TRATAMIENTO DEL CÁNCER DE PULMÓN AVANZADO Dr Claudio Martin Jefe del Servicio de Oncología Torácica Instituto Alexander Fleming Hospital de Rehabilitación Respiratoria Maria Ferrer Buenos Aires . Argentina Instiituto Alexander Fleming IAF

NSCLC - 2014 Traditional Adenocarcinoma Squamous Cell Ca Squamous AKT BRAF VEGFR ALK HER2 Traditional RET EPHA/B PDGFR FGFR Unknown INSR EGFR PI3K Squamous MAPK KRAS Adenocarcinoma Squamous Cell Ca Large Cell FGFR1 Amp EGFRvIII Unknown PI3KCA EGFR TK DDR2 Adapted from W. Pao and N Girard, Lancet Oncol, 2011

NCSLC 80% no clear driver or oncogenic event platinum doublet cisplatin + pemetrexed doublet + bevacizumab SQUAMOUS ADENOCARCINOMAS LARGE CELL 20% NSCLC Oncogene Addicted EGFR mutated gefitinib, erlotinib afatinib ALK , ROS translocated crizotinib

Paradigm shift in individualization of lung cancer Oncogene driven Non-oncogene driven or unknown Targeted therapy Chemotherapy +/- antiangiogenesis

Los Dobletes alcanzaron su límite

Minor advances with standard therapy and no molecular selection (1st line) Arm ORR OS CALGB 97301 P 17% 6.7 Mo PCb 30% 8.8 Mo ECOG 15942 PC 21% 7.8 Mo GC 22% 8.1 Mo DC 7.4 Mo ECOG 45993* 15% 10.3 Mo Bevacizumab/ PCb 35% 12.3 Mo *Nonsquamous NSCLC C = cisplatin; Cb = carboplatin D = docetaxel; G = gemcitabine P = paclitaxel 1. Lilenbaum et al., J Clin Oncol 2005; 23:190-196 2. Schiller et al., New Engl J Med 2002; 346:92-98 3. Sandler et al., New Engl J Med 2006; 355:2542-2550

HISTOLOGY INTERACTION Efficacy ( Pemetrexed) Safety ( Bevacizumab )

Cis/Pem vs Cis/Gem in First-line NSCLC –Study Design Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1 Randomization Factors Stage Performance status Gender Histologic vs cytologic diagnosis History of brain metastases R Each cycle repeated q3 weeks up to 6 cycles Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8 Vitamin B12, folate, and dexamethasone given in both arms Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

Cis/Pem vs Cis/Gem in First-line NSCLC – Overall Survival Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

Cis/Pem vs. Cis/Gem in Advanced NSCLC Scagliotti GV et al. JCO 2008; 26:3543

Pemetrexed: Efficacy according histology across different clinical trials . Scaglioti.SG. Oncologist 2009

Histology and safety concern Bevacizumab

Angiogenesis: A hallmark of cancer leading to malignant growth Sustaining proliferative signaling Resisting cell death Evading growth suppressors Cancer Activating invasion and metastasis Inducing angiogenesis Enabling replicative mortality Hanahan & Weinberg. Cell 2011

Bevacizumab in NSCLC E4599 trial design1 AVAiL trial design2 Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) CP x 6 (n=444) PD* Avastin (15mg/kg) every 3 weeks + CP x 6 (n=434) Avastin PD AVAiL trial design2 Placebo + CG x 6 (n=347) PD* Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1,043) Avastin (15mg/kg) every 3 weeks + CG x 6 (n=351) Avastin PD CP = carboplatin/paclitaxel; CG = cisplatin/gemcitabine In the E4599 trial [Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006], 878 patients with recurrent or advanced NSCLC (stage IIIB or IV) were randomised to 15mg/kg Avastin with carboplatin/paclitaxel (CP) (n=434) or CP alone (n=444) every 3 weeks for six cycles until disease progression or unacceptable toxicity. The 15mg/kg dose was chosen based on its activity in an earlier phase II trial [Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004]. The primary endpoint for E4599 was overall survival (OS). In the Avastin in Lung cancer (AVAiL [BO17704]) trial, 1,043 patients with advanced or recurrent non-squamous NSCLC were randomised to cisplatin/gemcitabine (CG) for up to six cycles plus 7.5 mg/kg Avastin (n=345), 15 mg/kg Avastin (n=351) or placebo (n=347) every 3 weeks until disease progression or unacceptable toxicity [Manegold C, von Pawel J, Zatloukal P. Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. Presented at ASCO 2007]. Following the positive survival results of the E4599 trial for Avastin-based therapy versus chemotherapy alone, the primary endpoint of AVAiL was amended from OS to progression-free survival (PFS). References 1Sandler A, et al. N Engl J Med 2006;355:2542–50 2Manegold C, et al. J Clin Oncol 2007;25(Suppl. 18): (Abs. LBA7514) Avastin (7.5mg/kg) every 3 weeks + CG x 6 (n=345) Avastin PD *No cross over permitted CP=carboplatin + paclitaxel CG=cisplatin + gemcitabine PD=progression of disease 1. Sandler, et al. N Engl J Med 2006;355:2542-2550. 2. Reck, et al. J Clin Oncol 2009;27:1227-1234. 14

bevacizumab (15mg/kg c/3 w) to progresión ECOG 4599 Paclitaxel 200mg/m2 carboplatino AUC 6 (PC) (c/3 w) x 6 ciclos Elegibles NSCLC Non-squamous No hemoptysis No Brain Metastasis NO AAS / AINES NO Anticoagulation No crossover allowed (PCB) PC x 6 ciclos + bevacizumab (15mg/kg c/3 w) to progresión Stratified RT versus no RT E IIIB o IV versus recurrent W <5% versus >5% Measurable versus non-measurable IAF Sandler A et al. NEJM 355:2542-50 2006

E4599: OVERALL SURVIVAL 12 m 24 m Median PC 44.4% 15.4% 10.3 m 1.0 12 m 24 m Median PC 44.4% 15.4% 10.3 m 0.8 BPC 51.0% 22.0% 12.3 m Median 12.3 meses HR: 0.80, P = .013 0.6 Probabilidad SG Median 10.3 meses 0.4 0.2 0.0 6 12 18 24 30 36 42 48 Ptes en riesgo PC 444 318 190 104 36 9 5 1 BPC 434 340 216 127 54 25 8 3 Months Sandler A et al. NEJM 355:2542-50 2006

AVAiL CG  6 + placebo PD NoAvastin After PD No previous therapy, stage IIIB, IV o recurrent NSCLC non squamous (n=1,050) CG  6 + Avastin 7.5mg/kg cada 3 weeks PD CG  6 + Avastin 15mg/kg cada 3 weeks PD Exclusion: Anticoagulation: Invading / abutting major blood vessels Cisplatin 80mg/m2 i.v.; gemcitabine i.v. 1,250mg/m2 days1 y 8 each 3 weeks Primary Endpoint: Progression Free Survival Secundary endpoints:: OS, TTF, Response Rate Reck M et al, JCO 27 :1227 1234, 2009

AVAiL: Progression Free Survival (ITT)Primary Endpoint Placebo CG N = 347 Bv 7.5 N = 345 Bv 15 N = 351 SLP mediana (meses) 6.1 6.7 6.5 HR [IC 95% ] - - - 0.75 [0.62, 0.91] 0.82 [0.68, 0.98] valor p 0.0026 0.0301 1.0 1.0 0.8 0.8 0.6 0.6 Probabilidad SLP 0.4 0.4 Placebo +CG Bv 7.5mg/kg + CG This graph shows the Kaplan-Meier analysis of PFS, the primary objective of the trial. The HRs represent the comparison of each bevacizumab arm to placebo. Both doses met the pre-defined primary endpoint and are both statistically significant with respect to placebo. The study was not designed to compare bevacizumab arms. Bevacizumab provided a statistically significant clinical benefit as measured by PFS in both B containing arms. 0.2 0.2 Bv 15mg/kg + CG 0.0 0.0 3 6 9 12 15 18 Tiempo (meses) Reck M et al, JCO 27: 1227-1234, 2009

How to select the better option in second line in patients without mutation ? Docetaxel Pemetrexed EGFR TKI Shepperd F NEJM 2005 353 123 : 32, Hanna N JCO V 22 # 19 1589-1597( 2004)n

No difference egfr tki vs chemo Significant benefit with Chemo in PFS Egfr test range from 12 to 56 % No difference egfr tki vs chemo Significant benefit with Chemo in PFS

Non-oncogene driven or unknown Targeted therapy Chemotherapy +/- antiangiogenesis

INCIDENCIA DE DRIVERS ONCOGÉNICOS Barlesi F asco 2013 # 8000

Number of patients 4605 Mutation Rate 1176/4605 (25.5% IC95% 24.2-26.7) Colombia 309/1252 (EGFR 24.7%) México 419/1247 (EGFR 33.6%) Perú 201/393 (EGFR 51.1%) We are presenting today the update results with four thousand six hundred and 5 patients evaluated for EGFR mutation. The results were as follows . For mexico the mutation rate was 33.6percent In colombia it was positive in 24,7 percent. 51 percent of patients were egfr positive in peru and 14,4 percent of patients had EGFR mutation positive in Argentina. For Latin america as a whole we found EGFR mutations in 25, 5 percent of four thousand six hundred and five evaluated patients Argentina 247/1713 (EGFR 14.4%) Bramuglia, Martin, Cardona WCLC 2013

La mutación del gen EGFR produce cambios conformacionales e incremento de la activación del EGFR EGFR WT EGFR Mutado Ligando Dominio extracelular Dominio Trans-membrana Dominio Tirosina kinasa ATP Fosforilación tirosina Proliferación Ras-Raf-MAPK Sobrevida Pi3K-AKT Several studies (in both chemotherapy-naı¨ve NSCLC patients and those with previously treated NSCLC) have shown that patients who are particularly responsive to gefitinib have tumors containing somatic activating mutations in the EGFR gene. A response rate of 75% has been reported in EGFR mutation-positive patients of Asian origin receiving gefitinib first-line (47–49). Response rates of 50% have been reported in non-Asian patients who are EGFR mutationpositive (50). Response rates in EGFR mutation-positive patients receiving gefitinib after previous chemotherapy have been reported to be between 76 and 91% in Asian studies and between 58 and 70% in non-Asian patients (68,69). The most common mutations reported occur in exons 18–21 and are small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain (42,55,70–73). At least two of the common mutation types (deletions in exon 19 and the L858R missense mutation) are associated with an increase in the amount and duration of ligand-dependent activation, which explains the much greater sensitivity to EGFR-TKIs of cells bearing these mutations (72). Greater sensitivity of mutation-positive cells to EGFR-TKIs results in greater inhibition of the intracellular tyrosine kinase domain of the EGFR and blocking of the signal transduction pathways implicated in the proliferation and survival of cancer cells. The cells with EGFR mutations become ‘oncogene addicted’ and respond to EGFR-TKI therapy with a significant increase in apoptosis, which translates to the tumor shrinkage reported in clinic. Internalización EGFR Degradación/reciclado Señales EGFR más prolongadas en la membrana celular IAF

Mutaciones identificadas en el gen del EGFR Efecto no claro sobre sensibilidad a EGFR TKIs Confiere sensibilidad/resistencia a EGFR TKIs EGFR transcripto 18 L688P V689M I715S L718P S720X Extracellular domain P694X V700D E709X 18 Exones 1–16 G719A/S G735S V738F V742A T751I S752Y D761N EGFR Deleciones 19 L730F P733L E746K Trans- membrane domain Exón 17 D761Y A763V N765A S768I T783A L792P L798F G810S Tyrosine- kinase domain D770_N771 insNPG 20 Exones 18–24 T790M Cromosoma 7 L858R 21 N826S L838V T847I I853T A859T E866K L833V H835L H850N V851X G863D A864T Regulatory domain L861X Exones 25–28 TKI = inhibidor de la tirosinquinasa Riely, et al. Clin Cancer Res 2006

Progression-free survival Six randomized Phase III studies confirm benefit for first-line reversible EGFR-TKI in EGFR M+ NSCLC Author EGFR TKI n EGFR mutation Response rate (%) Progression-free survival (months) Overall survival IPASS1,2 Gefitinib 1217 261 71 vs 47 p=0.0001 9.5 vs 6.3 HR 0.48 0.36‒0.64 21.6 vs 21.9 HR 1.0 0.76–1.33 First-SIGNAL3 309 42 85 vs 38 p=0.002 8.0 vs 6.3 HR 0.544 0.27–1.10 27.2 vs 25.6 HR 1.04 0.50–2.18 NEJGSG-0024 224 74 vs 31 p<0.001 10.8 vs 5.4 HR 0.30 0.22–0.41 30.5 vs 23.6 WJTOG-34055 192 62 vs 32 p<0.0001 9.2 vs 6.3 HR 0.5 0.34–0.71 30.9 vs NR HR 1.64 0.75–3.6 OPTIMAL6 Erlotinib 154 83 vs 36 13.1 vs 4.6 HR 0.16 0.10–0.26 Not mature EURTAC7 153 58 vs 15 9.7 vs 5.2 HR 0.37 0.25–0.54 19.3 vs 19.5 HR 1.04 0·65–1·68 EGFR = epidermal growth factor receptor; HR = hazard ratio; NR = not reported; NSCLC = non-small cell lung cancer; TKI = tyrosine kinase inhibitor 1. Mok T, et al. N Engl J Med 2009;361:947–957; 2. Fukuoka M, et al. J Clin Oncol; 29:2866‒2874; 3. Han J-Y, et al. J Clin Oncol 2012;10:1122‒118; 4. Maemondo M, et al. N Engl J Med 2010;362:2380–2398; 5. Mitsudomi T, et al. Lancet Oncol 2010;11:121–128; 6. Zhou C, et al. Lancet Oncol 2011;12:735‒742; 7. Rosell R, et al. Lancet Oncol 2012;13:239–246

No dif en OS x el crossover ALEXANDER FLEMING Yang J paco # 8004

ALEXANDER FLEMING Yang J paco # 8004

Quality of life: EORTC QLQ C-30 Difference in mean scores over time (longitudinal analysis) 10 5 -5 Global health status/QoL Overall health Quality of life Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning Treatment difference 3.28 3.52 3.13 4.83 4.50 0.85 3.24 1.18 Favors afatinib Favors cis/pem Yang JC, et al.

Tumor cell proliferation ALK Or Inversion Translocation ALK fusion protein* ALK Partner gene Cell survival Tumor cell proliferation *Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,2 1. Inamura K et al. J Thorac Oncol. 2008;3:13-17 2. Soda M et al. Proc Natl Acad Sci USA. 2008;105:19893-19897 Figure based on: Chiarle R et al. Nat Rev Cancer. 2008;8(1):11-23 Mossé YP et al. Clin Cancer Res. 2009;15(18):5609-5614; and Data on file. Pfizer Inc. 30

EML4-ALK fusion variants in NSCLC Several EML4-ALK fusion variants have been identified in NSCLC that demonstrate gain-of-function properties. ALK tyrosine kinase activity is required for transforming activity. Evidence shows ALK inhibitors lead to tumor shrinkage in vivo, and suggests oncogene addiction, and the potential target for therapeutic intervention. EML4-ALK E13;A20 EML4 ALK E6;A20 EML4 ALK E20;A20 EML4 ALK E14;A20 EML4 ALK E13;A20 Variant 1 33% E18;A20 EML4 ALK E15;A20 EML4 ALK E2;A20 EML4 ALK E6a/b;A20 Variant 3a/b 29% E17;A20 EML4 ALK TFG-ALK TFG ALK KIF5B-ALK KIF5B ALK Coiled-coil domain Tyrosine kinase domain Adapted from Sasaki et al., Eur J Cancer 2010; 46:1773-1780

Molecular assays for detection of ALK fusion genes Hirsch et al., Clin Cancer Res 2010;16:4909–4911.

Crizotinib: First-in-human trial Cohort 5 (n=6) 300 mg BID Part 1 Dose escalation Cohort 6 (n=9) 250 mg BID MTD/RP2D Cohort 4 (n=7) 200 mg BID Cohort 3 (n=8) 200 mg QD Part 2 Dose expansion: Molecularly enriched cohorts Cohort 2 (n=4) 100 mg QD Cohort 1 (n=3) 50 mg QD ALK-positive NSCLC ROS1-positive NSCLC c-MET-positive tumors ALK-positive NSCLC cohort added 2008 Modified from Tan et al. J Clin Oncol 2010;28:15S abstract 2596 BID, twice daily; QD, once daily; MTD, maximum tolerated dose; RP2D, randomized phase 2 dose

ALEXANDER FLEMING/ MARIA FERRER Open-label, Multicenter, Phase II Study of Crizotinib in Advanced ALK-positive Non-Small Cell Lung Cancer PROFILE 1005 ALK+ NSCLC with measureable lesions ECOG PS: 0–3 Not eligible for Phase 3 study (A8081007) PD in chemo arm of study A8081007 ≥1 prior platinum- based chemotherapy Stable/controlled brain metastases allowed Crizotinib 250 mg BID administered continuously (21-day cycle) Primary endpoints: ORR, safety, and tolerability Secondary endpoints: OS, TTR, duration of response, disease control rate, PK, biomarkers, PRO/HRQoL (EORTC QLQ-C30 and LC-13) N=400 (planned) ALEXANDER FLEMING/ MARIA FERRER

Tumor responses to crizotinib by patient PROFILE 10011 PROFILE 10052 Median time to response: 8 wk ORR 60.8 % ORR 59,8 % From Global Lung Council RR 61% RR 51 % 1. Camidge et al., ASCO 2011; Abs #2501 2. Riely et al., IASLC 2011; Abs #O31.05 KimD # 7533 asco 2012 Camidge DR et al. Lancet Oncol 2012; epub ahead of print – ALEXANDER FLEMING/ MARIA FERRER

CONCLUSIONS Platinum Doublets remains as standart treatment for patients without driver mutations Pemetrexed and Bevacizumab are candidates for non squamous cell carcinoma No clear benefit to add pemetrexed to bevacizumab in first line Chemotherapy is first option for EGFR WT in first and second line

CONCLUSIONES LA DETECCIÓN DE LOS GENES DE ALK Y EGFR Y SU TRATAMIENTO MODIFICA DRÁSTICAMENTE LA EXPECTATIVA DE VIDA EN PACIENTES CON CPNCP. TODOS LOS MÉDICOS QUE PARTICIPAN DEL CUIDADO DEL PACIENTE CON CÁNCER PULMONAR DEBEN SER PROACTIVOS EN LA BÚSQUEDA DE TEJIDO PARA REALIZACÍON DE ESTUDIOS MOLECULARES. EN UN FUTURO CERCANO NUEVAS TERAPIAS CONTRA DRIVERS ONCOGÉNICOS ESTARÁN DISPONIBLES Y SERÁ UN DESAFÍO LA OBTENCIÓN Y OPTIMIZACIÓN DEL MATERIAL

AAMR 2014 Claudio.martin@fibertel.com.ar ALEXANDER FLEMING