGFR mutations detected by TheraScreen EGFR29 test (central lab). Common: 19 deletions in exon 19 and L858R in exon 21; Uncommon: 3 insertions in exon 20, L861Q, T790M, G719S, G719A and G719C, S768I. Adapted from Yang et al. WCLC 2013. Presentation O03.05. Genotypes G719 X (n=18) L861Q (n=16) S768I (n=8) G719X (n=8) G719X + T790M (n=1) G719X + S768I (n=5) G719X + L861Q (n=3) G719X + T790M + L858R (n=1) L861Q (n=12) L861Q + G719X (n=3) L861Q + Del19 (n=1) S768I (n=1) S768I + G719X (n=5) S768I + L858R (n=2) ORR, n (%) 14 (78) 9 (56) 8 (100) Median PFS, months (95% CI) 13.8 (6.8-NE) 8.2 (4.5-16.6) 14.7 (2.6-NE) Median OS, months (95% CI) 26.9 (16.4-NE) 16.9 (15.3-22.0) NE (3.4-NE)
Qué TKI elegir? Who is better...for this patient??? Is there a difference anyway?
2L EGFR mut population Urata Y, et al. J Clin Oncol 2016
A phase III randomised controlled trial of erlotinib vs gefitinib in NSCLC with EGFR mutations (19 or 21). 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months.108). The response rates and 56.3% vs 52.3% (P=0.530) median overall survival were 22.9 vs 20.1 months (95% CI 0.63-1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172)..Yang et al. British Journal of Cancer (2017); 1-7.
Dacomitinib vs Erlotinib in 2L Patients With EGFR-Mutated Advanced Non Small-Cell Lung Cancer Archer 1009 This was a pooled subset analysis from two randomized prospective trials evaluating the safety and efficacy of second-line dacomitinib vs erlotinib in 121 patients with EGFR-mutant advanced non small cell lung cancer (NSCLC). Median progression-free survival in patients with exon 19/21 mutations (n = 101) was 14.6 vs 9.6 months in patients treated with dacomitinib vs erlotinib, respectively (P =.146). Median overall survival was 26.6 vs 23.2 months in the same groups, respectively (P =.265).(Annals Oncology Journal January 21, 2016) The results showed that dacomitinib has similar efficacy to erlotinib in advanced EGFR-mutated NSCLC.
ARCHER 1050: Randomized Phase III Study Dacomitinib vs Gefitinib Advanced NSCLC Adenocarcinoma EGFR exon 19/21 mut+ First-line treatment PS 0-1 R A N D O M I Z E 1 >350 accrued 1 Dacomitinib 45mg qd Gefitinib 250mg qd Primary endpoint in PFS 14.8 vs 9.5 months N= 440 patients Stratification -Race -Exon 19 v 21
LUX-Lung 7 Paz-Ares et al. Ann Oncol 2016; 27 (suppl 6): abstr LBA4
LBA43: Afatinib (A) vs gefitinib (G) in patients (pts) with EGFR mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC): overall survival (OS) data from the phase IIb trial LUX-Lung 7 (LL7) Paz-Ares L, et al Key results Median PFS (independent review), months Afatinib (n=160) Gefitinib (n=159) HR (95%CI) p-value 11.0 10.9 0.74 (0.57, 0.95) 0.0178 Median TTF, months 13.7 11.5 0.75 (0.60, 0.94) 0.0136 Median DoR, months 10.1 8.3 Median OS, months 27.9 24.5 0.86 (0.66, 1.12) 0.2580 Treatment discontinuation due to drug-related AEs was low in each arm (6%) Conclusions In patients with EGFR m+ NSCLC, afatinib significantly improved PFS, TTF and ORR compared with gefitinib, with no significant difference in OS AEs were tolerable and resulted in equally low rates of treatment discontinuation Paz-Ares et al. Ann Oncol 2016; 27 (suppl 6): abstr LBA43
1L EGFR mut population Paz Ares L, et al. ESMO 2016
Overall summary of AEs Events, % Afatinib (n=160) Gefitinib (n=159) Any AE 98.8 100.0 Drug-related AEs 97.5 96.2 AEs leading to dose reduction* 41.9 1.9* Drug-related AEs leading to discontinuation 6.3 6.3 Serious AEs 44.4 37.1 Drug-related serious AEs 10.6 4.4 Drug-related fatal AE - 0.6 *No dose reductions foreseen for gefitinib according to prescribing information Including four patients with drug-related ILD (no drug-related ILD on afatinib) One patient died of hepatic failure AE, adverse event; ILD, interstitial lung disease
After reduction (<40 mg) Estimated PFS probability Before reduction ( 40 mg) Patients (%) Lux-Lung 7 update Treatment-related AEs in patients who had a dose reduction from 40 mg (n=63) PFS in patients who received a dose reduction within the first 6 months of treatment 10 0 80 6 0 4 0 2 0 100,0 63,5 95, 2 25,4 81, 0 All grade 60, 3 20,6 7,9 Grade 3 28, 6 3,2 1.0 0.8 0.6 <40 mg in first 6 months (n=47) Median, mo 12.8 11.0 HR (95% CI) p-value 1.34 (0.90 2.00) 0.1440 40 mg for first 6 months (n=113) 0 Any Diarrhoea Rash/acne Stomatitis Nail effect 0.4 0.2 0 No. at risk: <40 mg 40 mg 0 3 6 9 12 15 8 1 4 Time (months) 27 30 33 36 39 1 2 2 ParK K, et al. WCLC 2016 47 45 34 28 22 15 11 10 9 7 3 1 0 0
Frecuency of withdrawal AEs According to type of EGFR-TKI Takeda et al. Lung Cancer 2015
Can we improve efficacy of EGFR TKIs?
Futuro New 1L combinations: Afatinib +/- Cetuximab (SWOG 1403) Erlotinib +/- Ramucirumab (RELAY) Erlotinib- bevacizumab CNS disease and TKI election: Icotinib (BRAIN) AURA3 Ph3 trial results
1ª línea EGFR m+ Erlotinib + BVZ BELIEF Phase II trial Fase II BELIEF (2015 ECC) 1ª Línea: erlotinib + BVZ n=109 EGFRm+ (Del 19, L858R) 37 pts T790m+ pretratamiento SLP 1a: 72.4% SLPm 16m TRO: 70.3% 72 pts T790m- pretratamiento SLP 1a: 49.4% SLPm: 10.5m TRO: 79.2%
New 1L combinations? SWOG 1403 RELAY - Phase II (PFS)/III (OS) - Only common mut, no CNS - N=53 pts - Afa 40 mg +/- Cetux 500 mg/m2/2 w - No toxicity differences (71% vs 63% grade 1-2 rash) - Phase I (DLT)/III (PFS) - Only common mut, no CNS - N=14 pts - Erlo 150 mg +/- Ramu 10 mg/kg/2 w - No DLT (no unexpected tox) Goldberg SB, et al. WCLC 2016 Nakagawa K, et al. WCLC 2016
Intracranial PFS, % BRAIN: A Phase III Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201) Wu YL, et al Key results Intracranial PFS (ipfs) and PFS were both longer with icotinib than WBI with or without chemotherapy 100 80 60 40 20 Δ24.0% 48.0% 72.0% 43.0% ipfs Group N Events Median, months (95%CI) WBI ± chemo 73 34 4.8 (2.4, 7.2) Icotinib 85 46 10.0 (5.6, 14.4) 47.0% 47.0% Δ4.0% 43.0% HR 0.56 (95%CI 0.36, 0.90) p-value 0.014 0 6 months 12 months 0 5 10 15 20 25 30 Time, months Wu et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.05
Objective response rate, % BRAIN: A Phase III Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201) Wu YL, et al Key results (cont.) ORR and DCR were superior with icotinib than WBI with or without chemotherapy Δ26.2% p<0.001 67.1% Δ17.6% p=0.014 84.7% 67.1% WBI ± chemo Icotinib Δ43.9% p<0.001 Δ24.0% p=0.001 78.8% 55.0% 54.8% 40.9% 11.1% Intracranial ORR Intracranial DCR Overall ORR Overall DCR Conclusion In advanced EGFR mutant NSCLC with brain metastases, icotinib should be used as a first-line treatment Wu et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.05
La carrera continua: inhibidores de tercera generación también buscan una oportunidad en primera línea
PL03.03: Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) Papadimitrakopoulou V, et al Study objective To compare osimertinib to platinum-based doublet chemotherapy in patients with centrally-confirmed EGFR T790M-positive advanced NSCLC Key patient inclusion criteria Locally advanced or metastatic NSCLC Disease progression following first-line EGFR-TKI therapy EGFR T790M mutation WHO PS 0 1 Stable asymptomatic CNS metastases allowed (n=419) R 2:1 Stratification Osimertinib 80 mg/day (n=279) Ethnicity (Asian vs. non-asian) Pemetrexed 500 mg/m 2 + carboplatin AUC5 or cisplatin 75 mg/m 2 q3w* (n=140) PD Optional crossover to osimertinib PD Primary endpoint PFS by investigator assessment *Optional maintenance pemetrexed Patients could receive study treatment beyond PD, as long as they experience clinical benefit Secondary endpoints OS, ORR, DoR, DCR, BICR-assessed PFS Papadimitrakopoulou et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.03
Probability of progression-free survival PL03.03: Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) Papadimitrakopoulou V, et al Key results PFS by investigator assessment 1.0 0.8 0.6 mpfs, months (95%CI) HR (95%CI) 10.1 (8.3, 12.3) 0.30 (0.23, 0.41) 4.4 (4.2, 5.6) p<0.001 No. at risk 0.4 0.2 0.0 0 3 6 9 12 15 18 Time, months 279 140 Osimertinib Platinumpemetrexed 240 93 162 44 88 17 50 7 13 1 0 0 PFS by BICR was consistent with investigator-based analysis: HR 0.28 (95%CI 0.20, 0.38); p<0.001 PFS benefit with osimertinib was observed across all subgroups including: ethnicity, sex, EGFR-TKI sensitising mutation status and CNS metastases Papadimitrakopoulou et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.03
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FLAURA study design A Phase III, double-blind, randomised study to assess the safety and efficacy of Osimertinib vs. EGFR-TKI as first-line treatment in patients with EGFRm, locally advanced or metastatic NSCLC FLAURA Phase III study Local testing* of biopsy sample with central confirmation for sensitivity 650 treatment-naïve patients with EGFR-sensitising mutation-positive (EGFRm) NSCLC, who are eligible for first-line treatment with EGFR-TKI will be randomised 1:1 to osimertinib vs. gefitinib or erlotinib Status Ongoing Randomise ~650 treatment-naïve patients 1:1 Osimertinib (80 mg p.o. QD) EGFR-TKI SoC Gefitinib (250 mg p.o. QD) or erlotinib (150 mg p.o. QD) Recruiting Patients randomised to the SoC treatment arm may receive open-label treatment with AZD9291 on central confirmation of both objective disease progression and T790M tumour *cobas EGFR Mutation Test (Roche Molecular Systems), to confirm presence of EGFR mutation known to be associated with EGFR-TKI sensitivity Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation (US sites will not be offered option as gefitinib is not approved in that territory; Japan gefitinib only) NCT02296125. www.clinicaltrials.gov; AstraZeneca. Data on file; Ramalingam SS, et al. Ann Oncol 2015;26:(suppl 1; abstract 141TiP); Ramalingam SS, et al. J Clin Oncol 2015;33:(suppl abstract TPS8102). 40
Tratamiento a la progresión de TKI Progresión indolente y asintomática Progresión local Progresión sintomática
Abordaje clínico de las resistencias a TKI-EGFR Progresión indolente y asintomática Continuar con el TKI-EGFR? Estudio Aspiration Park, Ann Oncol 2014: abstr 12230
Re-Biopsia Realizar biopsias es esencial en el momento de la progresión para identificar el mecanismo de resistencia y seleccionar el tratamiento adecuado Estrategias de tratamiento en la progresión
Mechanism of acquired resistance to EGFR-TKI therapy Yu HA,, et al. Clinical Cancer Research. 2013 Apr 15;19(8):2240 7.
The main Question???
Conclusiones Las mutaciones de EGFR definen una población sensible al tratamiento con TKI Diferente actividad según el tipo de mutación Diferente perfil de toxicidad Diferentes patrones de progresión pueden requerir diferentes estrategias de tratamiento. Oligoprogresión: tratamiento local, proseguir TKI Progresión sistémica: cambio de tratamiento Relevancia de la biopsia en la progresión para determinar el mecanismo de resistencia