CES2019-01: Cáncer de pulmón 2

Continuación de la clase previa. No se alcanzó a cubrir el SCLC

1. Lung cancer: “relevant” subgroups NSCLC SCLC NSCLC with “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%

2. Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01 Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas No Mutation Detected KRAS 22% EGFR 17% EML4-AKL 7% Double Mutants 3% BRAF 2% PIK3CA 2% HER2 MET AMP MEK1 NRAS AKT1 Erlotinib Gefitinib Afatinib Selumetinib Crizotinib

3. How to handle small tissue samples in lung cancer p63 and TTF1 H&E SCC Non-SCC ( Adeno ) Genomics SCLC NeuroEndocrine EGFR ALK/EML4 ROS1 BRAF Her2 p63+ TTF1 + PD-L1 by IHC (in advanced NSCLC) PD-L1 by IHC (in advanced NSCLC) Chromogranin Synaptophysin

4. Lung cancer: anatomic staging PET-CT +/- Brain MRI NSCLC

5. TNM Staging system: Lung Cancer TNM8

6. T-descriptor Every cm counts… Previous (TNM 7th) T1a T1a T1b T2a T2a T2b T3 Rami-Porta R, J Thoracic Oncol, 2015 Proposed (TNM 8th) Up to 1 cm: T1a >1-2 cm: T1b >2-3 cm: T1c >3-4 cm: T2a >4-5 cm: T2b >5-7 cm: T3 >7 cm: T4 International Association for the Study of Lung Cancer, 2015

7. 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

8. N-descriptor No changes in the TNM 8th Edition… Exploratory subgrouping (for future validation) - N1a: Single N1 - N1b: Multiple N1 - N2a1: Single N2 (skip metastasis) - N2a2: Single N2 + N1 - N2b: Multiple N2 Asamura H et al. J Thoracic Oncol, 2015, in press International Association for the Study of Lung Cancer, 2015

9. Lymph-node stations in lung cancer: General Plan  Supraclavicular: - Station 1  Superior mediastinal: - Stations 2-4  Aortic: - Stations 5/6  Inferior mediastinal: - Stations 7-9  N1 nodes: - Stations 10-14 http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

10. M-descriptor • M1a: as it is • M1b: single metastasis in a single organ • M1c: multiple metastases in a single organ or in several organs

11. N – Regional Lymph Nodes Regional lymph nodes cannot be assessed Nx No regional lymph node metastasis N0 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 metastasis M0 Distant metastasis M1 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 organ M1b Multiple extrathoracic metastases in one or several organs M1c International Association for the Study of Lung Cancer, 2015

12. STAGE T N M Occult TX N0 M0 Tis N0 M0 IA1 T1a(mi)/T1a N0 M0 IA2 T1b N0 M0 IA3 T1c N0 M0 IB T2a N0 M0 IIA T2b N0 M0 IIB T1a-T2b N1 M0 T3 N0 M0 IIIA T1a-T2b N2 M0 T3 N1 M0 T4 N0/N1 M0 IIIB T1a-T2b N3 M0 T3/T4 N2 M0 IIIC T3/T4 N3 M0 IVA Any T Any N M1a/M1b IVB Any T Any N M1c International Association for the Study of Lung Cancer, 2015

13. 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

14. 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 intent Mostly unresectable

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 Surgery , followed by adjuvant chemotherapy Systemic therapy Multimodal therapy : ( ie , Chemo-Radiation , followed by Immunotherapy )

16. Lung cancer: anatomic staging PET-CT +/- Brain MRI Potentially resectable Nonresectable/metastatic Extrathoracic metastases SVCS Vocal cord / phrenic nerve paralysis Malignant pleural effusion Cardiac tamponade Tumor within 2 cm of the carina Contralateral lung metastases Supraclavicular metastases Contralateral mediastinal LN involvement Pulmonary artery involvement Mediastinal LN assessment ie, Mediastinoscopy NSCLC N2/N3 disease N0/N1 disease Unresectable stage III Stage IV Physiologic staging Surgery +/- CT Definitive Chemo-RT

17. Lung cancer: anatomic staging PET-CT +/- Brain MRI Potentially resectable Nonresectable/metastatic Extrathoracic metastases SVCS Vocal cord / phrenic nerve paralysis Malignant pleural effusion Cardiac tamponade Tumor within 2 cm of the carina Contralateral lung metastases Supraclavicular metastases Contralateral mediastinal LN involvement Pulmonary artery involvement Mediastinal LN assessment ie, Mediastinoscopy NSCLC N2/N3 disease N0/N1 disease Unresectable stage III Stage IV Physiologic staging Surgery +/- CT Definitive Chemo-RT

18. 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.

19. 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 intent Mostly unresectable

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 Surgery , followed by adjuvant chemotherapy Systemic therapy Multimodal therapy : ( ie , Chemo-Radiation , followed by Immunotherapy )

21. NSCLC Stage IV With “driver” mEGFR ALK+ ROS1 Osimertinib Alectinib Crizotinib FLAURA , 2018 ALEX , 2017

22. 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

23. HER/erbB family Salomon DS, et al. Crit Rev Oncol Hematol 1995;19:183–232 Woodburn JR. Pharmacol Ther 1999;82:241–50 HER1 EGFR erbB1 HER2 erbB2 neu EGF TGF- α Amphiregulin Betacellulin HB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins Betacellulin Cysteine- rich domains Tyrosine- kinase domains HER3 erbB3 HER4 erbB4 Ligands:

24. Proliferation Apoptosis Resistance Transcription TGF α Interleukin-8 bFGF VEGF Metastasis Angiogenesis Shc PI3K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 EGF Pathway www.clinicaloptions.com

25. EGFR in NSCLC: two distinct pathways Nucleus Adaptor Survival PIP 2 PI3K PIP 3 PTEN AKT Apoptosis regulators Proliferation Adaptor Transcription factors MAPK MEK RAF GTP-RAS GDP - RAS Sordella, et al. Science 2004 ATP ATP Greater signalling through the MAPK pathway producing excessive cell proliferation Higher affinity for ATP than mutant receptor, so greater competition with EGFR TKIs for binding sites; higher concentrations needed to inhibit Successful inhibition of wild-type EGFR reduces proliferation and halts tumour growth Higher incidence of stable disease EGFR wild-type

26. EGFR in NSCLC: two distinct pathways ATP Nucleus Adaptor Survival PIP 2 PI3K PIP 3 PTEN AKT Apoptosis regulators Proliferation Adaptor Transcription factors MAPK MEK RAF GTP-RAS GDP - RAS Sordella, et al. Science 2004 ATP Preferential signalling through the PI3K-mediated anti-apoptotic pathway – ‘oncogene addiction’ Reduced affinity for ATP means EGFR TKIs have less competition for binding sites; lower concentrations sufficient to inhibit Successful inhibition of mutated EGFR produces ‘apoptotic shock’ Higher incidence of complete or partial response EGFR mutation +ve

27. 1st-line Osimertinib in mutant EGFR metastatic NSCLC (2018) 1st-line Alectinib in mutant ALK/EML4 metastatic NSCLC (2017)

28. NSCLC Stage IV No driver identified PS0/1 PD-L1≥50% PD-L1<50% Pembrolizumab Pembrolizumab + Chemo KEYNOTE-189 KEYNOTE-407 2018 KEYNOTE-24 2016

29. Inmunología tumoral Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico

30. Inmunología tumoral Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico Receptor de célula T (TCR) MHC II y antígeno MHC II: Major histocompatibility complex

31. Inmunología tumoral Cebado (priming) y activación de las células T Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Linfocito T CD8+/Citotóxico Co-estimuladora CD28 Co-estimuladora B7.1

32. En la periferia... Mientras tanto...

33. Inmunología tumoral Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Antígeno + MHC-1

34. Inmunología tumoral Activación de la respuesta inmunológica CD8 efectora Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico Antígeno + MHC-1 Receptor de células T (TCR) +++ Respuesta inmune antitumoral Presente

35. Extent of disease Staging

36. Inmunología tumoral Las células tumorales expresan PD-L1 (PD-L2) cuando hay estimulación continuada del IFN-Gamma, " apagando" al linfocito T Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico IFN-γ IFN-γR PD-L1 PD-1 - - - Respuesta inmune antitumoral Frenada

37. Célula T Célula tumoral MHC TCR PD-1 PD-L1 Cancer cell T-cell Anti-PD-L1 Anti-PD-1 Bloqueo PD-1 Respuesta inmune antitumoral Se restablece Los anticuerpos anti-PD-1 (anti-PD-L1, anti-PD-L2) restablecen la respuesta antitumoral de linfocitos T Interacción Célula T-Célula Tumoral Interaction

38. Pembrolizumab + Chemotherapy in Non- Squamous metastatic KEYNOTE-489 NSCLC (2018) Pembrolizumab in High-PD-L1 expression metastatic KEYNOTE-24 NSCLC (2016)

39. Pembrolizumab + Chemotherapy in Squamous metastatic KEYNOTE-407 NSCLC (2018)

40. Pembrolizumab + Chemotherapy in Squamous metastatic KEYNOTE-407 NSCLC (2018)

41. NSCLC Stage IV With “driver” No driver identified mEGFR ALK+ ROS1 PS0/1 PD-L1≥50% PD-L1<50% Pembrolizumab Pembrolizumab + Chemo Osimertinib Alectinib Crizotinib FLAURA , 2018 ALEX , 2017 KEYNOTE-189 KEYNOTE-407 2018 KEYNOTE-24 2016