Genotipying NSCLC in LATAM Andrés Felipe Cardona; on behalf of CLICaP and ONCOLGroup

Genotipying NSCLC in LATAM Andrés Felipe Cardona; on behalf of CLICaP and ONCOLGroup Clinical and Translational Oncology Group Institute of Oncology, Fundación Santa Fe de Bogotá Clinical Epidemiology Cochrane Colombian Branch / LATINREC / ONCOLGroup Spanish Lung Cancer Group 9 th Congress Barcelona, November 17 th 18 th, 2011

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Evidence for Palaeoamerican survival and develompment after major migrations 1. Red oval: Palaeoamericans 2. Black oval: Africans 3. Brown oval: Australians/Melanesians 4. Violet oval: Amerindians 5. Yellow oval: East Asians 6.. Green oval: South Asians 3 Nature. 2003;425:62-65.

Geographic of genome admixture in Latin American A mestizos Ancestry proportions in 13 mestizo populations Wang ES, et al. Plos Genetics. 2008;4(3):e1000037. 4

Lung cancer 2010 USA/LATAM 219.000/93.000 93.000 new cases Small-cell lung cancer (13%) Other NSCLC EGFR mutated (10% NSCLC ) KRAS mutated (25% of adenocarcinoma) Yearly incidence of cancers with driver mutations KRAS-mutated NSCLC 36.000 cases/year USA 15.800 cases/year LATAM EGFR-mutated NSCLC 18.000 cases/year USA 16.000 cases/year LATAM EML4-ALK NSCLC 9.000 cases/year USA 2440 cases/year LATAM CML 5.000 cases/year USA 3.800 cases/year LATAM 5

Molecular subtypes of lung carcinoma FGFR4 FGFR4 PIK3CA PIK3CA HER2 HER2 EML4-ALK BRAF BRAF Recently described EGFR LKB1 MEK1 ROS fusion gene PDGFR amp ERK BIM MET K-ras 6

Support to design Yes, we used the design proposed by the SLADB (Rosell et al. NEJM 2009) Yes, we include some information from the design of the 10.000 mutations project (NCI) Yes, we don't have enough money o develop everything, but the challenge allow us to learn how to work together 7

Study design Between subjects factorial design Target population Colombia incident cases of LAC 20 Accesible population LAC cases analized in a centralized laboratory Study sample LAC cases with complete genotipification EGFR + 10 10 KRAS + KRAS/EGFR Wt Random allocation Alk BRAF Control Her2 Measurment of clinical outcomes PI3K Main objective To establish the frequency of driver mutations in NSCLC in LATAM population. Methods Direct sequencing in patients from Argentina, Colombia, Mexico, and Peru was performed at each site. 8

Genotyping Non-Small Cell Lung Cancer (NSCLC) in Latin America (LATAM) CLICaP (Latin American Consortium for the Investigation of Lung Cancer) Frequency of mutations in EGFR and KRAS genes in four Latin-American countries (n=1,150). Frequency of EGFR mutations in NSCLC was 33.2% [95% CI 30.5-35.9] (Argentina 19.3%, Colombia 24.8%, México 31.2%, Perú67%). Frequency of KRAS mutations was 16.6%[95% CI 13.8-19.4]. EGFR mutations were independently associated with adenocarcinoma histology, older age, non-smokers and absence of KRAS mutations. Overall response rate to tyrosine kinase inhibitors (TKIs) in EGFR mutated patients (n=56) was 62.5% [95%CI 50-75] 75]. Arrieta O, et al. J Thorac Oncol. 2011;6:1955 1959. 9

Variable Argentina Colombia Mexico Peru Total Number of patients 244 322 381 203 1150 Mean age ±SD 61.3 ±10.1 58.8 ±12.8 59.8 ±13.2 62.8 ±10.9 60.3 ±12.2 Gender Female (%) 140 (57.4) 216 (67.1) 215 (56.2) 99 (48.8) 670 (58.4) Male (%) 104 (42.6) 106 (32.9) 164 (43.3) 104 (51.2) 478 (41.6) Histology Adenocarcinoma (%) 244 (100) 263 (81.7) 300 (79.6) 203 (100) 1010 (90.4) LCC (%) 6 (2.0) 3 (0.8) 9 (0.8) NOS/Non Differentiated (%) 16 (5.5) 14 (3.7) 30 (2.7) SCC (%) 8 (2.7) 60 (15.9) 68 (6.1) Smoking Status Smoker/Former (%) 84 (41.4) 72 (27) 188 (49.7) 69 (34) 448 (42.6) Never smoker (%) 119 (58.8) 195 (73) 190 (50.3) 134 (66) 603 (57.4) Ethnicity Caucasian (%) 243 (100) 51 (37) 6 (1.6) 6 (3) 306 (31.7) Mestizo/ Indigenous (%) 86 (62.3) 375 (98.4) 197 (97) 658 (68.2) Black (%) 1 (0.7) 0 0 1 (.1) Arrieta O, et al. J Thorac Oncol. 2011;6:1955 1959. 10

Variable Argentina Colombia México Perú Total EGFR sensitizing mutation status Positive (%) 47 (19.3) 80 (24.8) 119 (31.2) 136 (67) 382 (33.2) Negative (%) 197 (80.7) 242 (75.2) 262 (68.8) 67 (33) 768 (66.8) Exon 18 (+)(%) 1 (2.1) 11 (9.2) 12 (3.1) Exon 19 Deletion (+)(%) 30 (63.8) 54 (67.5) 76 (63.9) 25 (18.4) 185 (48.4) Exon 21 L858R(+)(%) 19 (40.4) 26 (32.5) 31 (26) 111 (81.6) 187 (48.9) Exon 20 S768I (+)(%) 2 (4.2) 10 (8.4) 12 (3.1) Complex mutations 2 (4.2) 0 11 (9.2) 0 13 (3.4) T790M basal Positive (%) 2 (0.8) 6 (5.2) 8 (2.1) 16 (2.2) Negative (%) 242 (99.2) 108 (94.7) 373 (97.9) 723 (97.8) KRAS Positive (%) 35 (17.1) 39 (16) 34 (16.8) 108 (16.6) Negative (%) 170 (82.9) 204 (84) 168 (83.2) 542 (83.4) Arrieta O, et al. J Thorac Oncol. 2011;6:1955 1959. 11

Age years Variable Argentina Colombia México Perú Total Mutant P Mutant P Mutant P Mutant P Mutan t P (UA*) P (MA**) OR [95% CI] 60 (%) > 60 (%) 10.8 27.4 0.001 26.9 24.8 0.68 28.9 33.3 0.34 66.4 68.8 0.72 30.1 36.3 Gender Female (%) 25.7 26.4 38.6 65.7 36 Male (%) 10.6 0.003 21.7 0.36 22 0.001 68.3 0.69 29.5 Histology 0.026 0.022 0.002 1.93 [1.3-2.9] 0.97 0.99 [0.65-1.5] Adenocarcinoma (%) 19.3 25.5 37.3 67.0 35.8 LCC (%) 33.3 0 22.2 NOS/Non Differentiated 18.8 28.6 23.3 SCC (%) - 0 0.353 3.3 <0.001 2.9 Smoking Status Smoker (%) 10.1 20.8 20.2 65 24.6 Never smoker (%) 34.5 <0.001 26.7 0.32 41.6 <0.001 67.9 0.69 41.6 Ethnicity Caucasian (%) 31.4 0 16.7 20.9 Mestizo/ Indigenous (%) - 25.6 0.631 31.7 0.096 68.5 0.016 + 41.9 KRAS Positive (%) 0 12.8 0 <0.00 4.6 Negative (%) - 13.5 0.017 37.3 0.003 81 1 43.4 <0.001 <0.001 <0.001 <0.001 <0.001 0.079 [0.027-0.23] 0.001 0.48 [0.3-0.74] 0.001 1.9 [0.075-0.52] <0.001 0.50 [0.019-0.128] Arrieta O, et al. J Thorac Oncol. 2011;6:1955 1959. 12

CLICaP data 2011 15.1 mo [95 CI 12.4-17.9] 16.4 mo [12.4-20.6] Survival Survival Time (months) Progression Free Survival Time (months) Overall Survival Arrieta O, et al. J Thorac Oncol. 2011;6:1955 1959. 13

CLICaP data 2011 dele19 16.5 months (IC95% 10.4-22.7) Log Rank P = 0.612 Survival L858R 16.0 months (IC95% 11.1-20.9) Time (months) Arrieta O, et al. J Thorac Oncol. 2011;6:1955 1959. 14

Main study schedule - Colombia + N=1 N=26 N=170 - N=60 + N=0 + N=1 N=36 N=322 N=242 - N=205 + N=35 N=20 + N=1 N=322 + N=80 15

Main characteristics of EGFR mutant population Variable N (%) Number of pts treated with 41 (51%) erlotinib (follow-up available data) Mean age (SD) 63 yrs (±12) Stratified age >65 yrs 13 (31.7) <65 yrs 24 (58.5) ND 4 (9.8) Sex Male Female Tobacco exposure Never smoker Former smoker Current smoker Main metastasis (site) Pleuropulmonary Brain Liver Bone ND 9 (22.0) 32 (78.0) 30 (73.2) 10 (24.4) 1 (2.4) 26 (63.4) 4 (9.8) 3 (7.3) 2 (4.9) 6 (14.6) 16 Hormonal receptor status (tumor tissue) Positive Negative ND TTF1 status Positive Negative ND Mutation type dele19 L858R T790M basal Positive Negative ND Line of treatment 1 2 3 ND Response Stable disease Partial response Complete response Progressive disease 22 (53.7) 11 (26.8) 8 (19.5) 22 (53.7) 11 (26.8) ND 8 (19.5) 26 (63.4) 15 (36.6) 2 (4.9) 23 (56.1) 16 (39.0) 17 (41.5) 14 (34.1) 9 (22.0) 1 (2.4) 7 (17.1) 30 (73.2) 2 (4.9) 1 (2.4) 1 (2.4) ND Overall response rate 32 (78.1) Clinical benefit 39 (95.2)

Colombia (ONCOLGroup study) P = 0.093 Survival Median 14.7 mo IC95% (11.8-17.6) Survival Colombia IC95% (11.8-17.6) México IC95% (8.8-13.1) Time (months) Time (months) Progresion free survival Cardona AF, et al. ASCO 2011. 17

Colombia (ONCOLGroup study) P = 0.37 P = 0.016 Survival Male IC95% (10.7-15.4) Female IC95% (10.7-20.4) Exon 21 14.2 mo IC95% (11.9-16.6) Exon 19 17.7 mo IC95% (6.6-22.4) Time (months) PFS (by sex) Time (months) PFS (by type of mutation) 18

Colombia (ONCOLGroup study) P = 0.80 P = 0.61 >65-yo 17.4 mo IC95% (12.7-22.1) Never smoker 16.4 mo IC95% (16.0-17.7) <65-yo 13.6 mo IC95% (11.2-16.0) Former smoker 13.8 mo IC95% (11.9-15.2) PFS (by recoded age) PFS (by smoking status) 19

Colombia (ONCOLGroup study) P = 0.45 P = 0.80 Stable disease 1st line 17.4 mo IC95% (12.5-22.2) PR 15.6 mo IC95% (11.0-20.0) 2nd line 13.6 mo IC95% (8.9-18.3) 3d line 16.2 mo IC95% (9.9-22.5) PFS (according to response) PFS (according to line of treatment) 20

NSCLC with activating EGFR mutation in Chile 3 cancer centers in Santiago de Chile (Instituto Nacional del Cáncer, Clínica Alemana and Clinica Santa María). July 2009 to December 2010. The mutation detection methods were: direct sequencing (39,5%) and PCR with Thera Screen kit (60,5%). In 8,4 % of patients the sample was insufficient for DNA analysis N = 108 (62.5% female / 37.5% male) In females, the exon 21 L858R mutation was more frequent (53,3% vs 46,7% exon 19 deletion). In men, the 19 exon deletion was more frequent (77,8% vs 22,2% exon 21 L858R mutation). 21 Aren O, et al. ASCO 2011.

Latin America (32.8%) DelE19 54.3% L858R 44.5% México(31.2%) DelE19 63.9% L858R 26% Colombia(24.8%) DelE19 67.5% L858R 32.5% Perú(67%) DelE19 18.4% L858R 81.6% Chile(22%) DelE19 58% L858R 42% 22 Argentina(19.3%) DelE19 63.8% L858R 40.4%

Factors influencing genomic diferences in EGFR/KRAS incidence Classical Women Non-smokers Histology (adenocarcinoma) Histology pattern (leptidic, papillary) Age >65 years Regional HPV infections Nutritional status Genetic susceptibility Immunologic infections Wood smoke exposure (GSTP1) Differences in sensitivity of the Test selected to perform the analysis 23

EGFR mutations around the world Overall 14% E19 60% E21 30% E20 8% -38% Overall 17% E19 62% E21 37% E20 38% Overall 40% -50% E19 51% E21 42% E20 2% Overall 32.8% E19 54.3% E21 44.5% E20 2.2% Overall 15.8% E19 64.3% E21 24.7% 24

Thanks to all participants in the CLICaP Consortium and to the inconditional support of the SLCG Colombia: Andrés Felipe Cardona, Silvia Serrano, Henry Becerra, Pilar Archila, Carlos Vargas, Carlos Castro, Hernán Carranza, Jorge Miguel Otero, Diana Torres, Edgar Ospina, Pedro Ramos, Juan Alejo Jiménez, Ricardo Duarte, Mauricio Lema, Rubén Darío Salazar, Alejandro Garrido, Andrés Yepes, Jesus Insuasty, Oswaldo Sánchez, Joaquín Guerra, Luis Gabriel González, Marcela Urrego, Milton Lombana, Ricardo Bruges, Néstor Llinas, Adriana Castaño, Alejandro Hijuelos, Álvaro Llamas, Ángela Zambrano, Vanessa Ospina, Carlos Bonilla, Carlos Ortiz, Diego Pardo, Edgar Molina, Eduardo Larrota, Gabriel Rodríguez, Giovanna Rivas, Isabel Cristina Durango, Jaime González, Javier Pacheco, John Jairo Franco, Jorge Duque, Jorge López, Juan Guillermo Restrepo, Luis Rodolfo Gómez, Marcela Alcala, Mauricio Velásquez, Pedro Merchan Ricardo Plazas, Wilfredy Castaño. Peru: Edgar Amorin, Marco Lopez, Carlos Barrionuevo, José Carpio, Franz Cavero, Luis Mas. 25 México: Oscar Arrieta, Alma Delia Campos, Elena Aréchaga, José Borbolla, Jaime de La Garza, Luis Martínez, Alejandro Avilés, María Eugenia Vázquez, Francisco Corona, Javier Benjamín, Roberto Sánchez, Omar Macedo, Diana Flores, Paloma González. Venexuela: Zulay Pastran, Elizabeth Curcio, María Belen Fuentes. Uruguay: Mauricio Cuello. Argentina: Claudio Martin, Mariana Trigo, Magalí Broilo, Martin Richardet, Eduardo Richardet, Lucas Carranza, Alejandro Ferro, Felipe Palazzo, Karina Vera, Susana Sena, Zenon Beguelin, Romina Yapur, Miguel Muñoz, César Blajman, Julián Iturbe, María Geist Jorge Lescano, Gustavo Yankilevich.