2015 11 Inmunoterapia en nsclc

1. Coley, Am J Med Sci 1893;105:487-510

2. ILC, innate lymphoid cell; NK, natural killer. Abbas AK et al. Cellular and Molecular Immunology. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015. Tipos de respuesta inmune: innata y adquirida

3. Abbas AK et al. Cellular and Molecular Immunology. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.

4. AIS: Lymph, APCs and Effector cells Antigen Recognition Effector Functions B lymphocyte Helper T lymphocyte Cytotoxic T lymphocyte (CTL) Regulatory T lymphocyte Microbe Neutralization of microbe, phagocytosis, complement activation Activation of macrophages Inflammation T and B lymphocyte proliferation/ differentiation Killing of infected cells Suppression of other lymphocytes Antibody Cytokines Microbial antigen presented by antigen- presented cell Infected cell expressing microbial antigen Abbas AK et al. Cellular and Molecular Immunology. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.

5. Clinical observations and animal experiments have established that although tumour cells are derived from host cells, they elicit immune responses [because they have tumor Ags] Immuno-Oncology: The Rationale Tumor Microenvironment Abbas AK et al. Cellular and Molecular Immunology. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.

6. Estudio años 50 Abbas AK et al. Cellular and Molecular Immunology. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.

7. • The immune system can identify and eliminate tumor cells based on their expression of tumor-specific antigens1- 3 • An ideal cancer antigen:1 – Specifically and stably expressed by the tumour – Absent from normal tissues – Crucial for survival of cancer cell Tumour Antigens 1. Simpson AJ et al. Nat Rev Cancer. 2005;5(8):618-625. 2. 2. Cabellero OL, Chen Y-T. Cancer Sci. 2009; 100(11):2014-2021. Tumor cell Tumor antigen Microbial proteins/ mutated proteins/ fusion proteins

8. Tipo de antígeno Ejemplos Productos de oncogenes mutados y de genes supresores tumorales Productos de oncogenes: mutaciones Ras (10% de los carcinomas), p210 (producto de reordenamiento bcr/abl) Productos de genes supresores: p53 mutado (en el 50% de los tumores) Productos de oncogenes no mutados pero sobreexpresados HER2neu (mama, otros) Formas mutadas de genes celulares no involucradas en tumorogénesis Varias proteínas mutadas en melanoma reconocidas por liinfocíticos T citotóxicos Productos de genes que son silentes en tejidos normales Antígenos de cáncer /testículo expresados en melanoma y muchos carcinomas; normalmente expresados en testículos y placenta Antígenos tumorales

9. Tipo de antígeno Ejemplos Proteínas no-oncogénicas normales sobreexpresadas en células tumorales Tirosinasa, gp100, MART en melanomas (normalmente expresados en melanocitos) Productos de virus oncogénicos Proteínas del papilomavirus E6 y E7 (carcinoma cervical) Proteína EBNA-1 del EBV (linfomas, carcinoma nasofaríngeo) Antígenos oncofetales CEA; AFP Glicolípidos y glicoproteínas GM2; GD2 en melanomas Antígenos de diferenciación normalmente presentes en tejido de origen PSA en carcinoma de próstata CD20 en linfomas B Antígenos tumorales

10. Tumour Immunity: Immune Surveillance Chen DS, Mellman I. Immunity 2013; 39:1-10.

11. Tumour Immunity: Immune Surveillance Chen DS, Mellman I. Immunity 2013; 39:1-10.

12. Inmunoedición Dorff TB. Ther Adv Med Oncol. 2009 Nov;1(3):183–205.

13. Los tumores pueden evadir el sistema inmune Mechanisms of Tumor Immune Escape Specialized tumour mechanisms for evading host immune responses Poor immunogenicity of tumour Rapid growth and spread may overwhelm the capacity of the immune system to effectively control the tumour Razones potenciales por las que la respuesta antitumoral es incapaz de erradicar las células transformadas Tumor Microenvironment Abbas AK et al. Cellular and Molecular Immunology. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.

14. Los tumores usan mecanismos complejos para evadir y suprimir el sistema inmune 1. Drake CG et al. Adv Immunol. 2006;90:51-81. 2. 2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271. Inhibition of tumour antigen presentation eg, down-regulation of MHC I 1APC

15. Los tumores usan mecanismos complejos para evadir y suprimir el sistema inmune 1. Drake CG et al. Adv Immunol. 2006;90:51-81. 2. 2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271. Inhibition of tumour antigen presentation eg, down-regulation of MHC I 1APC Secretion of immunosuppressive factors eg, TGF-β 2 Tumour cell

16. Los tumores usan mecanismos complejos para evadir y suprimir el sistema inmune 1. Drake CG et al. Adv Immunol. 2006;90:51-81. 2. 2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271. Inhibition of tumour antigen presentation eg, down-regulation of MHC I 1APC Secretion of immunosuppressive factors eg, TGF-β 2 Tumour cell Inhibition of attack by immune cells eg, disruption of T-cell checkpoint pathways 3 Inactive T cell

17. Los tumores usan mecanismos complejos para evadir y suprimir el sistema inmune 1. Drake CG et al. Adv Immunol. 2006;90:51-81. 2. 2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271. Inhibition of tumour antigen presentation eg, down-regulation of MHC I 1APC Secretion of immunosuppressive factors eg, TGF-β 2 Tumour cell Inhibition of attack by immune cells eg, disruption of T-cell checkpoint pathways 3 Inactive T cell Recruitment of immunosuppressive cell types eg, Treg 4

18. Los tumores usan mecanismos complejos para evadir y suprimir el sistema inmune 1. Drake CG et al. Adv Immunol. 2006;90:51-81. 2. 2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271. Inhibition of tumour antigen presentation eg, down-regulation of MHC I 1APC Secretion of immunosuppressive factors eg, TGF-β 2 Tumour cell Inhibition of attack by immune cells eg, disruption of T-cell checkpoint pathways 3 Inactive T cell Recruitment of immunosuppressive cell types eg, Treg 4

19. T-Cell Activation: Priming Two signals in a T-cell response govern whether the cell will be activated or inhibited1 – The primary signal takes place when antigens are presented through the major histocompatibility complex to the T-cell receptor2 – The secondary signal may be a co-stimulatory or a co-inhibitory signal, which will lead to T-cell activation or T-cell inhibition, respectively1,2 1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 2. Weber J. Semin Oncol. 2010;37(5):430-439. T cell APC Primary Signal MHC TCR T cell APC Secondary Signal MHC TCR 1 1 2

20. T-Cell Regulation: Checkpoint Pathways Activation of T cells depends on the balance of the co-stimulatory and co- inhibitory signals, which are also known as checkpoint pathways1,2 Activates T cell T cell APC Co-stimulatory signal MHC TCR Co- stimulatory 1 2 Inhibits T cell T cell APC Co-inhibitory signal MHC TCR Co- inhibitory 1 2 1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 2. Weber J. Semin Oncol. 2010;37(5):430-439.

21. Checkpoint Pathways Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. APC/ Tumor T cell B7-DC(PD-L2) CD40 CD40L CD137 OX40 CD137L OX40L MHC CD28B7-2 (CD86) TCR Activation Inhibition Inhibition Inhibition Activation Activation Activation Inhibition The number of molecules regulating T- cell activation is high and the system is very complex The expression of certain molecules and their interaction with receptors in the T cell cause either activation or inhibition of the T cell Adapted from Pardoll, 2012. “Brakes” to the immune reaction PD-1 B7-1 (CD80) B7-H1(PD-L1) LAG-3 B7-1 (CD80) CTLA-4

22. Chen DS, Mellman I. Immunity 2013; 39:1-10.

23. De la teoría a la práctica Tumor MicroenvironmentLymph Node CTLA-4, cytotoxic T-lymphocyte antigen-4; PD-1, programmed death-1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. CTLA-4 pathway PD-1 pathway CTLA-4B7-1 (CD80 PD-1 PD-L1 (B7-H1)MHC TCR MHC TCR

24. Over the last several years, multiple compounds targeting CTLA-4 or PD-1/PD-L1 have been developed: PD-1: • Nivolumab [BMS] • Pembrolizumab [MSD] • Pidilizumab [Medivation] • AMP-514 [MedImmune/Amplimmune] • AMP-224 [MedImmune/Amplimmune] • PDR001 [Novartis] PD-L1: • Atezolizumab/MPDL3280A [Roche/Genentech] • BMS-936559 [BMS] • Durvalumab/MEDI4736 [MedImmune/AZ] • Avelumab/MSB0010718C [EMD Serono/Merck KGaA/Pfizer] Targeting the CTLA-4 and PD-1 Checkpoint Pathways CTLA-4: • Ipilimumab [BMS] • Tremelimumab [MedImmune/AZ]

25. ¿Por qué el cáncer de pulmón? Figure: Somatic mutation frequencies observed in exomes from 3,083 tumor-normal pairs Lawrence et al; Nature 499, 214–218 (11 July 2013) Lung tumors along with other malignancies such as bladder and melanoma display a high number of somatic mutations rendering these tumors more immunogenic

26. Mayor M, European Journal of Cardio-Thoracic Surgery. 2015 Oct 29;:ezv371–10.

27. Ellis LM. J Clin Oncol; 2014 Apr 20;32(12):1277–80. Summary of recommended targets for meaningful clinical trials goals: Lung Cancer Primary End Point Secondary End Point Current baseline median OS(m) Improvement over current OS that would be clinically meaningful (months) Targets HR Improvement in 1-year survival rate (%) Improvement in PFS (months) Lung cancer Non-squamous 13 3.25-4 0.76-0.8 53 61 4 Lung cancer Squamous 10 2.5-3 0.77-0.8 44 63 3

28. Agent Immunoth. approach Study design Population Results SRL172 O’Brien Ann Oncol 2014 Nonspecific vaccine (killed Mycob) Open label: CT + SLR172 (phase III) Stage III/IV unresectable NSCLC Primary OS endpoint not met Tecemotide Butts Lancet Oncol 2014 Tumor-specific MUC1 vaccine START: Tecemotide vs placebo (phase III) Stage III after CT-RDT Primary OS endpoint not met MAGE-3 Vanteenkiste ESMO 2014 Tumor specific MAGE-3 vaccine MAGRIT: MAGE- vs placebo Stage IB-IIIA resected MAGE- 3 positive Primary DFS endpoint not met GVAX Nemunaitis Cancer Gen Ther 2006 Autologous tumor cell vaccine GVAX alone (phase I/II) Advanced NSCLC No responses Failed Immunotherapies tested in NSCLC

29. Agent Immunoth. approach Study design Population Results Belagenpumatucel-L Giaconne ECCO 2014 TGF-b- blocking allogenic tumor cell vaccine STOP: maintenance vs placebo (phase III) Stage III/IV NSCLC; no disease progressión after frontline therapy Primary OS endpoint not met; predefined subgroups benefit Talactoferrin Nemunaitis Ann Oncol 2013 Dendritic cell activation FORTIS-M: talactoferrine vs placebo (phase III) Stage III/IV NSCLC refractory to 2 or more therapies Primary OS endpoint not met CPG 7909 Manegold Ann Oncol 2012 Dendritic cell activation Chemotherapy + CPG 7909 (phase III) Stage III/IV NSCLC naïve to chemotherapy Primary OS endpoint not met Failed Immunotherapies tested in NSCLC

30. CTLA-4 = cytotoxic T-lymphocyte-associated protein 4 PD-1 = programmed death 1; PD-L1 = programmed death ligand 1 Please note that atezolizumab has not received regulatory approval in any country yet 1. Mellman, et al. Nature 2011 2. Chen & Mellman. Immunity 2013 7 Killing of cancer cells (immune and cancer cells) Anti-CTLA-4 CTLA-4 is a major negative regulator of T cell activationand inhibition of CTLA-4 can enhance T cell stimulation, resulting in more potent anti-tumour responses1 Ipilimumab Tremelimumab Anti-PDL1/PD1 PD-L1 expression on tumour cells and tumour-infiltrating immune cells can inhibit T cell activity via its receptor PD-1, dampening the anti-tumour immune response. Inhibition of PD-L1 or its receptor PD-1 may restore T cell effector function2 Atezolizumab (anti-PDL1) Durvalumab (anti-PDL1) Nivolumab (anti-PD1) Pembrolizumab (anti-PD1) CD28 OX40 GITR CD137 CD27 HVEM CTLA-4 PD-1 TIM-3 BTLA VISTA LAG-3 T cell targets for modulating activity Activating Receptors Inhibitory Receptors T cell stimulation Agonistic Antibodies Blocking Antibodies T cell

31. Pennell NA. Understanding the Rationale for Immunotherapy in Non-Small Cell Lung Cancer. Seminars in Oncology. 2015 Oct;42 Suppl 2:S3–S10.

32. Chemoterapy- naïve stage IIIB/IV NSCLC (n=204) R A N D O M I Z E Concurrent ipilimumab + P/C (n=70) Phased ipilimumab + P/C (n=68) Placebo+ P/C (n=66) Ipilimumab q 12 weeks Ipilimumab q 12 weeks Placebo q 12 weeks 1:1:1 - P/C: 175 mg/m2 paclitaxel + AUC=6 carboplatin q 3 weeks x 6 doses - Concurrent ipilimumab: 10 mg/kg q 3 weeks x 4 doses - Phased ipilimumab: placebo q 3 weeks x 2 doses followed by IPI q 3 weeks x 4 doses - Primary endpoint: inmune-related PFS (irPFS) Lynch. Journal of Clinical Oncology. 2012 Jun 8;30(17):2046–54.

33. Lynch. Journal of Clinical Oncology. 2012 Jun 8;30(17):2046–54. Phased ipilimumab regimen improved WHOPFS in patients with squamous histology: HR: 0.40 (95% CI, 0.18-0.87)

34. Zielinski; Ann Oncol 2013,24(5):1170-1179

35. Pennell NA. Understanding the Rationale for Immunotherapy in Non-Small Cell Lung Cancer. Seminars in Oncology. 2015 Oct;42 Suppl 2:S3–S10.

36. Gettinger SN. J Clin Oncol; 2015 Jun 20;33(18):2004–12. NIVOLUMAB: phase I dose-escalation cohort expansion trial N=129 RR:17%

37. CheckMate 017: Nivolumab vs Docetaxel in Previously Treated Squamous NSCLC Open-label, randomized phase III trial Primary endpoint: OS Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL Pts with stage IIIB/IV squamous NSCLC and ECOG PS 0-1 with failure of 1 previous platinum doublet chemotherapy (N = 272) Nivolumab 3 mg/kg IV q2w (n = 135) Docetaxel 75 mg/m2 IV q3w (n = 137) Until disease progression or unacceptable toxicity Stratified by previous paclitaxel therapy (yes vs no) and region Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015;[Epub ahead of print].

38. CheckMate 017: Baseline Characteristics Characteristic Nivolumab (n = 135) Docetaxel (n = 137) Median age, yrs (range) 62 (39-85) 64 (42-84) Male, % 82 71 Current/former smoker, % 90 94 ECOG PS 1, % 79 73 Stage IV disease,* % 78 82 CNS metastasis, % 7 6 Prior paclitaxel, % 34 34 PD-L1 expression,† %  ≥ 1%  ≥ 5%  ≥ 10%  Not quantifiable 47 31 27 13 41 29 24 21 *Stage not reported in 1 pt in the nivolumab and 1 pt in the docetaxel groups. †83% of pts had quantifiable PD-L1 expression. PD-L1 expression measured in pre-treatment tumor biopsies with validated, automated immunohistochemical assay using PD-L1 antibody clone 28–8. Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015;[Epub ahead of print].

39. CheckMate 017: OS in the ITT Population Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015;[Epub ahead of print]. 0 3 6 9 12 15 18 21 24 100 80 60 40 20 0 OverallSurvival (%ofPatients) MosAt Risk, n Nivolumab Docetaxel 135 137 113 103 86 68 69 45 52 30 31 14 15 7 7 2 0 0 HR for death, 0.59 (0.44-0.79) P < .001 Nivolumab Docetaxel Median OS Months (95%CI) 1-yr OS % of patients (95%CI) Nivolumab (n=135) 9.2 (7.3-13.3) 42 (34-50) Docetaxel (n=137) 6.0 (5.1-7.3) 24 (17-31)

40. Brahmer, J. NEJM 2015;373:123-35 Variable Nivolumab (n=135) Docetaxel (n=137) Objective response (%) 20 9 Odds ratio (95% CI) 2.6 (1.3-5.5) p value 0.008

41. Brahmer, J. NEJM 2015;373:123-35 Duración de la respuesta: NR nivolumab, 8.4 m docetaxel Mediana número de ciclos: 8 nivolumab, 3 docetaxel

42. Brahmer, J. NEJM 2015;373:123-35

43. CheckMate 017: Tx-Related Aes Treatment-Related AEs ≥ 10%, % Nivolumab (n = 131) Docetaxel (n = 129) Any Grade Grade 3/4 Any Grade Grade 3/4 All events 58 7 86 55 Leading to discontinuation 3 2 10 7 Fatigue 16 1 33 8 Decreased appetite 11 1 19 1 Asthenia 10 0 14 4 Nausea 9 0 23 2 Diarrhea 8 0 20 2 Vomiting 3 0 11 1 Myalgia 2 0 10 0 Anemia 2 0 22 3 Peripheral neuropathy 1 0 12 2 Neutropenia 1 0 33 30 Febrile neutropenia 0 0 11 10 Alopecia 0 0 22 1 Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015; [Epub ahead of print].

44. CheckMate 017: Select Tx-Related irAEs Treatment-Related irAEs, % Nivolumab (n = 131) Docetaxel (n = 129) Any Grade Grade 3/4 Any Grade Grade 3/4 Endocrine  Hypothyroidism 4 4 0 0 0 0 0 0 Gastrointestinal  Diarrhea  Colitis 8 8 1 1 0 1 20 20 0 2 2 0 Hepatic  ALT increase  AST increase 2 2 2 0 0 0 2 1 1 1 1 1 Pulmonary  Pneumonitis  Lung infiltration  Interstitial lung disease 5 5 1 0 1 1 0 0 1 0 0 1 0 0 0 0 Renal  Blood creatinine increase  Tubulointestinal nephritis 3 3 1 1 0 1 2 2 0 0 0 0 Skin 9 0 9 2 Hypersensitivity/infusion reaction 1 0 2 1 Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015; [Epub ahead of print].

45. CheckMate 057: Nivolumab vs Docetaxel in Previously Treated Non-Squamous NSCLC Open-label, randomized phase III trial Primary endpoint: OS Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL Pts with stage IIIB/IV squamous NSCLC and ECOG PS 0-1 with failure of 1 previous platinum doublet chemotherapy (N = 582) Nivolumab 3 mg/kg IV q2w (n = 292) Docetaxel 75 mg/m2 IV q3w (n = 290) Until disease progression or unacceptable toxicity Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2015 Sep 27;:150927150118000–13.

46. Borghaei H, New England Journal of Medicine. 2015 Sep 27;:150927150118000–13. HR= 0.73 (96% CI, 0.59-0.89) P=.0002 Median OS Months (95%CI) 1-yr OS % of patients (95%CI) Nivolumab (n=135) 12.2 (9.7-15) 51 (45-56) Docetaxel (n=137) 9.4 (8.1-10.7) 39 (33-45)

47. Variable Nivolumab (n=135) Docetaxel (n=137) Objective response (%) 19 12 Borghaei H, New England Journal of Medicine. 2015 Sep 27;:150927150118000–13. Duración de la respuesta: 17.2 nivolumab, 5.6 m docetaxel Mediana número de ciclos: 6 nivolumab, 4 docetaxel

48. Predictive relationship of PD-L1 expression level for efficacy of nivolumab Borghaei H, New England Journal of Medicine. 2015 Sep 27;:150927150118000–13.

49. Borghaei H, New England Journal of Medicine. 2015 Sep 27;:150927150118000–13. OS by PD-L1 expression

50. CheckMate 057: Safety Profile Treatment-Related Adverse Events, % Nivolumab (n = 292) Docetaxel (n = 290) Any Grade Grade 3/4 Any Grade Grade 3/4 All events 69 10 88 54 Fatigue 16 1 29 5 Nausea 12 1 26 1 Decreased appetite 11 0 16 1 Asthenia 10 < 1 18 2 Diarrhea 8 1 23 1 Peripheral edema 3 0 10 < 1 Myalgia 2 < 1 11 0 Anemia 2 < 1 20 3 Alopecia < 1 0 25 0 Neutropenia < 1 0 31 27 Febrile neutropenia 0 0 10 10 Leukopenia 0 0 10 8 Paz-Ares L, et al. ASCO 2015. Abstract LBA109.

51. CheckMate 057: Select Tx-Related irAEs Treatment-Related irAEs, % Nivolumab (n = 292) Docetaxel (n = 290) Any Grade Grade 3/4 Any Grade Grade 3/4 Endocrine Hypothyroidism 7 0 0 0 Gastrointestinal Diarrhea 8 1 23 1 Hepatic Increased ALT Increased AST 3 3 0 < 1 1 1 < 1 0 Pulmonary Pneumonitis 3 1 < 1 < 1 Skin Rash Pruritus Erythema 9 8 1 < 1 0 0 3 1 4 0 0 0 Hypersensitivity/infusion reaction 3 0 3 < 1 Paz-Ares L, et al. ASCO 2015. Abstract LBA109.

52. Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR)

53. Atezolizumab was associated with significant improvements in OS in the ITT population Median OS for atezolizumab was 12.6 months compared with 9.7 months for docetaxel (HR 0.73 [95%CI 0.53, 0.99], p=0.040) POPLAR: all patient efficacy ITT OS (n=287) Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA

54. Subgroup (% of enrolled patients) 0.2 21 0.80 0.69 0.73 Hazard Ratio In favor of atezolizumab In favor of docetaxel ITT (N=287) Squamous (34%) Non-Squamous (66%) Median OS (95% CI), mo Atezolizumab Docetaxel 10.1 (6.7, 14.5) 8.6 (5.4, 11.6) 15.5 (9.8, NE) 10.9 (8.8, 13.6) 12.6 (9.7, 16.4) 9.7 (8.6, 12.0) Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA POPLAR: OS by histology

55. • Patients with higher PD-L1 expression demonstrated improved OS with atezolizumab • Tumour cells and tumour-infiltrating immune cells were both independent predictors of survival improvement with atezolizumab Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA TC3 or IC3 (high) TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 TC0 or IC0

56. Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC)

57. ORR by line of therapy TC3 or IC3 and TC2/3 or IC2/3 subgroups Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA

58. Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA BIRCH: Overall Survival by Line of Therapy TC2/3 or IC2/3 Subgroup Median OS, mo (95% CI) 6-mo OS, % 1L (Cohort 1) 14.0 (14.0, NE) 82% 2L (Cohort 2) NE (11.2, NE) 76% 3L+ (Cohort 3) NE (8.4, NE) 71%

59. Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA Subgroup Median OS, mo (95% CI) 6-mo OS, % 1L (Cohort 1) NE (10.4, NE) 79% 2L (Cohort 2) NE (10.6, NE) 80% 3L+ (Cohort 3) NE (NE, NE) 75% BIRCH: Overall Survival by Line of Therapy TC3 or IC3

60. KEYNOTE-001: Subanalysis of Phase I Pembrolizumab Trial in NSCLC • Administered tumor assessment: imaging every 9 wks – Primary: RECIST v.1.1 (independent central review) – Secondary: immune-related response criteria (irRC; investigator assessed) • Tumor biopsy – Tumor biopsy within 60 days prior to first dose of pembrolizumab required – Tumor PD-L1 expression determined by prototype assay to inform enrollment; Samples were independently reanalyzed using clinical trial IHC assay Treatment-naive or previously treated advanced NSCLC (N = 495) Pembrolizumab IV 2 mg/kg q3w (n = 6) Mandatory tumor biopsy Pembrolizumab IV 10 mg/kg q3w (n = 287) Pembrolizumab IV 10 mg/kg q2w (n = 202) CR, PR, SD PD, unacceptable AE, or investigator decision Continue dosing and assessments every 9 wks Off study Garon EB. N Engl J Med. 2015 May 21;372(21):2018–28.

61. PD-L1 NSCLC Sample IHC Staining Negative Weak positive (1% to 49%) PD-L1 = 0% positive PD-L1 = 2% positive PD-L1 = 100% positive Strong positive (50% to 100%) Garon EB. N Engl J Med. 2015 May 21;372(21):2018–28.

62. 100 80 60 40 20 0 Keynote-001: Pembrolizumab Efficacy in Overall Population PFS OS100 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Mos PFS,% OS,% 0 4 8 12 16 20 24 Mos 28 ORR by RECIST, % (95% CI) N All Cohorts Total 495 19.4 (16.0-23.2)  Treatment naive 101 24.8 (16.7-34.4)  Previously treated 394 18.0 (14.4-22.2)  Nonsquamous 401 18.7 (15.0-22.9)  Squamous 85 23.5 (15.0-34.0) All patients Previously treated Treatment-naïve All patients Previously treated Treatment-naïve Garon EB. N Engl J Med. 2015 May 21;372(21):2018–28.

63. Keynote-001: Pembrolizumab Efficacy by PD-L1 Expression PFS OS Proportion score for 356 pts in training, validation groups with slides sectioned ≤ 6 months of staining 100 80 60 40 20 0 PFS,% 100 80 60 40 20 0 OS,% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months 0 4 8 12 16 20 24 Months 28 PS ≥ 50% (n = 119) PS < 1% (n = 76) PS 1 - 49% (n = 161) PS ≥ 50% (n = 119) PS < 1% (n = 76) PS 1 - 49% (n = 161) ORR by RECIST, % (95% CI) N All Cohorts Percent PD-L1 staining  ≥ 50% 73 45.2 (33.5-57.3)  1% - 49% 103 16.5 (9.9-25.1)  < 1% 28 10.7 (2.3-28.2) Garon EB. N Engl J Med. 2015 May 21;372(21):2018–28.

64. Pembro 10 mg/kg Q3W Nonrandomized (N = 38) • PD-L1+ or PD-L1– tumors • ≥2 previous therapies Randomized (N = 280) • PD-L1+ tumors • ≥1 previous therapy Pembro 10 mg/kg Q3W Pembro 10 mg/kg Q2W R (3:2) Pembro 10 mg/kg Q2W Nonrandomized (N = 43) • PD-L1– tumors • ≥1 previous therapies Pembro 10 mg/kg Q3W Nonrandomized (N = 33) • PD-L1+ tumors • ≥2 previous therapies Pembro 2 mg/kg Q3W Nonrandomized (N = 55) • PD-L1+ tumors • ≥1 previous therapies • Patients with tumors of any histology eligible • Treatment continued until confirmed disease progression, intolerable toxicity, or other reason • Response assessed every 9 weeks per RECIST v1.1 per central reviewa • PD-L1 assessment1 – Enrollment: Prototype assay using the Merck 22C3 antibody – Relationship with efficacy: Dako PD-L1 IHC 22C3 pharmDx™ Assay aTreatment decisions were managed per irRC by investigator review. 1. Garon EB et al. N Engl J Med. 2015;372:2018-20. Soria et al. Ann Oncol 2015; 26 (suppl 6): abstr 33LBA Efficacy and Safety of Pembrolizumab (MK-3475) for Patients With Previously Treated Advanced NSCLC Enrolled in KEYNOTE-001

65. Soria et al. Ann Oncol 2015; 26 (suppl 6): abstr 33LBA

66. Survival: Patients Treated at 10 mg/kg Data cutoff date: January 23, 2015. OS PFS Median, mo (95% CI) 6-mo Rate, % Median, mo (95% CI) 6-mo Rate, % TPS ≥50% (n = 99) 15.5 (10.0-NR) 71.6 5.8 (2.1-10.3) 49.9 TPS 1%-49% (n = 127) 7.8 (5.8-12.4) 57.3 2.3 (2.1-3.4) 25.3 TPS <1% (n = 68) 8.6 (5.5-12.0) 57.1 2.1 (2.0-4.0) 23.2 Total (N = 394) 11.3 (8.8-14.0) 63.0 3.0 (2.2-4.0) 34.0 99 75 45 8 3 0 127 90 44 5 1 0 68 49 21 0 0 0 394 287 154 19 7 0 65 59 34 216 17 12 9 51 4 3 0 11 0 4 8 12 16 20 24 28 32 0 10 20 30 40 50 60 70 80 90 100 Time, months OS,% Soria et al. Ann Oncol 2015; 26 (suppl 6): abstr 33LBA

67. KEYNOTE-010: Phase II/III Pembrolizumab Trial in NSCLC • Primary endpoint: OS • Secondary endpoints: – PFS – Safety • Evaluations: at week 12; every 6 weeks therefore • Subgroup of strongly PD-L1 + assessed (>50%) Pts with stage IIIB/IV squamous NSCLC and ECOG PS 0-1 with failure of 1 previous platinum doublet chemotherapy or EGFR/ALK- targeted agents and PD-L1 + >1% (N = 1034) Pembrolizumab IV 2 mg/kg q3w (n = 6) Pembrolizumab IV 10 mg/kg q3w (n = 287) Docetaxel IV 75 mg/kg q3w (n = 202) CR, PR, SD PD, unacceptable AE, or investigator decision Continue dosing and assessments every 9 wks Off study

68. Checkpoint inhibitors in 2/3L NSCLC POPLAR PhII allcomer 2/3L atezo vs. doc (n=287) CheckMate 017 PhIII 2L Sq nivo vs. doc (n=272) CheckMate 057 PhIII 2L NSq nivo vs. doc (n=582) KEYNOTE-001 PhIb (inc. NSCLC) pembro (n=394 for previously treated) ORR, % Atezo 15% vs doc 15% Nivo 20% vs doc 9% Nivo 19% vs doc 12% Pembro 18% Notes G3–4 treatment-related AEs: 12 vs 39% G3–4 treatment-related AEs: 7 vs 55% Reduction from baseline in lung cancer symptoms with nivolumab G3–4 treatment-related AEs: 10 vs 54% Low incidence of immune-related AEs Refs. Spira, et al. ASCO 2015 Spigel, et al. ASCO 2015 Reckamp, et al. WCLC 2015 Gralla, et al. WCLC 2015 Paz-Ares, et al. ASCO 2015 Garon, et al. AACR 2015 Nivo OS Doc OS Pem OS Pem PFS Atezo OS Nivo PFS Doc PFS Nivo OS Doc OS Nivo PFS Doc PFS Doc OS Atezo PFS Doc PFS HR 0.59 p=0.00025 HR 0.62 p=0.0004 HR 0.73 p=0.0015 HR 0.92 p=0.3932 HR 0.77 p=0.1071 HR 0.98 p=0.8606

69. Combination therapy: 1L NSCLC PD-L1/PD-1 inhibitors are being combined with chemotherapy and other immunotherapies in the 1L setting GP28328 PhIb solid tumours (incl. 1L NSCLC) atezo + chemo (n=58) KEYNOTE-021 PhI/II 1L NSCLC pembro + chemo (n=49) CheckMate 012 PhI 1L NSCLC nivo (N) + chemo (n=56) CheckMate 012 PhI 1L NSCLC nivo (N) + ipi (I) (n=49) Atezo + carbo/ pac Atezo + carbo/ pem Atezo + carbo/ abrax Pembro + carbo/ pac Pembro + carbo/ pem N10 + gem/ cis N10 + pem/ cis N10 + carbo/ pac N5 + carbo/ pac N1 q3w + I1 q3w N1 q2w + I1 q6w N3 q2w + I1 q12w N3 q2w + I1 q6w n 8* 17* 16* 25 24 12 15 15 15 31 40 38 39 ORR, % Grade 3–4 treatment- related AEs 69% 35% 45% 29% 35% 29% 28% 71% 54% 85% 32% 38% 25% 47% 73% 29% 50 77 56 28 58 33 47 47 43 13 25 39 31 Refs. Camidge, et al. WCLC 2015 Papadimitrakopoulos, et al. ASCO 2015 Gettinger, et al. ESMO 2014 Rizvi, et al. WCLC 2015

70. Nuevos retos • Nuevas toxicidades • Pseudoprogresión • Biomarcadores

71. Nuevas toxicidades

72. Summary of PD-1/PD-L1 Blockade Immune- Mediated Toxicities Occasional (5% to 20%)  Fatigue  Rash: maculopapular and pruritus – Topical treatments  Diarrhea/colitis – Initiate steroids early, taper slowly  Hepatitis/liver enzyme abnormalities  Infusion reactions  Endocrinopathies: thyroid, adrenal, hypophysitis Infrequent (< 5%)  Pneumonitis  Grade 3/4 toxicities uncommon Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. Patnaik A, et al. ASCO 2012. Abstract 2512. Brahmer JR, et al. N Engl J Med. 2012;366:2455-2465. Herbst RS, et al. ASCO 2013. Abstract 3000.

73. Immune Adverse Events • Onset: – Average is 6-12 wks after initiation of therapy – Can occur within days of the first dose, after several months of treatment, and after discontinuation of therapy • Pt complaints are autoimmune and drug related until proven otherwise – Rule out infections, metabolic causes, tumor effects, etc • Early recognition, evaluation, and treatment are critical

75. Pseudoprogresión 8-10-2014 19-2-2015

76. Will These PD-1/PD-L1 Agents End Up Being “Untargeted Use of Targeted Therapy”?

77. Hansen AR, Siu LL. JAMA Oncol. 2015. 25% 46% 16-68%Cumplirían criterios

78. McLaughlin J. JAMA Oncol. 2015 Nov 12;:1–9. N=49

79. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelakanou V, Rehman J, et al. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer. JAMA Oncol. 2015 Nov 12;:1–9.

80. N=160 PD-L1: TC and IC Overall discordance rate: 48% Ilie M, Ann Oncol. 2015 Oct 19;:mdv489–7.

81. En todos los casos discordantes la biopsia infravaloró el resultado del especimen quirúrgico, fundamentalmente en células inmunes

82. Eficacia y seguridad Grado de innovación del fármaco Necesidad no cubierta Severidad de la enfermedad Biomarcador eficiente y seguro Coste

83. Para concluir… Inmunoterapia en cáncer de pulmón: funciona Cambio de estándar en segunda línea? Futuro: combinaciones Múltiples checkpoints Radioterapia Quimioterapia Necesitamos biomarcadores Anti-PD1 vs Anti-PDL1?? Mecanismos de resistencia

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