Lung Cancer Treatment: A Multidisciplinary Approach
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Presentación, en 14/08/2018, en el Hotel Estelar Milla de Oro, Medellín, auspiciada por Merck-Sharp & Dohme.
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Lung Cancer Treatment: A Multidisciplinary Approach
- 1. Lung cancer today: a group endeavor Mauricio Lema Medina MD Clínica de Oncología Astorga, Clínica SOMA, Medellín
- 2. Conflicts of interest for this lecture Mauricio Lema Lecture fees by: Boehringer-Ingelheim, BMS, MSD
- 3. @onconerd
- 5. Multidisciplinary Integration of Biomarker Testing in Early-Stage NSCLC Pulmonologist Interventional radiologist Surgeon Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Goal: Maximize “cure” rateIdentify pt Select diagnostic strategy Biopsy Pathologist Histology evaluation
- 6. Lung cancer: “relevant” subgroups (for early-stage) disease NSCLC SCLC 10%90% Adenocarcinoma Squamous Large-cell p63 and TTF1 H&E Squamous Non-Squamous (Adeno)SCLC p63+ TTF1+ Chromogranin Synaptophysin
- 7. Multidisciplinary Integration of Biomarker Testing in Early-Stage NSCLC Pulmonologist Interventional radiologist Surgeon Pathologist Radiologist Nuclear medicine Pulmonologist Thoracic surgeon Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Goal: Maximize “cure” rateIdentify pt Select diagnostic strategy Biopsy Histology evaluation Determine Extent (TNM) Assess resectability Radiologist Nuclear medicine Pulmonologist Thoracic surgeon Ancillary studies
- 8. Lung cancer toolkit What’s needed to treat Staging procedures Seek metastatic disease - Scenario: Supected early disease PET-CT If available Brain MRI Not everyone agrees Mediastinoscopy Before definitive surgery, to avoid N3 (unresectable) disease.
- 9. T – Primary Tumour Tx Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Tumour 3 cm or less in greatest diameter surrounded by lung or visceral pleura, without evidence of main bronchus T1a(mi) Mininally invasive adenocarcinoma T1a Tumour 1 cm or less in greatest diameter T1b Tumour more than 1 cm but not more than 2 cm T1c Tumour more than 2 cm but not more than 3 cm T2 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following features: Involves main bronchus (without involving the carina), invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region T2a Tumour more than 3 cm but not more than 4 cm T2b Tumour more than 4 cm but not more than 5 cm T3 Tumour more than 5 cm but not more than 7 cm or one tha directly invades any of the following: chest wall, phrenic nerve, parietal pericardium, or associated separate tumour nodule(s) in the same lobe as the primary T4 Tumours more than 7 cm or one that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary
- 10. N – Regional Lymph Nodes Regional lymph nodes cannot be assessedNx No regional lymph node metastasisN0 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N1 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)N2 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s) N3 M – Distant Metastasis No distant metastasisM0 Distant metastasisM1 Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural or pericardial nodules or malignant pleural or pericardial effusion M1a Single extrathoracic metastasis in a single organM1b Multiple extrathoracic metastases in one or several organsM1c International Association for the Study of Lung Cancer, 2015
- 11. 8th Edition of the TNM Classification for Lung Cancer N0 N1 N2 N3 M1a M1b M1c T1a IA1 IIB IIIA IIIB IVA IVA IVB T1b IA2 IIB IIIA IIIB IVA IVA IVB T1c IA3 IIB IIIA IIIB IVA IVA IVB T2a IB IIB IIIA IIIB IVA IVA IVB T2b IIA IIB IIIA IIIB IVA IVA IVB T3 IIB IIIA IIIB IIIC IVA IVA IVB T4 IIIA IIIA IIIB IIIC IVA IVA IVB International Association for the Study of Lung Cancer, 2015
- 12. Place your patient where she/he belongs Early Stage NSCLC (All) Non-T4. Non-N3 Non-M1 Mostly, Non-N2 Locally-Advanced NSCLC M0 (a must) T4 or N3 or Unresectable N2 (ie, bulky) Advanced-NSCLC M1 (a must)
- 14. Multidisciplinary Integration of Biomarker Testing in Early-Stage NSCLC Pulmonologist Interventional radiologist Surgeon Pathologist Radiologist Nuclear medicine Pulmonologist Thoracic surgeon Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Goal: Maximize “cure” rateIdentify pt Select diagnostic strategy Biopsy Histology evaluation Determine Extent (TNM) Define therapy Early stage Multidisciplinary team (tumor board) Assess resectability Radiologist Nuclear medicine Pulmonologist Thoracic surgeon Ancillary studies
- 15. 8th Edition of the TNM Classification for Lung Cancer N0 N1 N2 N3 M1a M1b M1c T1a IA1 IIB IIIA IIIB IVA IVA IVB T1b IA2 IIB IIIA IIIB IVA IVA IVB T1c IA3 IIB IIIA IIIB IVA IVA IVB T2a IB IIB IIIA IIIB IVA IVA IVB T2b IIA IIB IIIA IIIB IVA IVA IVB T3 IIB IIIA IIIB IIIC IVA IVA IVB T4 IIIA IIIA IIIB IIIC IVA IVA IVB International Association for the Study of Lung Cancer, 2015 Upfront resection feasible Mostly palliative intentMostly unresectable
- 16. Multidisciplinary Integration of Biomarker Testing in Early-Stage NSCLC Pulmonologist Interventional radiologist Surgeon Pathologist Radiologist Nuclear medicine Pulmonologist Thoracic surgeon Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Goal: Maximize “cure” rateIdentify pt Select diagnostic strategy Biopsy Histology evaluation Determine Extent (TNM) Define therapy Surgery SBRT Adjuvant Chemo +/- RT Early stage Treat Multidisciplinary team (tumor board) Assess resectability Radiologist Nuclear medicine Pulmonologist Thoracic surgeon Ancillary studies Thoracic surgeonPathologist Histology evaluation Multidisciplinary team (tumor board)
- 17. 8th Edition of the TNM Classification for Lung Cancer N0 N1 N2 N3 M1a M1b M1c T1a IA1 IIB IIIA IIIB IVA IVA IVB T1b IA2 IIB IIIA IIIB IVA IVA IVB T1c IA3 IIB IIIA IIIB IVA IVA IVB T2a IB IIB IIIA IIIB IVA IVA IVB T2b IIA IIB IIIA IIIB IVA IVA IVB T3 IIB IIIA IIIB IIIC IVA IVA IVB T4 IIIA IIIA IIIB IIIC IVA IVA IVB International Association for the Study of Lung Cancer, 2015 Surgery, followed by adjuvant chemotherapy Systemic therapyMultimodal therapy: (ie, Chemo-Radiation, followed by Immunotherapy)
- 18. Consider surgery Pneumonectomy Lobectomy + Mediastinal LN dissection Assess ability to undergo surgery Enough FEV1 Normal arterial CO2 Acceptable cardiac function Acceptable PS Early Stage NSCLC Stages I and II, some stages III Consider adjuvant platinum-doublet chemotherapy for stage II and III Consider adjuvant radiotherapy if N+ or R1 resection
- 20. 8th Edition of the TNM Classification for Lung Cancer N0 N1 N2 N3 M1a M1b M1c T1a IA1 IIB IIIA IIIB IVA IVA IVB T1b IA2 IIB IIIA IIIB IVA IVA IVB T1c IA3 IIB IIIA IIIB IVA IVA IVB T2a IB IIB IIIA IIIB IVA IVA IVB T2b IIA IIB IIIA IIIB IVA IVA IVB T3 IIB IIIA IIIB IIIC IVA IVA IVB T4 IIIA IIIA IIIB IIIC IVA IVA IVB International Association for the Study of Lung Cancer, 2015 Systemic therapy
- 21. Oxford overview HR: 0.73 in favor of Cisplatin-based Chemo Equivalent to 1.5-2.5 increase in OS
- 22. Multidisciplinary Integration of Biomarker Testing in Advanced NSCLC Adapted from Gandara D, et al. ASTRO/ASCO/IASLC Symposium on Molecular Testing. 2012. Pulmonologist Interventional radiologist Surgeon Pathologist Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Palliative care Goal: Identify “actionable” targets (ie, oncogenes) Identify pt Identify target lesion Biopsy Histology evaluation Molecular biomarker testing
- 23. Lung cancer toolkit What’s needed to treat Tissue diagnosis Histology. Morphology Squamous Adeno NSCLC NOS SCLC. IHC Squamous: p63-p40 Adeno: TTF+, Napsin PD-L1 expression (mNSCLC) SCLC: High Ki67, Chromogranin, synaptophysin Genotyping Non-Squamous, advanced NSCLC EGFR ALK/EML4 ROS1, and others.
- 24. How to handle small tissue samples in lung cancer p63 and TTF1 H&E SCC Non-SCC (Adeno) Genomics SCLC EGFR ALK/EML4 ROS1 BRAF Her2 p63+ TTF1+ PD-L1 by IHC (in advanced NSCLC) PD-L1 by IHC (in advanced NSCLC) Chromogranin Synaptophysin
- 25. Therapeutic Decision Making Histologic Subtyping Genotyping for Predictive Biomarkers These factors are interlinked and not independent Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394. Interlinking Themes in Therapeutic Decision Making for Advanced NSCLC
- 26. What Tools Can Facilitate Personalized Therapy in Advanced-Stage NSCLC? • The questions: • How do we optimize therapy in individual pts (ie, first line, second line, third line)? • How do we best integrate new diagnostic testing platforms for targeted therapy or immunotherapy to achieve optimal results (eg, next- generation sequencing in tissue or cell-free DNA in plasma)? Chemotherapy Checkpoint InhibitorsTargeted Therapy Genomics-driven TKIs: EGFR ALK ROS1 Histologic subtyping for chemotherapy Anti–PD-1 Anti–PD-L1 Anti–CTLA-4
- 27. Tumor Cell Cytotoxic T8 Lymphocyte PD-L1 PD-1 - - - Tumor Cell Cytotoxic T8 Lymphocyte + + + Active T-Cell anti-tumor cytotoxicity Inactive T-Cell anti-tumor cytotoxicity PD-1: Programmed cell death protein 1 (CD279) Involved in regulating the immune system’s response to cytotoxic T-cells
- 28. Lung cancer: “relevant” subgroups NSCLC SCLC NSCLC with a “Driver” NSCLC without a “Driver” 10% 15% 75% PD-L1 expression 1-50% 25% PD-L1 expression ≥50% 25% 90% EGFR: 10% ALK/EML4: 4% ROS1: 1% Mostly, adenocarcinoma Adenocarcinoma Squamous Large-cell PD-L1 expression ≤1% 25%
- 29. Multidisciplinary Integration of Biomarker Testing in Advanced NSCLC Adapted from Gandara D, et al. ASTRO/ASCO/IASLC Symposium on Molecular Testing. 2012. Pulmonologist Interventional radiologist Surgeon Pathologist Oncologist Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Palliative care Goal: Identify “actionable” targets (ie, oncogenes) Identify pt Identify target lesion Biopsy Histology evaluation Molecular biomarker testing Determine therapy
- 30. Early Palliative Care for Patients with Metastatic Non–Small-Cell Lung Cancer Temel JS, NEJM, 2010 Early palliative: median OS: 11.6 mo Standard care: median OS: 8.9 mo HR: 1.7 Newly diagnosed metastatic NSCLC Early palliative care Standard care n=74 n=77
- 31. Multidisciplinary Integration of Biomarker Testing in Advanced NSCLC Adapted from Gandara D, et al. ASTRO/ASCO/IASLC Symposium on Molecular Testing. 2012. Pulmonologist Interventional radiologist Surgeon Pathologist Oncologist Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Palliative care Goal: Identify “actionable” targets (ie, oncogenes) Identify pt Identify target lesion Biopsy Histology evaluation Molecular biomarker testing Determine therapy
- 33. •Untreated stage IV NSCLC •Non-squamous •ECOG PS 0-1 •No significant hemoptysis 1:1 Carboplatin + Paclitaxel + Bevacizumab Carboplatin + Paclitaxel + Bevacizumab ECOG 4599 Primary endpoint: OS Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., … Johnson, D. H. (2006). Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer. New England Journal of Medicine, 355(24), 2542–2550. https://doi.org/10.1056/NEJMoa061884 Carbo/Pacli + Bevacizumab (PCB): 1 year OS
- 34. •Untreated stage IV NSCLC •Non-squamous •ECOG PS 0-1 •No significant hemoptysis 1:1 Cisplatin + Pemetrexed + Maintenance Pemetrexed Cisplatin + Pemetrexed PARAMOUNT Primary endpoint: OS Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., … Johnson, D. H. (2006). Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer. New England Journal of Medicine, 355(24), 2542–2550. https://doi.org/10.1056/NEJMoa061884 Maintenance Pemetrexed achieves > 1 yr OS
- 35. Targeted therapy in mNSCLC (mEGFR, ALK/EML4+, etc) Stage IV
- 37. Extracellular Domain Transmembrane Domain Intracellular Domain EGF PATHWAY EGFR: transmembrane protein Tyrosine Kinase Domain Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174. www.clinicaloptions.com
- 38. Kinase domain N-lobe EGFR mutations in human cancer CR2 476-621 L1 1-163 N-lobe 686-769 L2 310-475 CRD 961-1211 CR1 164-309 TM 622-644 JM 645-685 C-lobe 773-960 L858R lung R108K neuronal L861Q lung Frequency of mutation: ≥40% <5% 5-40% Ligand bs Ligand bs A1048V stomach R677H neuronal C624F neuronal P598V glioblastoma, neuronal P596L glioblastoma, neuronal R324L neuronal D1012H lung 686 960 Kinase domain C-lobe E709K lung, prostate E709A lung E709G lung G719S lung, intestine G719C lung G719A lung L833V lung T790M lung, neuronal, oesophagus L858R lung L858Q lung L858M lung H835P breast H835L breast, lung T710I breast E872K breast E872X oesophagus L861Q lung, neuronal L861R lung L861V lung E866K breast, lung delL747-A751insP lung delL747-A751insS lung delL747-T751 lung delL747-S752 lung delE747-A750insP lung delL747-P753 lung delL747-P753insQ lung delL747-P753insS lung delE746-T751insA lung delE746-T751insI lung delE746-A751 lung delE746-T750insRP lung delK745-E749 lung delE746-A750 lung delE746-S752insA lung delE746-S752insV lung delE746-S752insVA lung EGFRvIII: delV30-R297insG glioblastoma, lung, breast Catalytic site R108K neuronal T263P glioblastoma, neuronal A289V glioblastoma, neuronal A289D glioblastoma, neuronal A289T glioblastoma, neuronal delD770-N771insSVD lung delD770-N771insG lung delH773_V774insNPH lung delV774_C775insHV lung delV769-D770insASV lung S768I lung, neuronal, oesophagus S768ins lung H774M lung H773R lung
- 39. LUX-Lung 3: OS in Del19 and L858R mEGFR Del19 L858R Afatinib (n=112) Cis/Pem (n=57) Afatinib (n=91) Cis/Pem (n=47) Mediana, mo 33.3 21.1 27.6 40.3 HR (95% CI) P-valor 0.54 (0.36-0.79) P=0.0015 1.30a (0.80-2.11) P=0.2919 L858RDel19 aHR=1.02 (0.62-1.69), cuando se ajustan los imbalances del línea basal No. en riesgo: Afatinib 112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0 Cis/Pem 57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0 Tiempo de supervivencia global (meses) Tiempo de supervivencia global (meses) ProbabilidadddeSGestimada 0 3 6 9 12 15 18 21 24 27 0.0 0.2 0.4 0.6 0.8 1.0 ProbabilidadddeSGestimada 30 33 36 39 42 45 48 51 0.0 0.2 0.4 0.6 0.8 1.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. en riesgo: Afatinib 40 91 89 83 79 75 69 60 53 49 46 43 39 24 19 11 3 0 0 Cis/Pem 47 43 42 40 38 34 30 28 27 25 20 19 16 14 9 4 1 0 Yang et al. Lancet Oncol. 2015; 16:141-51. Afatinib Cis/Pem
- 40. PROFILE 1014: Crizotinib vs Chemotherapy in ALK/EML4+ mNSCLC Crossover to Crizotinib: 84%
- 41. BSC (4 mo) Platinum doublets + Bevacizumab or Platinum + Pemetrexed (12 mo) Cisplatin-based with old drugs (6-10 mo) 1st-Line Afatinib mEGFR+ (30 mo) 1st-Line Crizotinib ALK/EML4+ (>45 mo)
- 42. Control Targeted therapies Survival Time Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341. Survival Pattern with Chemotherapy (Control), Targetet therapies
- 43. Multidisciplinary Integration of Biomarker Testing in Advanced NSCLC Adapted from Gandara D, et al. ASTRO/ASCO/IASLC Symposium on Molecular Testing. 2012. Pulmonologist Interventional radiologist Surgeon Pathologist Oncologist Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Palliative care Goal: Identify “actionable” targets (ie, oncogenes) Identify pt Identify target lesion Biopsy Histology evaluation Molecular biomarker testing Determine therapy Progression rebiopsy Determine new therapy Progression rebiopsy Treat Treat
- 44. Relative Frequencies of Acquired Resistance Mechanisms to EGFR TKIs Yu HA, et al. Clin Cancer Res. 2013;19:2240-2247. T790M 60% HER2 8% Unknown 18% HER2 + T790M 4% MET amplification 3% Small cell + MET 1% Small cell 1% Small cell + T790M 2% MET + T790M 3%
- 45. Liquid biopsy for T790M: Cobas EGFR Mutation Test V.2 Positive in 76.7% of tissue-positive specimens Negative in 98.2% of tissue-negative
- 46. AURA 3: Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer 46 Osimertinib (n=279) Platinum-pemetrexed (n=140) Basado en el análisis del investigador: HR por progression de enfermedad o muerte, 0.30 (95% Cl, 0.23–0.41) P<0.001 Mediana PFS (95% Cl) 10.1 (8.3–12.3) 4.4 (4.2–5.6) Probabilidaddesobrevidalibrede progresión 1. 0 0. 8 0. 6 0. 4 0. 2 0 0 3 6 9 12 15 18 279 140 240 93 162 44 88 17 50 7 13 1 0 0 No. al riesgo Osimertinib Platinum- pemetrexed Meses Mok, T. NEJM, 2017
- 48. Tumor Cell Cytotoxic T8 Lymphocyte PD-L1 PD-1 - - - Tumor Cell Cytotoxic T8 Lymphocyte + + + Active T-Cell anti-tumor cytotoxicity Inactive T-Cell anti-tumor cytotoxicity PD-1: Programmed cell death protein 1 (CD279) Involved in regulating the immune system’s response to cytotoxic T-cells
- 50. PD-L1 expression in NSCLC
- 51. Examples of PD-L1 IHC Staining of NSCLC Samples Using the Clinical Trial Assay Brown: PD-L1 staining Blue color: HNE counterstain PS < 1% PS 1% to 49% PS ≥ 50% 5 x magnification 40 x magnification Garon EB, et al. N Engl J Med. 2015;372:2018-2028. Image courtesy of E. Garon.
- 52. Blueprint PD-L1 IHC Assay Comparison Project: Phase 1 ▪ Analytical comparison of % tumor cell staining (tumor proportion score), by case (n = 39), for each assay ▪ Data points represent the mean score from 3 pathologists for each assay on each case ▪ No clinical diagnostic cutoff applied ▪ Conclusion: 3 of 4 assays are analytically similar for tumor cell staining 22C3 (pembrolizumab), 28-8 (nivolumab), and SP263 (durvalumab) SP142 (atezolizumab) Hirsch FR et al. J Thorac Oncol. 2017;12:208-222. 100 80 60 40 20 0 1 3 5 7 9 11 13 15 17 19 %TumorCellStaining 23 25 27 29 31 33 35 3721 39 22C3 28-8 SP142 SP263
- 53. Tumor Cell Cytotoxic T8 Lymphocyte PD-L1 PD-1 - - - Tumor Cell Cytotoxic T8 Lymphocyte - - - Tumor Cell Cytotoxic T8 Lymphocyte + + + Pembrolizumab Nivolumab And many others…
- 54. •Untreated stage IV NSCLC •PD-L1 TPS ≥50% •ECOG PS 0-1 •No activating EGFR mutation or ALK translocation •No untreated brain metastases •No active autoimmune disease requiring systemic therapy 1:1 Pembrolizumab Platinum-doublet Chemotherapy KEYNOTE-024 Primary endpoint: OS Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., … Brahmer, J. R. (2016). Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small- Cell Lung Cancer. New England Journal of Medicine, 375(19), 1823–1833. https://doi.org/10.1056/NEJMoa1606774 Median OS with Pembrolizumab superior to chemo: 30 vs 14 months (2017) Brahmer JR, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS ≥50%. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract OA 17.06 (ID 9582). Hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005
- 55. Control Targeted therapies Immune checkpoint blockade Combinations/sequencing Survival Time Survival Time ? Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341. Survival Pattern with Chemotherapy (Control), Targetet therapies, Immune checkpoint blockade and combinations (potential)
- 56. 56 KEYNOTE 001 W H Y P E M B R O L I Z U M A B I N N S C L C L O N G - T E R M O S F O R P A T I E N T S W I T H A D V A N C E D N S C L C E N R O L L E D I N T H E K E Y N O T E - 0 0 1 S T U D Y O F P E M B R O L I Z U M A B . Leighl– ASCO 2017 A L I V E AT 3 Y E A R S 26%
- 57. BSC (4 mo) Platinum doublets + Bevacizumab or Platinum + Pemetrexed (12 mo) Cisplatin-based with old drugs (6-10 mo) 1st-Line Afatinib mEGFR+ (30 mo) 1st-Line Crizotinib ALK/EML4+ (>45 mo) 1st-Line Pembrolizumab PD-1 >50% (30 mo)
- 58. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. New England Journ Metastatic nonsquamous NSCLC No sensitizing EGFR or ALKmutations Treatment-naive for metastatic NSCLC ECOG PS 0/1 Measurable disease Tumor sample for PD-L1 status available No CNS metastasis symptoms No significant autoimmune disease/treatment 2:1 Stratification Smoking history By PD-L1 expression (<1% vs ≥1%) Cisplatin vs Carboplatin Pembrolizumab + Pemetrexed + Platin Pemetrexed + Platin Endpoints: Coprimary endpoints OS / PFS (by central review)
- 59. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small- Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ
- 60. 60 KeyNote 189 P D - L 1 e x p r e s s i o n i n <1% - 31% 1-49% - 31% ≥50% - 32% Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ
- 61. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. New England Journ
- 62. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ
- 63. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ
- 64. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ PD-L1 <1% PD-L1 1-49% PD-L1 ≥50%
- 65. 65 61. 71. 73. 52. 51. 48. KeyNote 189 C h e m o + P e m b r o l i z u m a b i n m e t a s t a t i c N S C L C 1 2 - m o n t h O S i n P e m b r o l i z u m a b + C h e m o v s C h e m o 61% 52% 71% 51% 73% 48% PD-L1 TPS <1% PD-L1 TPS 1-49% PD-L1 TPS ≥50%% Pembro + Chemotherapy Chemotherapy Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ
- 66. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ Overall Response Rate (by TPS)
- 67. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ PFS
- 68. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ In conclusion, in patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations, the addition of pembrolizumab to induction therapy with pemetrexed and a platinum-based drug and to pemetrexed maintenance therapy resulted in significantly longer overall survival and progression- free survival and a higher response rate than the addition of placebo at a cost of a low incidence of renal dysfunction at the first interim analysis. The survival benefit for pembrolizumab- combination therapy was observed across all categories of PD-L1 expression.
- 69. KeyNote 189 - Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., … Garassino, M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non– Small-Cell Lung Cancer. New England Journ In conclusion, in patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations, the addition of pembrolizumab to induction therapy with pemetrexed and a platinum-based drug and to pemetrexed maintenance therapy resulted in significantly longer overall survival and progression- free survival and a higher response rate than the addition of placebo at a cost of a low incidence of renal dysfunction at the first interim analysis. The survival benefit for pembrolizumab- combination therapy was observed across all categories of PD-L1 expression.
- 71. Multidisciplinary Integration of Biomarker Testing in Advanced NSCLC Adapted from Gandara D, et al. ASTRO/ASCO/IASLC Symposium on Molecular Testing. 2012. Pulmonologist Interventional radiologist Surgeon Pathologist Oncologist Multidisciplinary team (tumor board) Referring physician Med oncologist Thoracic surgeon Radiation oncologist Pulmonologist Radiologist Pathologist Palliative care Goal: Identify “actionable” targets (ie, oncogenes) Identify pt Identify target lesion Biopsy Histology evaluation Molecular biomarker testing Determine therapy Progression rebiopsy Determine new therapy Progression rebiopsy Treat Treat
- 72. mEGFR+… mOS 30 mo, and improving with anti- EGFR ALK+… mOS >45 mo, and improving with anti- ALK PD-1>50%… mOS 30 mo, and improving with anti-PD-1 Non-Squamous… improved OS with Chemo + Pembrolizumab mNSCLC Only through accurate histopathology, genotyping and IHC can these results be achieved
Editor's Notes
- NSCLC, non-small-cell lung cancer.
- NSCLC, non-small-cell lung cancer.
- 8
- 12
- NSCLC, non-small-cell lung cancer.
- NSCLC, non-small-cell lung cancer.
- 18
- NSCLC, non-small-cell lung cancer.
- 23
- 25
- NSCLC, non-small-cell lung cancer.
- NSCLC, non-small-cell lung cancer.
- SG = supervivencia global (OS = overall survival); TRO=tasa de respuesta objetiva (ORR = objective response rate ) SLP= supervivencia libre de progresión (PFS = progression-free survival) HR= Razón de riesgos (HR = hazard ratio)
- NSCLC, non-small-cell lung cancer.
- TKI, tyrosine kinase inhibitor.
- Puntos de conversación El punto final primario de AURA3 fue PFS por evaluación del investigador Osimertinib mostró 10,1 meses de mediana de SLP en comparación con 4,4 meses con platino-pemetrexed (CRI de 0,30, P <0,001) PFS por BICR fueron consistentes con la evaluación del investigador Referencia Mok TS, Wu Y-L, Ahn M-J, y col. Osimertinib o platino-pemetrexed en cáncer de pulmón EGFR T790M-positivo. N Engl J Med. 6 de diciembre de 2016. DOI: 10.1056 / NEJMoa1612674. [Epub antes de imprimir].
- NSCLC, non-small-cell lung cancer; PS, proportion score.
- NSCLC, non-small-cell lung cancer.