Ca. Pulmon .2012
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Ca. Pulmon .2012
- 2. Cáncer Pulmonar (rodeado de negatividad) Estigmatizado por su relación al tabaco “self inflicted “. Poca cobertura e información de adelantos en los medios de comunicación. Poco interés por las celebridades. Pobre apoyo de organizaciones para los pacientes y familiares. Ideas pesimistas de Médicos, pacientes y familiares sobre resultados de tratamiento.
- 3. NSCLC: how oncologists would choose to be treated (1987) 118 Canadian doctors who treat lung cancer If they had NSCLC, would they choose to be treated with chemotherapy? After surgery for For advanced disease For symptomatic early disease confined to the chest metastatic disease No No No Yes; 3% Yes; 9% Yes; 15% Mackillop WJ, et al. Int J Radiat Oncol Biol Phys 1987;13:929–34
- 4. NSCLC: how oncologists would choose to be treated (1994) 105 Japanese doctors who treat lung cancer If they had NSCLC, would they choose to be treated with chemotherapy? After surgery for After surgery for For symptomatic early disease (stage locally advanced metastatic disease I) disease No No No Yes; 24% Yes; 62% Yes; 33% Motohiro A, et al. Lung Cancer 1994;11(1–2):43–50
- 5. ‘Mayor SV’ . . . estabamos cumpliendo los objetivos? 50 40 Pacients (%) 30 20 10 0 Etapa de diagnostico Temprana Localmente avanzada Avanzada Terapia ‘Standard’ Cirugía RT CT ±RT ±CT +CT + BSC SV 2-años SV 5-años 40% 25-30% 3% 44% con cirugía + CT RT = radioterapia CT = quimioterapia Adapted from Jemal A, et al. CA Cancer J Clin 2003;53:5–26
- 6. INICIO DEL CONOCIMIENTO DE BIOLOGIA MOLECULAR
- 7. thyroid transcription factor 1 PRIMARIO COMPROBACION POR IHQ
- 8. (PREDICE NO RESPUESTA DE TK)
- 9. CDDP PEMETREXED TK CETUXIMAB
- 11. CARCINOMA PULMONAR (ETIOLOGIA) TABAQUISMO (CIGARRILOS, PIPAS, PUROS). 80% DE LOS CASOS TABAQUISMO DE SEGUNDA MANO (30%). 3000 MUERTES ANUALES. RIESGO OCUPACIONAL: Asbesto Radon Hidrocarburos Policiclicos Aromaticos Metales (arsenico, cromo, niquel)
- 12. Tasa de Mortalidad por cancer pulmonar (1930-1998) e influencia del tabaquismo 80 Pulmón y bronquios (hombre) Pulmón y bronquios (mujer) 60 -1.7 tasa por Tabaco 100,000 86% (Hombres) 40 49% (Mujeres) población Hombre/ mujer +3.4 20 0 1930 1940 1950 1960 1970 1980 1990
- 13. Sequential changes during lung cancer pathogenesis Early Intermediate Late Normal Hyperplasia Invasive Dysplasia CIS epithelium carcinoma 3p LOH/small telomeric deletions 3p LOH/contiguous ~80% Microsatellite alterations deletions ~50% 9p21 LOH ~70% Telomerase Telomerase upregulation ~80% dysregulation myc overexpression ~60% 8p21-23 LOH ~80% Neoangiogenesis ~40% Loss of Fhit immunostaining ~40% p53 LOH p53 mutations ~70% Aneuploidy ~80% Methylation ~100 5q21 APC-MCC LOH % ~30% K-ras mutation ~20% LOH, loss of heterozygosity Hirsch et al 2001
- 14. Factores de Crecimiento Crecimiento Tumoral y Metástasis Metástasis Mutaciones en – Familia HER Efectos Tumorales – VEGF – metástasis – MPM´s – proliferación – Ras – pérdida de apoptosis – p53 – replicación infinita – COX-2 – angiogésis – invasión Tumor Primario Hanahan D, Weinberg RA. Cell. 2000;100:57-70.
- 15. HER1/EGFR Inhibidores: Modo de Actividad Antitumoral Anticuerpo Monoclonal TK inhibidor ↓ Proliferacion ↑ Apoptosis ↓ Invasion ↑ Sensibilidad a radioterapia ↓ Metastasis ↓ Adhesion ↓ Angiogenesis Etessami A, Bourhis J. Drugs Fut. 2000;25:895-899. Moyer J, Barbacci EG, Iwata KK, et al. Cancer Res. 1997;57:4838-4848. Harari PM, Huang SM. Semin Radiat Oncol. 2002;12(Suppl 2):21-26.
- 16. GLOBOCAN 2002 Latino America 23 paises Poblacion total 550 milliones (2004) – poblacion proyectada para 2050 de 767 milliones La casa del Tabaco – Despues del descubrimiento de las americas, Los Europeos adaptaron el habito del tabaco El consumo del tabaco es la causa mas importante de cancer pulmonar en Latino america El cancer pulmonar causa el 16% de mortalidad por cancer en hombres y 7% en mujeres
- 17. Incidencia y Mortalidad mundial de 15 tipos de cancer mas comunes, 2000 Hombres Mujeres Pulmón Mama Colon/recto Gastrico MAYOR MORTALIDAD Higado Próstata 18 MUERTES /HORA Cervix uterino Esófago Vejiga Linfoma No-Hodgkin Cavidad Oral Leucemias Pancreas Ovario Riñón 1200 1000 800 600 400 200 Miles Parkin et al 2001
- 18. 8
- 19. Major presenting symptoms of lung cancer Patients 100 (%) 80 60 40 20 0 Dyspnoea Cough Pain Loss of Haemoptysis appetite Baseline major presenting symptoms Hollen et al 1999
- 20. FIE SIN BRE TR TOM OM AS BO P SIS ARA NE OP LA SIC O S
- 21. Lung Cancer Subtypes The WHO classification for primary lung cancer recognizes 4 major histology types[1] *Including adenosquamous carcinoma; carcinomas with pleomorphic, sarcomatoid or Other* sarcomatous elements; 24.0% carcinoid tumor; carcinomas of Adenocarcinoma salivary gland type; and 38.3% unclassified carcinoma Large-cell carcinoma Small-cell 5.0% carcinoma 19.7% 13.0% Squamous cell carcinoma Percent distribution by histology among histologically confirmed lung cancer cases, 2001-2004[2] 1. Brambilla E, et al. Eur Respir J. 2001;18:1059-1068.2. SEER Database. Lung and Bronchus Cancer (Invasive), 1975-2004.
- 22. Types of lung cancer: small-cell lung cancer (SCLC) Approximately 20% of all lung cancers Cellular classification – small-cell carcinoma – mixed small-cell/large-cell carcinoma – combined small-cell carcinoma Occurs almost exclusively in smokers and is more prevalent in women than men Lesions most commonly originate in central part of chest Tendency to disseminate early Initially chemosensitive, becoming resistant
- 23. Types of lung cancer: non-small-cell lung cancer (NSCLC) Squamous-cell carcinoma (~30%) Adenocarcinoma (30-50%) • Most commonly found in men • Most common type of lung cancer in women and non-smokers • Closely correlated with smoking (dose • Lesions are usually peripheral dependent) • Worldwide incidence increasing • Tends to spread locally • Highly expressed genes encoding small- • More readily detected in sputum airway-associated and immunologically related proteins • Highly expressed genes encoding proteins with detoxification/ • K-ras mutations frequently reported anti-oxidant properties • Bronchoalveolar carcinoma is a subtype Large-cell carcinoma (10-25%) • Very primitive, undifferentiated cells • Lesions are usually peripheral • High tendency to metastasise
- 30. Lung cancer diagnosis/staging Physical examination Detect signs Bronchoscopy Precise location of tumour, obtain biopsy .90% FNA Cytology. Peripheral lesions Chest X-ray Detect position, size, number of tumours CT scan Detect chest wall invasion, mediastinal lymphadenopathy, distant metastases PET scan Lymph node staging. S:82% E:92%. Inf vrs Ca? Laboratory analysis Detect changes in hormone production, and haematological manifestations of lung ca. Mediastinoscopy Access to mediastinal adenopathy Bone Scan Bone Metastases NCCN Guidelines 2010
- 32. Adeno Carcinoma Pulmonar PET /CT post Tx. EC IIIB T2 N2 Mo
- 33. Carcinoma Escamoso TAC 11-1-2011 Pulmonar. 72 años. Dx. Oct. 2009 IMAGEN PET METABOLISMO FUSION NECROSIS
- 37. Survival by Pathologic Stage: IASLC New Classification Deaths/N MST 5-Yr, % IA 1168/3666 119 73 IB 1450/3100 81 58 IIA 1485/2579 49 46 100 IIB 1502/2252 31 36 IIIA 2896/3792 22 24 80 IIIB 263/297 13 9 IV 224/266 17 13 Patients (%) 60 40 20 0 0 2 4 6 8 10 Survival Yrs Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thoracic Oncol. 2007;2:706-714.
- 38. NSCLC: treatment options overview Stage I Stage II • Lobectomy or segment/wedge resection • Lobectomy, pneumonectomy, • Curative radiotherapy if surgery is segment/wedge resection as contraindicated appropriate • Adjuvant RT ?? • Curative radiotherapy if surgery • Adjuvant QT ?? contraindicated • Adjuvant chemotherapy • Adjuvant radiotherapy Stage IIIA Stage IV • Surgery alone • Chemotherapy (platinum based), • Chemotherapy + modest survival benefits radiotherapy/neoadjuvant therapy • New chemotherapy agents • Post-operative radiotherapy • External beam radiotherapy (palliative • Radiotherapy alone relief) Stage IIIB • Endobronchial laser or brachytherapy • Chemotherapy alone for obstruction • Chemotherapy + radiotherapy • Radiotherapy alone PDQ Guidelines 2000
- 39. 1000000 new lung cancers yearly 80% NSCLC 33% resectable NSCLC 75% candidates to adjuvant Chemo 180.000 patients candidates to adjuvant Chemo 4.5% increase in survival 7000 deaths could be avoided
- 43. The treatment algorithm for NSCLC Early Advanced (stage I/II/IIIa) NSCLC (stage IIIb/IV) Surgery + Suitable for chemotherapy? chemotherapy Yes No First-line (PS4, frail Radiotherapy Elderly/ elderly) (if unfit for No Yes PS2–3? surgery) PT-based Single BSC doublet agent Locally advanced Relapse Chemotherapy (PT doublet) Chemotherapy Tarceva + concomitant Second-/ – docetaxel radiotherapy third-line – pemetrexed PS = performance status; PT = platinum; BSC = best supportive care
- 44. Carcinoma Pulmonar (Historia y desarrollo) 100 BSC + CDDP (6-8m) 80 BSC (2-4m) 1990s Sobrevida (%) 60 Meta-analisis 40 confirman beneficio de 20 SVida con QT en 0 NSCLC avanzado 0 6 12 18 24 Tiempo desde randomizacion (meses) Resultados Tx. Con protocolos basados cisplatin (11 ensayos) 1930 1940 1950 1960 1970 1980 1990 2000 2010 NSCLC Collaborative Group. BMJ 1995;311:899–909
- 45. Carcinoma Pulmonar Historia . E1594 (n=1155) 1.0 Cisplatino/paclitaxel (R) 1990s distribution function SVida Cisplatino/gemcitabine 0.8 Cisplatino/docetaxel QT 1era linea NSCLC Carboplatino/paclitaxel (R) 0.6 avanzado llego 0.4 “PLATEAU” 5 10 15 20 25 30 0.2 Sv ½ 7.9m Urgente necesidad de TR: 19% 0 Nuevos opciones de tratamiento Meses 1930 1940 1950 1960 1970 1980 1990 2000 2010 Schiller JH, et al. N Engl J Med 2002;346:92–8
- 46. Carcinoma Pulmonar Historia Terapeutica 1.0 Carboplatin/paclitaxel + Avastin Carboplatin/paclitaxel 2005 0.8 Probability 0.6 Avastin + QT significativamente prolonga sobrevida comparado 0.4 con QT sola en 1 era. Linea 0.2 NSCLC avanzado 10.3 12.3 0 Primer estudio fase III que 0 6 12 18 24 30 36 42 Time (months) aumenta SVida media mas alla de 1 año Sandler A, et al. J Clin Oncol 2005;23 (Suppl. 16):2s (Abs. LBA4) Aprobado US 1930 1940 1950 1960 1970 1980 1990 2000 2010 Sandler A, et al. N Engl J Med 2006;355:2542–50
- 47. History of Therapy in Advanced NSCLC: FDA Approval Dates Docetaxel Gefitinib 2002 2003 Standard therapies First line Docetaxel Erlotinib Second line Pemetrexed 1999 Third line 2004 Maintenance Paclitaxel Bevacizumab Not approved Gemcitabine 2006 1998 *Label does not include Pemetrexed NSCLC-specific indication Vinorelbine 2008/2009 1994 Carboplatin* 12+ 1989 Median Cisplatin* OS (mos) 1978 ~ 8-10 ~6 ~ 2-4 1970 1980 1990 2000 Bevacizumab + PC BSC Single-agent platinum Doublets Histology-directed therapy 1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non- small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
- 48. ‘Better life’ . . . are we meeting the objective? Benefits Che moth e r apy Tumour control Improved survival Disadvantages Significant toxicity – myelosuppression – neuropathy Limited improvement in QoL i.v. administration Need for premedication
- 49. Interlinking Factors to Guide Personalized Therapy in NSCLC Clinical Factors Histologic Factors Molecular Factors Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
- 50. Histology Will Be Suboptimal for Selecting Chemotherapy (or Targeted Therapy) Histologic subtyping groups tumors based on microscopic pattern recognition by a pathologist (using 1800s’ technology) At best, histology = “crude molecular selection” Van LeeuwenHoek Molecular Profiling
- 51. “ It is much more important to know what kind of patient has a disease, than to know what kind of disease a patient has” Caleb Parry. 18th Century physician, Bath. “We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes” J.D Watson. Time Magazine 20 March 1989
- 52. Why Perform Molecular Testing? Outcomes of Molecular Testing Predictive: Who is likely to do better with a particular For predictive and therapy? prognostic value Prognostic: Who is likely to do better or worse, independent of therapy? Give best treatments first (eg, consider timing of EGFR TKI) To improve clinical Provide access to agent (eg, crizotinib for ALK-positive outcomes NSCLC) Identify subsets who might benefit from targeted therapy (eg, cetuximab) To facilitate clinical May improve patient outcomes research Better understanding of molecular oncology
- 53. Importance of Molecular Staging Early-Stage NSCLC Treatment Protocol Stage IA+B: Observation Stage II-IIIA: Adjuvant therapy Diagnosis Tumor is resected and measured Who to treat? 27% of stage IA and 42% of stage IB patients recur and die – Q: How to identify individuals at higher risk? 41% of patients with stage II NSCLC are cured with surgery alone and do not need adjuvant treatment – Q: How to identify patients that can be cured by surgery alone? – Q: How can patient selection among those given adjuvant therapy improve HR and cure rate?
- 54. Potential Oncogenic Drivers in NSCLC KRAS Adenocarcinoma EGFR BRAF HER2 Other PIK3CA ALK c-MET Other ALK (~ 5%) Bang Y, et al. ASCO 2010. Abstract 3. Reprinted with permission.
- 55. Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas No Mutation Detected KRAS 22% AKT1 NRAS EGFR MEK1 EML4-AKL 17% MET AMP 7% HER2 PIK3CA 2% BRAF 2% Double Mutants 3% Mutations found in 54% (280/516) of tumors completely tested (95% CI: 50% to 59%) Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01
- 56. Interpatient Heterogeneity in the Molecular Characteristics of NSCLC Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 65-yr-old male smoker, squamous KRAS Mt In 2012: Most oncologists would agree that these patients have very different malignancies Most oncologists would agree that these patients should receive different therapy
- 57. Interpatient Heterogeneity in the Molecular Characteristics of NSCLC Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 65-yr-old male 39-yr-old smoker, female squamous never-smoker, adenoca KRAS Mt EGFR Mt In 2012: Most oncologists would agree that these patients have very different malignancies Most oncologists would agree that these patients should receive different therapy
- 58. Interpatient Heterogeneity in the Molecular Characteristics of NSCLC Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 65-yr-old male 39-yr-old smoker, female squamous never-smoker, adenoca KRAS Mt EGFR Mt 54-yr-old male never-smoker, adenoca ALK fusion Most oncologists would agree that these patients have very different malignancies Most oncologists would agree that these patients should receive different therapy
- 59. Prevalence of EGFR Mutations by Smoking Status EGFR mutation status (exons 19 and 21) determined in 2142 adenocarcinoma samples from Memorial Sloan- Kettering Cancer Center Incidence of EGFR EGFR Mutations Detected mutations in tumors 36% – 52% of never smokers – 15% of former smokers – 6% of current smokers 60% Never (n = 302) 4% Current (n = 20) Former (n = 181) D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070.
- 60. HER1/EGFR Inhibidores: Modo de Actividad Antitumoral Anticuerpo Monoclonal TK inhibidor ↓ Proliferacion ↑ Apoptosis ↓ Invasion ↑ Sensibilidad a radioterapia ↓ Metastasis ↓ Adhesion ↓ Angiogenesis Etessami A, Bourhis J. Drugs Fut. 2000;25:895-899. Moyer J, Barbacci EG, Iwata KK, et al. Cancer Res. 1997;57:4838-4848. Harari PM, Huang SM. Semin Radiat Oncol. 2002;12(Suppl 2):21-26.
- 61. Angiogenesis Tumoral Tumor 1. Secrecion de 4. Aparecen Factores nueva vasculatura angiogenicos tumoral 2. Destruccion Proteolitica De matriz 3. Proliferacion extracellular y migracion endotelial Brote capilar
- 62. Agentes Blanco para vias VEGF Anticuerpos Anti-VEGF VEGF Soluble (bevacizumab) VEGFRs (VEGF-Trap) Anticuerpos VEGFR (IMC-1121b) P P P P P P P P VEGFR-1 VEGFR-2 Endotelio Inh. pequeña-molecula VEGFR – Vatalanib (PTK787) – Sunitinib (SU11248) – Sorafenib (BAY 43-9006) Podar and Anderson. Blood. 2005;105:1383. – ZD6474
- 63. Agentes Biologicos dirijidos a blancos moleculares específicos involucrados en la formación y desarrollo del tumor Cetuximab Avastin Receptor VEGF (control de angiogénesis) VEGF r PTK/ZK (TKI) HER1/EGFR Tarceva TKIs Control cel crecimiento y multiplicacion HER1/EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor
- 65. Prospective Trials of EGFR TKIs vs Chemotherapy in EGFR-Mutated Patients Trial Treatment N RR, % Median PFS, Mos Median OS, Mos TKI Chemo TKI Chemo TKI Chemo NEJ002[1] Gefitinib vs carboplatin/ 230 74 31 10.8 5.4 30.5 23.6 paclitaxel WJTOG3405[2] Gefitinib vs Not cisplatin/ 172 62 32 9.2 6.3 30.9 reached docetaxel OPTIMAL[3] Erlotinib vs Not carboplatin/ 165 83 36 13.1 4.6 NR reported gemcitabine EURTAC[4] Erlotinib vs Not platinum-based 174 58 15 9.7 5.2 NR reported doublet 1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 4. Rosell R, et al. ASCO 2011. Abstract 7503.
- 66. IPASS: PFS in EGFR Mutation–Positive and –Negative Patients EGFR Mutation Positive EGFR Mutation Negative Gefitinib (n = 132) Gefitinib (n = 91) 1.0 Carboplatin/paclitaxel (n = 129) 1.0 Carboplatin/paclitaxel (n = 85) HR: 0.48 (95% CI: 0.36-0.64; HR: 2.85 (95% CI: 2.05-3.98; 0.8 P < .0001) 0.8 P < .0001) Probability of PFS Probability of PFS Gefitinib events , n (%) 97 (73.5) Gefitinib events, n (%) 88 (96.7) 0.6 C/P events, n (%) 111 (86.0) 0.6 C/P events, n (%) 70 (82.4) 0.4 0.4 0.2 0.2 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Mos Mos Treatment by subgroup interaction test, P < .0001 Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy Front-line EGFR TKI should be restricted to EGFR mutation–positive patients Mok TS, et al. N Engl J Med. 2009;361:947-957.
- 67. Respuesta a erlotinib Junio 2005 Agosto 2005
- 68. FLEX: Response and OS by IHC Score FLEX: Response Rate by EGFR Expression Levels Predictive Value of High EGFR for (IHC Score) Survival Benefit With CT + Cetuximab Low EGFR Expression High EGFR Expression (< 200), n = 776 (69%) (≥200), n = 345 (31%) Low EGFR High EGFR HR: 0.99 HR: 0.73 (95% CI: 0.84-1.16) 100 (95% CI: 0.58-0.93) 44.4 80 OS (%) 60 29.6 32.6 28.1 40 20 0 Mos 0 6 12 18 24 30 Mos P = .36 P = .002 Interaction P = .044 Treatment interaction test P = .040 CT + cetuximab O’Byrne et al. JPO 20120, CT + cetuximab CT 12 (suppl), S558 (LBOAI) CT Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.
- 69. Thymidylate Synthase Expression in Lung Cancer ma lung ou s rc ino al all am oc a N o rm S m ll Sq u en Ce Ad TS SCLC: highest TS Squamous: high TS Bhattacharjee A, et al. Proc Natl Acad Sci U S A. Adeno: low TS 2001;98:13790-13795.
- 70. EML4-ALK Translocations in NSCLC 1 HELP 496 981 EML4 Basic WD EML4-ALK frequency: ~ 4% (64/1709) EML4-ALK 1 496 1059 Primarily in adenocarcinoma variant 1 More common in younger patients More common in never-smokers 1 1058 1620 (~ 20%) ALK Kinase TM Soda M, et al. Nature. 2007;448:561-566.
- 71. Crizotinib in Patients With Advanced ALK-Positive NSCLC Crizotinib (PF-02341066) – Dual selective inhibitor of ALK and c-MET • ATP-competitive inhibitor • Orally available small molecule – Potent inhibition of cell growth and induction of apoptosis in NSCLC cell lines – Demonstrated safety in dose-escalation study 1. Tan W, et al. ASCO 2010. Abstract 2596.
- 72. Tumor Responses to Crizotinib for Patients With ALK-Positive NSCLC Kwak and colleagues evaluated safety and efficacy of crizotinib in ALK- positive NSCLC patients (N = 82) 60 PD SD PR CR 40 Percent Change From 20 0 Baseline -20 -40 -30% -60 -80 -100 10 20 30 40 50 60 70 79 Patient No. Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
- 73. Algorithm for Therapy of Advanced- Stage NSCLC: 2009 Proposed Treatment Algorithm EGFR mutation positive Molecular Good PS Clinical (PS) POOR PS Erlotinib Nonsquamous Histologic Squamous Single-agent chemotherapy Bevacizumab Bevacizumab First Clinical eligible ineligible line Platinum/pemetrexed (or other*) ± Platinum/pemetrexed Platinum/gemcitabine bevacizumab (or other*) (or other*) Maintenance End of first-line chemotherapy Bevacizumab or erlotinib or Pemetrexed or Based on previous Erlotinib pemetrexed erlotinib therapy Progression Chemotherapy by Based on Based on Based on previous therapy Second algorithm previous therapy previous therapy line *Docetaxel, paclitaxel, vinorelbine. Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
- 74. Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012 Advanced-Stage NSCLC & PS 0-1 EGFR mutation ELM4-ALK EFGR mutation and ALK EFGR mutation and ALK positive positive negative and nonsquamous negative and squamous histology histology Bevacizumab Bevacizumab appropriate inappropriate Erlotinib or Consider crizotinib Consider Consider Consider gefitinib first or second line carboplatin/paclitaxel + cisplatin or carboplatin cisplatin or first line bevacizumab combined with carboplatin or pemetrexed, docetaxel combined with cisplatin/pemetrexed or gemcitabine or docetaxel or ± bevacizumab paclitaxel gemcitabine or or paclitaxel cisplatin/vinorelbine or ± cetuximab cisplatin/vinorelbine ± cetuximab Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
- 75. Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012 Advanced-Stage NSCLC & PS 0-1 EGFR mutation ELM4-ALK EFGR mutation and ALK EFGR mutation and ALK positive positive negative and nonsquamous negative and squamous histology histology Bevacizumab Bevacizumab Molecular appropriateHistology: Clinical inappropriate Erlotinib or Consider crizotinib Consider Consider Consider gefitinib first or second line carboplatin/paclitaxel + cisplatin or carboplatin cisplatin or first line bevacizumab combined with carboplatin or pemetrexed, docetaxel combined with cisplatin/pemetrexed or gemcitabine or docetaxel or ± bevacizumab paclitaxel gemcitabine or or paclitaxel cisplatin/vinorelbine or ± cetuximab cisplatin/vinorelbine ± cetuximab Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
- 76. Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers Histology Maintenance Therapy Predictive Biomarkers Looking Forward to 2015: Moving From Empiric to Individualized From “One Size Fits All” to “Tailored” and “Individualized” Therapy
- 77. Transition From Empiric to Tailored and Individualized Cancer Therapy Empiric therapy Tailored and individualized therapy Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
- 80. Terapia Anti-VEGF normaliza microvasculature tumoral Jain RK. Nat Med 2001;7:987–9 AVASTIN Vasculature Anormal Normalizacion de vasculatura tumoral Vasculatura normal despues de Vasos aumentan Terapia anti-angiogenic therapy permeabilidad tortuosidad Normalidad de tamaño, forma y permeabilidad de vasos Difusion de medicamentos Reduccion de presion comprometida intratumoral. Mejoria de oxigenacion Potential mejoria en difusion de medicamentos
- 81. Terapia Anti-VEGF inhibe neo-vascularizacion Neovascularizacion despues de implantacion de celulas tumorales Control Antes de 1 dia despues 6 dias despues 9 dias despues implantation implantacion implantacion implantacion Celulas LLC Anti-VEGF therapy* Antes de 1 dia despues de 6 dias despues de 9 dias despues de implantacion celulas implantation implantacion implantation LLC * Anti-VEGF agent: SU11248 (VEGFR TKI) Osusky KL, et al. Angiogenesis LLC = Lewis lung carcinoma 2004;7:225–33
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- These are the current results obtained with the standard treatments in NSCLC. As you know, even in early stages 5-year survival rate remains unsatisfactory even if slightly improved with adjuvant chemotherapy as recently demonstrated in some trials especially IALT. Of course results obtained in locally advanced disease and metastatic stage are poorer with a two-year survival of locally advanced disease patients treated with the standard being platin-based doublet + radiation therapy being around 25 to 30% and the one-year survival rate of metastatic patients when treated by CT around 30% and the 5-year survival rate being negligible
- Since about 1950, >70,000 scientific articles have left no scientific doubt that prolonged smoking is an important cause of premature mortality and disability worldwide. 1 The cigarette industry in the USA experienced almost unbroken growth between 1913 and 1963, 2 and changes in smoking behaviour have been linked with changes in lung cancer mortality. 3 In the USA, a dramatic increase in mortality from lung cancer since the 1930s was observed. However, with increasing evidence that cigarettes cause lung cancer, cigarette consumption has declined in the USA. In the developing world, cigarette use is still increasing, at a rate of ~3.4% per year. 1,2 During 1990-1997, US mortality from lung cancer declined significantly among men (-1.7% per year), in contrast to rates for women, which continued to increase but at a much slower pace. The increase in incidence rate among women reached a plateau in the 1990s, with incidence in 1998 being 43.4 per 100,000. 4 Decreasing lung cancer incidence and mortality rates most likely result from decreased smoking rates over the previous 30 years, with decreasing smoking patterns among women lagging behind those of men. 4 Estimated figures for the year 2000 indicate that 86% of lung cancer cases in men and 49% in women were due to smoking, although there was considerable regional variation in these figures. 5 According to the World Health Organization, tobacco-related deaths are expected to increase from ~4 million per year in 1998 to ~10 million per year by the 2030s, with 70% of those deaths occurring in developing nations. 1 This is a higher death toll than is expected from maternal and major childhood conditions, malaria and tuberculosis combined. 1 References World Health Organization. The World Health Report 1999: making a difference. (www.who.int) Slade J. J Psychoactive Drugs 1989; 21: 281-291. Shopland DR. Environ Health Perspect 1995; 103 (Suppl 8): 131-142. American Cancer Society. Surveillance research, 2002. (www.cancer.org) Parkin DM, et al. Eur J Cancer 2001; 37 (Suppl 8): S4-S66. Source of slide figure: American Cancer Society ’s Cancer Facts and Figures - 2002. Reprinted with permission.
- Loss of heterozygosity is a molecular detection method used to indicate deletion of one allele of a tumour suppressor gene (TSG). Both copies of TSGs are usually lost or mutated in the cancer phenotype. The most frequent genetic abnormalities found in lung cancers occur in TSGs. For example, p53 is mutated in >90% of SCLC and >50% NSCLC. The retinoblastoma TSG is also mutated in >90% of SCLC but in only 15% of NSCLC. p16 is another component of the retinoblastoma pathway, which is rarely abnormal in SCLC but is inactivated in >50% NSCLC. Additional evidence has confirmed that SCLC and NSCLC differ significantly in the TSGs that are inactivated during their pathogenesis. 1 myc oncogenes are commonly overexpressed in both SCLC and NSCLC, while ras is not mutated in SCLC but is mutated in 30% of NSCLC. 1 Preneoplastic lesions have been found to contain several molecular genetic abnormalities identical to some found in invasive carcinoma. 2 These include p53 mutations and increased immunoreactivity, myc and ras upregulation, cyclin D1 overexpression, bcl-2 overexpression, allele loss at several loci (3p, 9p, 8p and 17p) and DNA aneuploidy. 2 Molecular changes detected frequently in dysplasia are regarded as intermediate changes, and those detected at the carcinoma in situ or invasive stages are regarded as late. Although there is a common order in which molecular changes occur, exceptions are found. References 1. Wistuba II, et al. Semin Oncol 2001; 28 (2 Suppl 4): 3-13. 2. Hirsch FR, et al. Clin Cancer Res 2001; 7: 5-22. Slide figure reproduced from reference 2 with permission from the American Association for Cancer Research, Inc.
- Cancer arises from the cumulative effects of multiple mutations in genes critical for cellular growth control, leading to aberrant cell growth. These mutations can result in: increased activity of oncogenes decreased activity of tumor suppressor genes dysregulation of growth factors or their receptors, such as the HER family and its ligands, leading to abnormal signal transduction dysregulation of cell-cycle regulatory proteins, such as p53. These deleterious mutations accumulate in the cell, overwhelming the usual controls, and allowing the tumor to evade the body ’ s defenses. Such mutations result in various abnormal properties, including the ability to divide indefinitely (cell immortality), insensitivity to apoptotic signals (absence of programmed cell death), stimulation of angiogenesis (establishing a tumor-supporting vascular network), and the capacity to invade other tissues (metastasis). These processes combine to drive uncontrolled cellular proliferation, and tumor growth and spread. Hanahan D, Weinberg RA. Cell . 2000;100:57-70.
- Anti-HER1/EGFR monoclonal antibodies prevent ligand binding and subsequent receptor activation. 1 Small-molecule TKIs inhibit the binding of ATP to the intracellular TK domain of the target receptor, blocking receptor phosphorylation and associated downstream signaling. 2 Receptor inhibition using TKIs or antibodies inhibits cellular processes promoting tumor growth and progression, such as proliferation, angiogenesis, and metastasis, and normal control mechanisms, like apoptosis, are restored. 1,2 HER1/EGFR inhibition also prevents tumor cells from evading damage by radiotherapy, so restoring or enhancing their sensitivity to this treatment. 3 1. Etessami A, Bourhis J. Drugs Fut. 2000;25:895-899. 2. Moyer J, Barbacci EG, Iwata KK, et al. Cancer Res. 1997;57:4838-4848. 3. Harari PM, Huang SM. Semin Radiat Oncol . 2002;12(Suppl 2):21-26.
- Based on the most recent incidence and mortality data available, Parkin et al estimated that in the year 2000 there would be over 10 million new cases, 6.2 million deaths and 22.4 million people living with cancer. 1 This estimate represents an increase of around 23% in incidence and mortality since the estimates for 1990. Lung cancer is the most common cancer in the world 1 with the highest mortality. 2 Areas with the highest incidence are Europe, North America, Australia/New Zealand and South America. The rates in China, Japan and South-East Asia are moderately high. In developing countries, the highest rates in men are seen in areas where the habit of smoking has been longest established: the Middle East, China, the Caribbean, South Africa, Zimbabwe and the Pacific. 1 In the USA, the 1-year relative survival rates for lung cancer have increased from 34% in 1975 to 41% in 1997, largely as a result of improvements in surgical techniques. 3 However, the 5-year relative survival rate for all stages combined is only 15%. The survival rate is 48% for cases detected when the disease is localised but only 15% of lung cancers are detected at this early stage. 2 References Parkin DM, et al. Eur J Cancer 2001; 37 (Suppl 8): S4-S66. Greenlee RT, et al. CA Cancer J Clin 2000; 50: 7-33 . American Cancer Society. Cancer facts and figures, 2002. (www.cancer.org) Slide figure reproduced from reference 1 with permission from Elsevier Science.
- The symptoms of non-small-cell lung cancer (NSCLC) are particularly severe and debilitating, and become worse during the final stages of the disease. Symptoms of advanced lung cancer can be more distressing than with other types of malignancy and are particularly associated with the site of the disease. In a recent study of 673 patients with NSCLC, the major presenting lung cancer symptoms at diagnosis were dyspnoea (87% of patients), cough (86%), pain (81%), loss of appetite (75%) and haemoptysis (41%). 1 Although 81% of these patients had three or more of these symptoms, there were some patients who presented with only one symptom (5% of patients) or no symptoms (2%). 1 Although not assessed in this study, weight loss is also a major symptom of NSCLC. Reference Hollen PJ, et al. Support Care Cancer 1999; 7: 140-148. Slide figure reproduced from reference 1 with permission from Springer-Verlag.
- WHO, World Health Organization
- Small-cell lung cancer (SCLC) accounts for ~20% of all lung cancer cases. 1 Cellular classification small-cell carcinoma mixed small-cell/large-cell carcinoma combined small-cell carcinoma (SCLC combined with neoplastic squamous and/or glandular components). Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumour (median survival from diagnosis of 2-4 months) but is much more responsive to chemotherapy and radiotherapy than other tumour types. 2 Owing to the tendency to disseminate early, SCLC is treated as a systemic disease, with chemotherapy as the cornerstone of treatment. Despite being initially chemosensitive, these carcinomas acquire drug resistance during the course of the disease. References Zöchbauer-Müller S, et al. Ann Oncol 1999; 10 (Suppl 6): 83-91. PDQ Treatment Guidelines 2000.
- About 80% of all lung cancer cases are NSCLC. The major cause of NSCLC is tobacco smoking (85% correlation) and it affects a large number of people in their productive middle years. The incidence of NSCLC is increasing as a result of ageing populations and increasing numbers of female smokers. However, tobacco smoking is by no means the only cause of lung cancer: environmental, dietary and genetic factors have all been identified as increasing the risk of the disease. There are three major types of NSCLC. Each type has a different incidence and pattern of occurrence by age, sex, race and geographical area. 1 The histological type of NSCLC may affect treatment outcome. Squamous-cell carcinoma: consists of layers of epithelial cells that secrete keratin, and therefore often present as obstructing tumours in the bronchi most commonly found in men represents 30% of all cases closely correlated with smoking has a molecular profile including high expression of genes involved in cellular detoxification and anti-oxidation. 2 Adenocarcinoma: most common type of lung cancer in women and non-smokers and the worldwide incidence is increasing characterised by high-level expression of small-airway-associated or imunologically related proteins 2 and k-ras mutations are frequently reported 3 a subtype of adenocarcinoma called bronchoalveolar carcinoma, which often presents at an earlier stage than other adenocarcinomas, can be less aggressive and has been associated with better survival in some studies. Early diagnosis and surgical treatment are therefore particularly valuable in nodular bronchoalveolar carcinoma 4 in contrast with other bronchial carcinomas, survival of patients with bronchoalveolar carcinoma is influenced more by the extent of lung involvement (eg presence of bilateral lesions or production of mucin by tumour cells) than by the extent of lymph node metastases 5 metastatic bronchoalveolar carcinoma can be an aggressive disease, with a prognosis similar to that seen for adenocarcinoma. 6 Adenocarcinoma and large-cell carcinoma: were found to recur after surgery more frequently than squamous-cell carcinomas in one study (0.088 and 0.042 recurrences per patient per year, respectively), even though all cancers were the same stage (T1 N0). 7 References Wingo PA, et al. J Natl Cancer Inst 1999; 91: 675-690. Nacht M, et al. Proc Natl Acad Sci USA 2001; 98: 15203-15208. Niklinski J, et al. Lung Cancer 2001; 34 (Suppl 2): S53-S58. Grover FL, Piantadosi S. Ann Surg 1989; 209: 779-790. Daly RC, et al. Ann Thorac Surg 1991; 51: 368-377. Feldman ER, et al. Mayo Clin Proc 1992; 67: 27-32. Thomas P, Rubinstein L. Ann Thorac Surg 1990; 49: 242-247.
- Current standard guidelines indicate that diagnosis may be made by bronchoscopy or cytology via a fine-needle aspirate. During the initial evaluation, all patients should have their history taken and undergo physical examination, chest X-ray and chest computed tomography (CT) scans (including the adrenal glands), liver CT scan or abdominal ultrasound. Other evaluations include a complete blood count, liver function tests, measurements of electrolytes, calcium, blood urea nitrogen, and creatinine, as well as a baseline ECG. Bone scans and/or brain CT scans may be appropriate in some patients. 1 The extent of the tumour, the involvement of the lymph nodes, and chest wall or mediastinal invasion can be determined with similar efficacy using either CT or magnetic resonance imaging (MRI). CT is used more commonly, although MRI may be preferable in specific situations, for example in evaluating superior sulcus tumours. 2 Positron emission tomography with radiolabelled fluoro-2-deoxyglucose combined with CT was significantly more accurate than CT alone in identifying lymph node involvement in NSCLC. 3 References NCCN Guidelines 2000. Webb WR, et al. Radiology 1991; 178: 705-713. Vansteenkiste JF, et al. J Clin Oncol 1998; 16: 2142-2149.
- IASLC, International Association for the Study of Lung Cancer; MST, median survival time.
- Stage I: 1 surgery is the treatment of choice and curative radiotherapy may be used in patients with contraindications to surgery many patients resected for stage I NSCLC may later develop regional or distant metastases. Investigations of adjuvant chemotherapy or radiotherapy following surgery are currently underway chemoprevention trials for second cancers in patients resected for stage I NSCLC are also underway. Stage II: 1 surgery is the treatment of choice and curative radiotherapy may be used in patients with contraindications to surgery many patients resected for stage II NSCLC may later develop regional or distant metastases. Investigations of adjuvant chemotherapy or radiotherapy following surgery are currently underway. Stage IIIA: 1 surgery alone in highly selected cases chemotherapy combined with radiotherapy, chemotherapy plus radiotherapy followed by surgery, or chemotherapy after surgery (encouraging results for patients with good performance status). Optimal sequencing and scheduling have yet to be determined. Neoadjuvant chemotherapy could be considered for patients with good performance status surgery and post-operative radiotherapy (can improve local control but there is controversy over whether it improves survival) radiotherapy (long-term survival benefit in 5-10% of patients; patients with high performance status are most likely to benefit). Stage IIIB: 1 radiotherapy alone (patients with advanced disease and high performance status are most likely to benefit) chemotherapy combined with radiotherapy (modest survival benefits compared with radiotherapy alone) chemotherapy and/or radiotherapy followed by surgery chemotherapy alone (for patients with malignant pleural effusion). Stage IV: 1 cisplatin-containing combination regimens produce higher response rates than single-agent chemotherapy current treatments produce modest survival benefits compared with supportive care alone and there is no standard regimen new chemotherapy agents are being evaluated in clinical trials external radiotherapy may be used for palliation of symptoms such as compression of the trachea, oesophagus or bronchus; bone or brain metastases; local pain; vocal cord paralysis; haemoptysis; or superior vena cava syndrome endobronchial laser therapy or brachytherapy may be useful in treating lesions obstructing the proximal airways. Many patients do not receive any treatment, even first line; the proportion of patients receiving treatment reduces with the stage of the disease. Reference 1. PDQ Treatment Guidelines 2000.
- Talking points Overview of treatment options in advanced NSCLC Discuss the factors that influence/limit treatment choices in NSCLC (e.g. stage of illness, previous therapy, patient characteristics etc.). Here are the details regarding the treatmen t options in NSCLC according to the stage of the disease. However, several factors will influence and often limit the treatment choices in NSCLC. For example, a patient a patient with an early stage, thus resectable may not be operable due to medical conditions often due to tobacco use. Also, elderly patients or poor performance status patients with advanced stage cannot receive platin-based chemotherapy which is the standard and will be treated either with best supportive care only or single agent chemotherapy.
- Image from BMJ paper Copyright ©1995 BMJ Publishing Group Ltd.
- Mandatory Slide ADDITIONAL INFORMATION The ECOG 1594 trial enrolled a total of 1207 patients with advanced NSCLC who were randomly assigned to cisplatin and paclitaxel or to 1 of 3 experimental regimens including cisplatin and gemcitabine, cisplatin and docetaxel, and carboplatin and paclitaxel The response rate of all 1155 eligible patients was 19%, with a median survival of 7.9 months The 1-year survival rate was 33%, and the 2-year survival rate was 11% The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the 3 experimental regimens On the basis of the safety results observed in this study, carboplatin/paclitaxel became the ECOG reference standard for its future studies REFERENCE Schiller et al. N Engl J Med . 2002;346:92 – 98.
- BSC, best supportive care; C, carboplatin; P, paclitaxel
- The survival benefit obtained with CT is well demonstrated although modest but this benefit is obtained at the expense of a significant toxicity, significant constraints due to iv administration of CT in most cases resulting in a limited improvement of QoL
- NSCLC, non-small-cell lung cancer .
- On the next slide, I show you my own overview of the role of histology. I think that although it is very useful to us right now, this is not how we will be selecting therapy in the future. Histology, after all, is a crude molecular selection, as I will show you. We see, on the left, early use of the microscope during the 1800s to differentiate different types of cancer, and on the right, the move to molecular profiling. Now, this particular molecular profile, this gene expression signature shown on the right, is of particular significance.
- There are 3 main reasons for performing molecular testing. The first would be to get the best sense of predictive and prognostic value, ie, how well people will do and particularly whether certain agents will be more effective, and so it is worth reviewing what is predictive and what is prognostic. Predictive means what is likely to be a more effective therapy; there are certain markers that may suggest that a certain treatment is more or less likely to be effective. Prognostic means who is likely to do better or worse regardless of the therapy employed. Another important reason, and really probably the most important, is to improve clinical outcomes for our patients. We are learning about the importance of molecular markers in our ability to select the best treatment and give that first. Importantly, we are also seeing new models where access to an agent may be tied to particular molecular testing, and that is now the case with crizotinib for ALK-positive non-small-cell lung cancer. Another issue is to identify subsets of patients who might be most likely to benefit from a particular therapy or a targeted therapy in particular. The third issue is to facilitate clinical research. A very large amount of the work that is being presented is just emerging from the last few years, which has all been predicated on tissue collection and molecular marker testing, and this gives a hint as to the potential value of ongoing and future molecular testing. Some of our biggest advances have been based on optimizing selection of the best treatments for particular patients, but we can only do that to the extent that we do molecular testing. More and more studies are requiring molecular testing, and it is becoming a very good investment to have that tissue available.
- NSCLC, non-small-cell lung cancer .
- NSCLC, non-small-cell lung cancer.
- Mt, mutation; NSCLC, non-small-cell lung cancer. The question that we just posed and what is shown on this slide emphasizes the first point of differentiation between patients with non-small-cell lung cancer, and that is recognition of great interpatient heterogeneity in the molecular characteristics. These are the differences between one patient and the next. In this cartoon, all the figures appear to be the same, but if we look at 3 patients individually, you will see this first patient is a 65-year-old male smoker, who has squamous cell carcinoma. His cancer is characterized by a KRAS mutation.
- Mt, mutation; NSCLC, non-small-cell lung cancer. The second patient, shown here, is a 39-year-old female never-smoker with adenocarcinoma. The leading characteristic for her cancer is that it is an adenocarcinoma that is defined by an EGFR mutation.
- Mt, mutation; NSCLC, non-small-cell lung cancer. Our third patient, shown here, is a 54-year-old male never-smoker with adenocarcinoma. His cancer is molecularly defined by an ALK fusion. Why is this important? I think it is obvious to everyone in the year 2012 that these patients are very different. Most oncologists would agree that these patients had different malignancies; most oncologists would also agree that these patients should receive different therapy.
- This was also investigated in another publication more recently that came out of Memorial Sloan-Kettering, which enrolled more than 2000 patients with adenocarcinomas and analyzed their probability of having an EGFR mutation based on their smoking status. The probability was 52% in never-smokers, 15% in former smokers, and 6% in current smokers. And, in fact, former smokers comprised 36% of the EGFR mutations detected in their sample over time.
- Anti-HER1/EGFR monoclonal antibodies prevent ligand binding and subsequent receptor activation. 1 Small-molecule TKIs inhibit the binding of ATP to the intracellular TK domain of the target receptor, blocking receptor phosphorylation and associated downstream signaling. 2 Receptor inhibition using TKIs or antibodies inhibits cellular processes promoting tumor growth and progression, such as proliferation, angiogenesis, and metastasis, and normal control mechanisms, like apoptosis, are restored. 1,2 HER1/EGFR inhibition also prevents tumor cells from evading damage by radiotherapy, so restoring or enhancing their sensitivity to this treatment. 3 1. Etessami A, Bourhis J. Drugs Fut. 2000;25:895-899. 2. Moyer J, Barbacci EG, Iwata KK, et al. Cancer Res. 1997;57:4838-4848. 3. Harari PM, Huang SM. Semin Radiat Oncol . 2002;12(Suppl 2):21-26.
- A tumour needs to establish new vasculature to obtain the nutrients necessary to sustain growth beyond 1-2 mm 3 . Angiogenesis is defined as the development of new capillaries from existing vessels. Tumours induce angiogenesis by increasing production and secretion of angiogenic factors and proteases that act in concert to promote angiogenesis. Secretion of angiogenic factors, such as vascular endothelial growth factor (VEGF) increase endothelial-cell-associated protease activity and stimulate endothelial cell migration and proliferation. Proteases secreted by tumour cells and endothelial cells degrade the extracellular matrix, allowing endothelial cell migration. Together these processes promote angiogenic sprouting and the formation of new tumour vasculature. New vessels formed during pathological angiogenesis, compared with those produced normally, are not well formed and are described as tortuous and leaky. Therapeutic inhibition of tumour angiogenesis should be effective in all solid malignancies and the biological effect should be tumour specific, as, apart from the female reproductive system, angiogenesis is quiescent in healthy tissues. Furthermore, genetically stable endothelial cells may be less prone to developing drug resistance than tumour cells. Drug delivery is facilitated because target tissue is in direct contact with blood. Tumour vasculature may be targeted by: preventing new blood vessel growth (angiogenesis inhibition) destroying existing tumour blood vessels (vascular targeting). Angiogenesis inhibition is potentially complementary to other antitumour strategies.
- Numerous agents that target the VEGF pathway are in clinical development, including agents targeting the VEGF ligand and those targeting the VEGFRs. Agents that inhibit the VEGF ligand from binding and activating its receptors include Antibodies that specifically inhibit VEGF Soluble VEGFRs, which bind to other ligands that interact with VEGFR-1 and VEGFR2 The strategies being employed to target VEGFRs are similar to those being used to target other growth factor receptors, such as EGFR. These include Antibodies that prevent receptor activation Small-molecule inhibitors Novel targeting agents such as ribozymes Agents targeting the VEGF ligand Inhibit VEGF activity with all its receptors Inhibit activities of the ligand on all cell types Antibodies affect the activity of specific ligands, while soluble receptors affect the activity of multiple ligands. Agents targeting the VEGFR Inhibit the activity of multiple VEGF family members acting through the same receptor Small-molecule inhibitors affect multiple receptors, including those in different families (eg, fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR]). Highly specific antibodies and ribozymes inhibit VEGF signaling through a single targeted receptor. Manley PW, Martiny-Baron G, Schlaeppi JM, Wood JM. Therapies directed at vascular endothelial growth factor. Expert Opin Investig Drugs . 2002;11:1715-1736. Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood. 2005;105:1383-1395.
- This diagram highlights some of the more promising targeted agents and their targets. These include biological agents like Avastin and Cetuximab as well as small molecules like Tarceva and PTK/ZK 787.
- Importantly, the IPASS trial was selecting patients on the basis of clinical features, such as Asian never or minimal prior smokers with an adenocarcinoma, and then investigated EGFR mutational status in retrospective analyses. There have since been 4 different studies that have selected patients prospectively on the basis of having an EGFR mutation, an activating mutation in exon 19 or exon 21, and these are shown in the table. And they are striking in their extreme concordance, all showing that response rate is strikingly and quite significantly higher to first-line EGFR tyrosine kinase inhibitor than to chemotherapy as first-line therapy in patients with an EGFR mutation, and progression-free survival also very consistently significantly longer in recipients of an EGFR tyrosine kinase inhibitor than standard chemotherapy first-line. In contrast, overall survival results are not as clear; most of these without complete maturation of the trial results, but in none of these yet a significant difference in overall survival. Again, suggesting the possibility or probability that if patients do cross over to receive an EGFR tyrosine kinase inhibitor, they can effectively be rescued to get the great benefit. But it is clear that the first-line clinical benefit is overwhelmingly greater with an EGFR tyrosine kinase inhibitor in patients who are identified as having an EGFR-activating mutation.
- CI, confidence interval; C/P, carboplatin/paclitaxel; HR, hazard ratio; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. On the next slide, we see that the results of this study were dictated by whether the patient had an underlying EGFR mutation. The overall progression-free survival actually showed a crossover and that was explained by what is seen here. In those patients who had tissue available, it was tested for EGFR mutation. If it was positive, the patients did better with gefitinib. If it was wild type, meaning no mutation, the patient actually benefitted more from chemotherapy. So, as shown, clinical characteristics are insufficient for selection of first line EGFR TKI therapy. Frontline EGFR TKI therapy outside of a clinical trial should, by and large, be restricted to patients who have an activating mutation.
- CI, confidence interval; CT, chemotherapy; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival. As you can see, there was a modest survival benefit in this trial overall, which on recent analysis, was amplified in those patients who had a great deal of EGFR protein expression in their cancer by an immunohistochemistry H-score.
- Adeno, adenocarcinoma; SCLC, small cell lung cancer; TS, thymidylate synthase. If we go to the next slide, you will see this is actually the signature for thymidylate synthase or TS expression in lung cancer, looking at adenocarcinoma vs normal lung, vs small-cell carcinoma, and vs squamous cell carcinoma. What this paper in the Proceedings of the National Academy of Science over 10 years ago showed us is that it is adenocarcinoma that tends to have the lowest levels of TS, which is one of the molecular targets for pemetrexed. So, perhaps this explains that observation of pemetrexed differential activity in nonsquamous cell carcinoma.
- NSCLC, non-small-cell lung cancer. This is quite a success story. As you can see from this slide, this abnormality was first described in 2007. We now know that this is not exclusive to only non-small-cell lung cancer, but it is found in some other tumor types. The overall frequency in non-small-cell lung cancer is uncommon, at about 4%. If patients are enriched, if it is adenocarcinoma; if it is a younger group of patients, or if it is never-smokers, then in my experience, the frequency goes up to over 20%. So, it is clearly worth looking for.
- NSCLC, non-small-cell lung cancer.
- NSCLC, non-small-cell lung cancer.
- NSCLC, non-small-cell lung cancer; PS, performance score. Taking that patient example, the next slide shows an algorithm that we published for looking at this situation in the year 2009. The purpose of this slide is not to drill down into the individual categories; it is to emphasize the point that in 2009, we really only had one molecular factor, and that was for selection of EGFR tyrosine kinase inhibitors such as erlotinib by activating EGFR mutation. The other factors—performance status, histology, whether or not a patient is eligible or appropriate for bevacizumab—these are what I would call clinical and histologic factors. So, these are the things in 2009 that allowed us to look at therapeutic options.
- NSCLC, non-small-cell lung cancer; PS, performance score. This next slide shows that same algorithm. It has been redesigned, but as you can see, the categories are identical, and the main significant change is now we have added AML4 ALK testing into the algorithm for patients who might be considered for crizotinib therapy. So, we now have a second molecular criterion, but you can see the remainder is still histology and clinical, such that the patient would be considered either on a nonsquamous histology base or squamous histology for various chemotherapy combinations, with or without bevacizumab for nonsquamous. Also, there is the new consideration of cetuximab, which although it is not FDA approved in the United States, it is going through that process and is part of the guidelines for therapy.
- NSCLC, non-small-cell lung cancer; PS, performance score. So, we now have a second molecular criterion, but you can see the remainder is still histology and clinical, such that the patient would be considered either on a nonsquamous histology base or squamous histology for various chemotherapy combinations, with or without bevacizumab for nonsquamous. Also, there is the new consideration of cetuximab, which although it is not FDA approved in the United States, it is going through that process and is part of the guidelines for therapy.
- NSCLC, non-small-cell lung cancer. Looking forward from 2012 over the next 3 years, what might we anticipate? We anticipate that we will move further from empiric therapy to individualized therapy. What are the criteria for making this transition?
- As you can see, for empiric therapy, the physician uses the patient characteristics. He uses his own experience. He uses the information he has gained from the literature. What about tailored and individualized therapy? This requires the availability of adequate tumor tissue for molecular profiling in every patient. So, this means that a small fine needle aspiration gaining only a few cells that can be called cancer is going to be insufficient for moving into this tailored and individualized therapy. We need enough tissue to do molecular profiling. We also need appropriate biomarkers to be developed. Lastly, we need to account for interpatient tumor heterogeneity between one patient and the next.