Hospital Universitario Elevada correspondencia entre mutaciones de EGFR en tejido y en ADN circulante de pacientes con cáncer de pulmón no microcítico con pobre performance status Discusión Luis Paz-Ares Hospital Universitario Virgen del Rocio Seville, Spain

Puntos de Discusión Relevancia de las mutaciones de EGFR (biomarcador) Correspondencia entre mutaciones en tejido tumoral y suero Potenciales implicaciones en el futuro

Puntos de Discusión Relevancia de las mutaciones de EGFR (biomarcador) Correspondencia entre mutaciones en tejido tumoral y suero Potenciales implicaciones en el futuro

Anti EGFR Agents in NSCLC Cetuximab: RR: 3/66 = 4.5% EGFR TKIs: Hanna et al J Clin Oncol 2006, Thatcher et al. Lancet 2006, Shepherd et al. NEJM 2005

Determinants of Sensitivity to EGFR-TKIs Clinical: gender, histology, ethnicity, smoking status Molecular: EGFR mutations, gene copy number, baseline AKT/MAPK, K-Ras mutations Post-therapy: skin rash

Main mutations of EGFR kinase domain Lynch et al. NEJM 2004 Huang et al. Clin Cancer Res 2004

In vitro Effect of EGFR Mutated Forms Paez et al. Science Lynch et al. NEJM Janne et al. JNCI L858R

Tumor Response based on EGFR Biomarkers Retrospective Studies Rate Tsao NEJM 2005; Capuzzo JNCI 2005; Hirsch J Clin Oncol 2005; Han JCO 2005; Takano JCO 2005; Cortes Funes Ann Oncol 2004; Taron CCR 2005

Patients included April 2005 – October 2007 N= 2211 EGFR mutations Patients included April 2005 – October 2007 N= 2211 Wild type N (%) Mutated N(%) p Sex: male female 1093 (93.3) 482 (69.9) 78 (6.7) 208 (30.1) <0.0001 Age (median, range) 61.41 (20.0 - 90.4) 64.4 (26.7 - 88.3) Smoking history ex current never 786 (91.6) 377 (95.7) 321 (62.2) 72 (8.4) 17 (4.3) 195 (37.8) Histology adeno BAC LCC others 1193 (83.8) 89 (73.0) 181 (90.0) 92 (96.8) 230 (16.2) 33 (27.0) 20 (10.0) 3 (3.2) SLCG data

Erlotinib as First Line Treatment in EGFR Mutated NSCLC: Response Rate PR SD PD All Patients (N=38) 5 (13,2%) 26 (68,4%) 2 (5,3%) Exon 19 (N=20) 4 (20%) 15 (75 %) 1 (5%) 0 (0%) Exon 21 (N=18) 1 (5,5%) 11 (61,1%) 4 (22,2%) 2 (11,1%) Overall RR: 82 % (95% CI: 66%-92%) Exon 19 RR: 95 % (95% CI:75%-100%) Exon 21 RR: 67 % (95% CI:41%-87%) Paz-Ares et al, ASCO 2006

Erlotinib as First Line Treatment in EGFR Mutated NSCLC: Response Rate PR SD PD All Patients (N=38) 5 (13,2%) 26 (68,4%) 2 (5,3%) Exon 19 (N=20) 4 (20%) 15 (75 %) 1 (5%) 0 (0%) Exon 21 (N=18) 1 (5,5%) 11 (61,1%) 4 (22,2%) 2 (11,1%) Overall RR: 82 % (95% CI: 66%-92%) Exon 19 RR: 95 % (95% CI:75%-100%) Exon 21 RR: 67 % (95% CI:41%-87%) Overall RR: 71% Exon 19 RR: 68.9 % Exon 21 RR: 75 % Paz-Ares et al, ASCO 2006 Sanchez et al, SEOM 2007

Erlotinib as First Line Treatment in EGFR Mutated NSCLC: TTP and Survival Time to Progression Overall Survival Time (months) 12 10 8 6 4 2 Cumulative Survival 1,0 ,5 0,0 Survival Function Censored Median TTP: 13,3 months Time (months) 12 10 8 6 4 2 Cumulative Survival 1,0 ,5 0,0 Survival Function Censored 1 year OS : 82 % Paz-Ares et al, ASCO 2006

Erlotinib as First Line Treatment in EGFR Mutated NSCLC: TTP and Survival Time to Progression Overall Survival TTP 13m Time (months) 12 10 8 6 4 2 Cumulative Survival 1,0 ,5 0,0 Survival Function Censored Median TTP: 13,3 months Time (months) 12 10 8 6 4 2 Cumulative Survival 1,0 ,5 0,0 Survival Function Censored 1 year OS : 82 % Sanchez et al, SEOM 2007

Prospective Studies of NSCLC with EGFR Mutations Treated with EGFR TKIs Author # Screened EGFR Mutations Drug RR TTP Inoue1 99 16 Gefitinib 75% 9,7 m Paz-Ares2 1047 127 Erlotinib 82% 13,3 m Okamato3 118 32 ND Sutani4 100 38 78% 9,4 m Morikawa5 123 46 62% 1 JCO 2006; 2-5 Proc ASCO 2006

Response (cases with response / total cases) by EGFR Mutation and FISH (Courtesy T. Mitsudomi) FISH positive FISH negative EGFR mutation 17/22 77% 5/5 100% EGFR wild-type 0/9 0% 0/10 This slide shows response rate according to FISH score and EGFR mutations. IF the tumors are positive for mutation and FISH, response rate was 17/22. And when both are negative, response rate was zero. However, when tumors are mutation positive yet negative for FISH, response rate was 100%. In contrast, when mutations are not present and positive for FISh, response rate was 0%, suggesting that mutations are determinant for respons and FISH are not at leat in our cohort.

Survival by EGFR mutation and FISH (Courtesy T. Mitsudomi) .2 .4 .6 .8 1 2 1 mutation positive .8 .6 negative .4 .2 This is survival curves according to mutational status or FISH. Again, in our cohort, mutational status are predictive for prolonged survival but not FISH. Wt 1 2 P=0.0053 P=0.4205

SLCG Phase III Trial in EGFR-mutated NSCLC GECP 06/01 O M Eligibility: No prior Rx Stage IIIB or IV Mutated EGFR (tumor, serum) ECOG PS 0-2 Erlotinib 150 mg/day PO Cross-over at PD Platinum-based Chemo

Response Rate According to EGFR Mutation Jackman CCR 2006; Hirsch J Clin Oncol 2005; Paz-Ares 2006

Response Rate According to EGFR Mutation Overall RR: 71% Exon 19 RR: 68.9 % Exon 21 RR: 75 % Response Rate Sanchez et al, SEOM 2007 Jackman CCR 2006; Hirsch J Clin Oncol 2005; Paz-Ares 2006

Outcome v EGFR Mutation Exon 19 deletions L858R Months Jackman CCR 2006; Hirsch J Clin Oncol 2005; Riely CCR 2006; Paz-Ares ASCO 2006

Outcome v EGFR Mutation Exon 19 deletions L858R Months ___exon 19 ___exon 21 Sanchez et al, SEOM 2007 Jackman CCR 2006; Hirsch J Clin Oncol 2005; Riely CCR 2006; Paz-Ares ASCO 2006

Kinetic Differences of EGFR Mutants Km (microM/L) Ki Ki/Km Relative Ratio Wild type 5.0 17.5 3.5 x 10 -3 1 L858R 10.9 6.25 5.7 x 10-4 6 Exon 19 Deletion 129.0 3.3 2.6 x 10-5 137 Caret CCR 2006

Puntos de Discusión Relevancia de las mutaciones de EGFR (biomarcador) Correspondencia entre mutaciones en tejido tumoral y suero Potenciales implicaciones en el futuro

Mutaciones EGFR: Tumor-Suero Correspondencia: 84/121 (69,4%) Kimura et al. 73% (8/11) Aumenta con el PS (carga tumoral ?) Wt suero n = 37 Muts suero n = 84 P PS 0 1 2 14/27 (51.8%) 20/63 (31.7%) 1/19 (5.3%) 13/27 (48.2%) 43/63 (68.3%) 18/19 (94.7%) 0.01 Necesita validación Dependencia del método de detección (sensibilidad) Especificidad (no evaluada) Valor predictivo del test positivo (Estudio GECP 06/01) Valor predictivo del test negativo ??

Puntos de Discusión Relevancia de las mutaciones de EGFR (biomarcador) Correspondencia entre mutaciones en tejido tumoral y suero Potenciales implicaciones en el futuro

Mutations associated with sensitivity/resistance to gefitinib/erlotinib EGFR ErbB-2 Ras Sensitive Resistant Unknown L858R T790M Many Exon 20 Ins K-Ras Exon 19 del L861Q G719A/C/S

Mechanisms of Adquired Resistance to EGFR TKIs Patient with adquired resistance to Gefitinib/Erlotinib 50% 50% EGFR T790M Non T790M Tumor addiction to EGFR EGFR independent (e.g. c- met amplification) Tx with 2nd Tx with other generation EGFR TKI therapies + EGFR TKI