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Fórum Câncer de Pulmão - 27/11/2017

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Palestra apresentada pelo CEO da empresa Evidências Cientificas, Otávio Clark com o tema "Câncer de Pulmão: diagnosticar e tratar adequadamente"

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Fórum Câncer de Pulmão - 27/11/2017

  1. 1. Preparado para: Contato Evidências: IMUNOTERAPIA CÂNCER DE PULMÃO Contact: Otávio Clark otavio.clark@evidencias.com.br Nov2017 otavio.clark@evidencias.com.br @otavioclark Otávio Clark
  2. 2. 2 Declaração de conflitos de interesse Sócio empresa de consultoria Evidências – a Kantar Health Company Trabalho para governo e empresas Auditoria médica oncologia e alto custo Farmacoeconomia Guidelines Registros Pesquisa clínica
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  5. 5. 5 No início era o núcleo (e o DNA)
  6. 6. 6 Depois o citoplasma… e as vias de sinalização intra-celular
  7. 7. 7 A membrana
  8. 8. 8 E, finalmente, o extra- celular…
  9. 9. 9 A long long time ago…
  10. 10. 10 Câncer de pulmão Câncer de pulmão Pequenas células Não Pequenas células Tratamento: QT platina Tratamento : QT platina/ irinotecan
  11. 11. 11 Câncer de pulmão Não Pequenas células Adenocarcinoma Escamoso Bronquílo-alveolar Histologianão escamosa
  12. 12. 12 Câncer de pulmão Não Pequenas células Adenocarcinoma Escamoso Bronquílo-alveolar Histologianão escamosa Tratamento com base em platina Tratamento com base em platina + bevacizumabe ou pemetrexede
  13. 13. 13 Câncer de pulmão Não Pequenas células Adenocarcinoma Escamoso Bronquílo-alveolar Com mutação EGFR Sem mutação EGFR
  14. 14. 14 Câncer de pulmão Não Pequenas células Mutação ALK (fusão)
  15. 15. 15 Não pequenas células Epidermóide EGFR Mutado Geftinibe/ Erlotinibe Egfr NÃO mutado QT (Taxano + platina) Adenocarcinoma EGFR Mutado Geftinibe/ Erlotinibe EGFR NÃO mutado Bevacizumab e + QT/ Pemetrexede Bronquíolo alveolar EGFR Mutado Geftinibe/ Erlotinibe EGFR NÃO mutado Bevacizumab e + QT/ Pemetrexede Pequenas células Diferentes tipos histológicos
  16. 16. 16 Não pequenas células Mutação EGFR? Inibidor EGFR Mutação ALK? Inibidor ALK Mutação PDL (1?) Imunoterapia Pequenas células Diferentes tipos biomarcadores
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  18. 18. 18 otavio.clark@evidencias.com.br @otavioclark Otávio Clark @otavioclark 19 98149 5375
  19. 19. 19 Desafios da imunoterapia
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  21. 21. 21 Resposta objetiva Stella. J Cancer 2011 Pezzuto. Oncology Letters 2015
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  23. 23. 23 Análise de dados de Sobrevivência Medida pelo “hazard ratio” / HR (razão de risco) Usualmente se relata também o tempo mediano Despreza os extremos Vantagens – mais preciso como medida central Desvantagem – perde benefícios de longo prazo Sobrevida em um ponto Ex.: Sobrevida em um ano Extremamente sujeita a erro
  24. 24. 24 Hazard Ratio: RT + Temozolomida X RT em tumores cerebrais HR= 0.63 (95% CI 0.53– 0.75) Lancet Oncol. 2009 May;10(5):459-66
  25. 25. 25 Sobrevida mediana RT + Temozolomida X RT em tumores cerebrais Sobrevida mediana = 12.1 x 14.3 meses Lancet Oncol. 2009 May;10(5):459-66
  26. 26. 26 Exemplo hipotético Tempo sobrevida Diferença de sobrevida mediana= 0 100% 50%
  27. 27. 27 Avaliação de medianas em curvas de sobrevida N Engl J Med. 2003 Dec 25;349(26):2495-502
  28. 28. 28 Como capturar o benefício da curva inteira? N Engl J Med. 2003 Dec 25;349(26):2495-502
  29. 29. 29 Breast Cancer Res Treat. 2010 May;121(1):121-31
  30. 30. 30 Breast Cancer Res Treat. 2010 May;121(1):121-31
  31. 31. 31 Breast Cancer Res Treat. 2010 May;121(1):121-31
  32. 32. 32 “Plateau” de longo prazo Pembrolizumabe para câncer de pulmão
  33. 33. 33 Probabilidade de sobrevida em pontos do tempo Stupp 2007Lancet Oncol. 2009 May;10(5):459-66
  34. 34. 34 Cálculo estatístico complexo, se feito à partir das curvas de sobrevida Aplica-se a estudos com sobrevida “em platô” no final da curva Diferente da sobrevida mediana Incorpora os efeitos de sobrevida de longo prazo Sem os problemas da análise em ponto específico Cálculo da sobrevida média N Engl J Med. 2010 Aug 19;363(8):711-23
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  38. 38. 38 Biopsy Specimen found to be Reliable for Evaluating DLL3 Expression in Small Cell Lung Cancer Dr. Li-Xu Yan of Guangdong General Hospital and Guangdong Academy of Medical Sciences in China • High levels of DLL3 in SCLC are correlated with poor survival trends. • Rovalpituzumab tesirine is a promising DLL3-targeted antibody-drug conjugate for the treatment of high-grade pulmonary neuroendocrine carcinomas (HGNEC). • Objective : to determine the reliability of the scoring system used to assess the correlation between paired biopsy and surgical specimens and HGNEC features and prognoses. • Between 2006 and 2015, the researchers recruited patients with de novo HGNECs, • 43 large cell neuroendocrine carcinoma (LCNEC) and 335 SCLC patients. • Biopsy specimen is a reliable material for evaluating DLL3 expression. • DLL 33 will be used in clinical studies of Rovalpituzumab
  39. 39. 39 Treatment Based On BRCA1 Expression Levels Does Not Increase Survival Rate of Stage II and III Non-Small Cell Lung Cancer N+ Resected Patients • Stage II and III non-small cell lung cancer (NSCLC) N+ resected patients • Customized chemotherapy (CT) treatment based on their specific BRCA1 expression levels X standard treatment • Hypothesis • Five year survival rate of the standard care control group (45%) could increase by 20% in an intervention group that received CT compatible with either their low, medium or high BRCA1 expression levels. • Intervention: • Control group standard Cis- Docetaxel • Experimental group: Cis-Gemcitabine (low BRCA1), Cis-Doc (intermediate BRCA1) or Docetaxel (high BRCA 1) • Results: • No increase overall survival rates among those patients who received individualized CT treatment • Median follow-up of 53 months • OS (control group) 69.3 months X experimental group 82.3 months, ranging from 74 months (low BRCA) to 80.5 months (intermediate BRCA) and 80.2 months (high BRCA). • For patients with resected NSCLC with lymph node involvement, postoperative platinum-based CT remains the standard of care.
  40. 40. 40 Non-Small Cell Lung Cancer Survival Rates Higher Among Patients Treated at Academic Centers Dholaria (Moffitt Cancer Center) • NSCLC cases between 2004 and 2013 from the National Cancer Database • Plotted overall survival (OS) by year of diagnosis and type of treatment facility. • More than 1 million NSCLC patients, separated by initial treatment facility type (academic: 31.5%, non-academic: 68.5%). • NSCLC treatment at academic centers was associated with reduced risk of death when compared to non-academic centers. • Four-year OS for academic and non-academic cohorts was 25% and 19%, respectively (p<0.001). • They also found that the survival difference between academic and community centers was greater among non-metastatic compared to metastatic NSCLC. • This difference remained significant even after adjusting for different characteristics • These findings highlight the importance of ensuring easier access to facilities with multidisciplinary expertise and training programs • Median OS for patients diagnosed from 2010 to 2013 (14.8 months) was significantly higher when compared to patients diagnosed from 2004 to 2009 (12.4 months), which points to major treatment advances for NSCLC (p<0.001).
  41. 41. 41 NEW HISTOLOGICAL CLASSIFICATION Travis - Dept of Pathology, Memorial Sloan Kettering Cancer Center, New York/NY/US The 2015 WHO Classification had a major impact on the new 8th Edition TNM Classification. Major changes include: 1)use of immunohistochemistry throughout; 2) New emphasis on genetic studies and personalized therapeutic strategies; 3) A new classification of lung cancer in small biopsy and cytology samples; 4) adoption of the 2011 IASLC/ATS/ERS lung adenocarcinoma classification; 5) reclassification of large cell carcinoma based upon immunohistochemistry and genetics. Primary tumor (T component) New T categories were introduced based on tumor size The recommendation is to measure it on computed tomography with the lung window, because the mediastinal window may underestimate it. The registered size should be the greatest dimension in any of the available projections: axial, coronal or saggital. Nodal involvement (N component)The present N categories (NX, N0, N1, N2 and N3) and their descriptors remain unchanged. Metastatic disease (M component) New definitions Stage grouping More stages have been created
  42. 42. 42 THE DUTCH-BELGIAN LUNG CANCER SCREENING TRIAL (NELSON) H. De Koning Public Health, Erasmus MC, Rotterdam/NL • The NELSON trial is Europe’s largest running lung cancer screening trial (started 2003) • Objectives: (1) to see if screening for lung cancer by multi-slice low-dose CT in high risk subjects will lead to a 25% decrease in lung cancer mortality or more; (2) to estimate the impact of lung cancer screening on health related quality of life and smoking cessation; (3) to estimate cost-effectiveness of lung cancer screening. • 15,792 participants were randomised screen X control • Screen: CT-screening at baseline, after 1 year, after 2 years and after 2,5 years X Control (no screen) • Three screen results were possible: negative (an invitation for the next round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). • The lung cancer detection rate across the four rounds were, respectively: 0.9%, 0.8%, 1.1% and 0.8%. • The cumulative lung cancer detection rate is 3.2% • The overall false-positive (over four rounds) is 1.2% • A 2-year interval detection equals to 1-year interval (p=0.09) • 2.5-year interval detected cancers that was significantly less favourable than after a 1-year screening interval (e.g. more stage IIIb/IV cancers). • On average, 69.4% of the screening-detected lung cancers across the four screening rounds in the NELSON trial were diagnosed in stage I and 9.8% in stage IIIb/IV. • The lung cancers found in the NELSON control group have yet to be investigated. • A question remains: does it reduces mortality?
  43. 43. 43 FIRST-LINE VERSUS SECOND-LINE ANTI-PD-(L)1 THERAPY FOR PATIENTS WITH POSITIVE PD-L1 EXPRESSION F. Barlesi Multidisciplinary Oncology & Therapeutic Innovations, Aix Marseille University • Tumor expressionhas been proposed to guide the patients’ selection but remains controversial • PD-L1 tumor expression of more than 1% and 50% is mandatory for the use of pembrolizumab monotherapy in second and first line, respectively. • Therefore, how to choose the best way to use ICIs for advanced NSCLC patients? • Many aspects may be considered in the decision, besides the PD-L1 expression • Current contra-indications to ICIs, • Factors predicting a higher risk of rapid progression on ICIs • Potential synergy for the concomitant combination of ICIs with chemotherapy or conversely a sequential use, • Side e ects for monotherapies and combinations, • Recent data on ICIs combinations versus standard chemotherapy.
  44. 44. 44 WHERE WE ARE NOW, AND WHERE WE WILL BE IN 10 YEARS: FROM NORTH AMERICAN PERSPECTIVE P. Bunn, Jr. Medical Oncology, University of Colorado • Stage 4 NSCLC 1st line Rx: In addition to complete staging, all patients with any histology should have PD-L1 testing of their tumor. • In addition patients with an adenocarcinoma histology and never smokers should have molecular testing that would include at least EGFR, ALK, ROS1 and BRAF. • Patients with a PD-L1 tumor proportion score (TPS) >49% who do not have a molecular driver can be treated with pembrolizumab as their first therapy. This therapy is continued for 2 years or until progression or unacceptable toxicity. • For those with a TPS score of 1-49, concurrent chemotherapy plus pembrolizumab may be considered • Patients with a molecular alteration in EGFR, ALK, ROS1, or BRAF are treated with the appropriate TKI or TKI combination in the case of v600E BRAF. • For patients with a lower TPS score or no molecular abnormality and PS0-1, the standard therapy is a platinum doublet chemotherapy with or without bevacizumab. • For patients with adenocarcinoma, the most frequently used regimen is pemetrexed with platinum • For patients with squamous carcinoma the platinum doublet • Patients receiving chemotherapy are restaged after 2 cycles. • Those with progressive disease are offered second line therapy.
  45. 45. 45 WHERE WE ARE NOW, AND WHERE WE WILL BE IN 10 YEARS: FROM NORTH AMERICAN PERSPECTIVE P. Bunn, Jr. Medical Oncology, University of Colorado • Second line: • Patients with stable disease or response receive 2 additional cycles and are then restaged again. • Those with acceptable toxicity and continued response are offered 2 additional cycles for a total of 6. • For patients receiving 1st line pembrolizumab, 2nd line treatment is chemotherapy. • For patients progressing on a 1st line TKI, the 2nd line therapy is most often a 2nd or 3rd generation TKI. • When therapy with a TKI is exhausted, the next line of therapy is standard chemotherapy as described above. • For patients who receive 1st line chemotherapy, the second line therapy is most often immunotherapy which can be any of the 3 approved agents for patients with a TPS score of >1 or nivolumab or atezolizumab for patients with a TPS score of 0. • 3rd Line Rx: Clinical trials may be substituted for any of these treatments in any lines of therapy. • Unresectable Stage III. The standard approach is currently concurrent chemotherapy with chest radiotherapy. • This is likely to change as positive results of a trial comparing CT/RT alone to CT/RT followed by immunotherapy with durvalumab were announced in mid-2017.
  46. 46. 46 Figura do slide anteror
  47. 47. 47 TREATMENT FOR SQUAMOUS CELL CARCINOMA P. Paik Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York/US • Squamous cell lung cancers (SQCLC) account for between 15-25% of non-small cell lung cancer (NSCLC) cases • They are, biologically, quite distinct from lung adenocarcinomas, though this remains a fact that has had little positive effect to date in the management of this disease. • Indeed, despite the FDA approval of a handful of new drugs for patients with SQCLCs since 2014, only modest gains in survival were achieved by these new agents. • Navigating the treatment landscape has been, by turns, straight-forward and frustrating. This is most evident in the rst-line setting where, apart from patients whose tumors exhibit high expression of PD-L1, a variety of platinum-based chemotherapy options are available, all with more or less equivalent • Second-line therapy is dictated then largely through exclusion. • Patients who received pembrolizumab tas rs-line treatment will cycle through platinum-based chemotherapy. • Patients who received platinum-based chemotherapy will, by and large, cycle through any one of a number of FDA-approved PD-1/PD-L1 antibody therapies, all with equivalent e cacy (pembrolizumab, nivolumab, atezolizumab). • There are, arguably, few clinically meaningful therapeutic options beyond this
  48. 48. 48 ANY ROLES OF SYSTEMIC THERAPY (CHEMOTHERAPY, TARGETED THERAPY, IMMUNOTHERAPY) FOR EARLY STAGE NSCLC WITH LIMITED PULMONARY RESERVE? S. Lu Department of Shanghai Lung Cancer Center, The standard treatment of early stage non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation Up to 25% of patients with stage I NSCLC are not lobectomy candidates because of severe medical comorbidity including limited pulmonary reserve. During the past decade, stereotactic ablative radiotherapy (SABR) has resulted in local control in excess of 90% of tumours with medically inoperable and operable clinical stage I NSCLC. What is the status of systemic chemotherapy for such patients?
  49. 49. 49 ANY ROLES OF SYSTEMIC THERAPY (CHEMOTHERAPY, TARGETED THERAPY, IMMUNOTHERAPY) FOR EARLY STAGE NSCLC WITH LIMITED PULMONARY RESERVE? S. Lu Department of Shanghai Lung Cancer Center, 1. Chemotherapy+ local treatment: 1. It seems that it is not recommended to add chemotherapy to local treatment for those medically inoperable, early stage NSCLC. It is reported that no evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC 2. Targeted Therapy+ local treatment: 1. No clear data about the targeted therapy for those medically inoperable, early stage NSCLC patients. 2. Further studies should be developed for these patients. 3. 3. Immunotherapy + local treatment: 1. Is a conceptually promising strategy, as radiation has potent immune-modulatory effects and may contribute not only to local control but also augment systemic antitumor immune response. 2. But prospective clinical trials evaluating the integration of radiation and immunotherapy are limited. 4. Summary: The assessment of treatment options for limited pulmonary reserve patients that requires uniform reporting of comorbidities and outcomes in clinical studies, which often is lacking. Systemic Therapy combined with local treatment could be a good option for these patients. Trials involving systemic therapy for patients with medically inoperable NSCLC should be developed.
  50. 50. 50 INTERPRETING PUBLISHED RESEARCH A. Tod School of Nursing and Midwifery, University of She eld, She eld/GB • BackgroundThe Evidence-Based Practice (EBP) or Evidence-based Healthcare (EBHC) movement has revolutionised health care in the last 20 years by promoting research appraisal • Much has changed since 1996 in terms of EBP and the environment in which it operates. • Now EBP is considered to comprise 3 components, • ‘Best Research Evidence’, • ‘Clinical Expertise’ and • ‘Patient Values, Experience and Preferences’. • EBP has now evolved into Evidence-Based Healthcare (EBHC), where evidence is mobilized to change practice at a policy, organisation or service level. • To address this change in emphasis a change to research methodologies is required, as well as a rethink regarding the hierarchy of evidence.
  51. 51. 51 INTERPRETING PUBLISHED RESEARCH A. Tod School of Nursing and Midwifery, University of She eld, She eld/GB • The Randomised Controlled Trial is not always adequate. • Mixed-methods approaches are more commonly employed and the value placed on qualitative, patient experience methods has increased. • Whilst meta- analysis and randomised controlled trial methodologies remain the gold standard to generate evidence of e ectiveness, EBH questions have become more complex and diverse. • These questions require different research approaches and tools to generate answers. • Tools to support research interpretation and application A key task in EBP is to interpret published research. Over the years a proliferation of strategies, tools and resources have been developed to support clinicians, researchers and academics in appraising, interpreting and applying evidence to enhance practice. • Published research is never going to tell you enough to support change. Need to incorporate patient and public view.
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  53. 53. 53 otavio.clark@evidencias.com.br @otavioclark Otávio Clark @otavioclark 19 98149 5375
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