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IV REUNIN GIDO-GGCP Dr. Jos Muoz Langa Servicio Oncologa Mdica Hospital Universitario y Politcnico La Fe Inmunoterapia en Cncer de Pulmn Baiona, 25 Abril 2015)

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1st-line combination with chemotherapy After failure of 1 prior chemotherapy Maintenance treatment after 1st-line chemotherapy 1st-line or unspecified setting single agent 1970198019902000 Erlotinib 2004 Docetaxel 1999 Gefitinib 2003 2010 Pemetrexed 2004 Erlotinib 2010 Pemetrexed 2009 Crizotinib 2011 (US)/2012 (EU) Erlotinib** 2013 Median OS, months 12+ ~810 ~6 ~24 13+ Carboplatin* 1989 Gemcitabine 1996 Vinorelbine 1994 Docetaxel 2002 Bevacizumab 2006 Pemetrexed 2008 Paclitaxel 1998 Nab-Paclitaxel 2012 Cisplatin* 1978 Despite advances, only small incremental OS benefits in overall patient population * Not approved in NSCLC, but commonly used; Restricted to patients participating in a clinical trial or continuing to benefit from treatment already initiated; Non-squamous NSCLC only; ALK-positive NSCLC only; **EGFR exon 19 deletions or exon 21 (L858R) substitution mutations only; # Afatinib is approved for the treatment of patients with activating EGFR mutations but only PFS data have been published (May 2014). U.S. Food and Drug Administration. Available at www.fda.gov. Accessed September 2014; European Medicines Agency. Available at http://www.ema.europa.eu. Accessed September 2014; NCCN Guidelines. Non-small cell lung cancer. v3.2014.www.fda.gov http://www.ema.europa.eu Afatinib**,# 2013

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Immuno-Oncology (I-O): can it address unmet needs in lung cancer? Immunotherapy represents a new hope for NSCLC patients, Cancer patient The field of immunotherapy has exploded in the last decade, and more and more patients are benefiting, Steven O'Day, USC The PD-1 antibodies stop lung cancer cells from blocking the body's natural immune response to cancer. A drug that can inhibit PD-1 may be able to treat a variety of cancers, which is very exciting, Myron Bednar, Hunterdon Regional Cancer Center We look forward to the potential for the combination of checkpoint inhibitors, like nivolumab, with small molecule inhibitors in patients with EGFR mutated lung cancer, Naiyer Rizvi, Memorial Sloan Kettering Cancer Center The high level of excitement around this space is that immune checkpoint inhibitors may apply to a very broad range of cancer types, as both monotherapies and combination therapies. The data we are seeing so far, including recently released at ASCO, also indicates the mechanism works in patients who have failed previous cancer therapies., Stephen Dunn, LifeTech Capital In any trial you get the odd patient who does very well, but this is an order of magnitude above that., Mick Peake, Glenfield Hospital

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Objetivos de la Charla: Revisar los fundamentos cientficos de la inmuno-oncologa en el cncer de pulmn y en qu se diferencia de otras modalidades de tratamiento. Discutir los ltimos avances en inmunoterapia para el tratamiento del cncer de pulmn. Analizar el problema de la identificacin de biomarcadores para las terapias inumono-oncolgicas y su potencial valor predictivo. Valorar el potencial de la inmunoterapia sola o en combinacin con otras modalidades de tratamiento en la prctica clnica.

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Dunn GP et al. Immunity. 2008; 21:137-148. Inmuno-edicin del Cncer: Las Tres E.

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The Cancer-Immunity Cycle Chen DS and Mellman I. Immunity. 2013;39.

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Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle Chen DS and Mellman I. Immunity. 2013;39.

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Mecanismos Tumorales para Escapar del Sistema Inmune Goldman et al, Nature Biotechnology, 2009

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Mecanismos Tumorales para Escapar del Sistema Inmune

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Duray et al, J of Immunol Research, 2010

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Activacin Clula T Proliferacin Supervivencia Produccin Citoquinas APC MHC Clula T TCR CD28B7 Molculas coestimulatorias Inmunidad Adaptativa: Activacin del Linfocito T Abbas AK et al. Cellular and Molecular Immunology. 6th ed. Philadelphia, PA: Elsevier Saunders, 2010

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CTLA-4 Anti cpo MHC TCR Seales Activacion Seales Inhibitorias CD28B7 Cel Dendritica T cell F. Presentacion Ag G.LinfaticoTejidos perifericos F. Efectora o citotxica T cellCancer cell MHC TCR Anti cpo PD-L1 Regulacin Negativa PD-1 Anti cpo Cancer cell T cell Blocking CTLA-4 and PD-1 pathways

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Sinapsis Inmunolgica: Regulacin funcin Linfocitos T

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Nirschl CJ Clin Cancer Res 2013

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Glennie M. BJCP 2013 Sinapsis Inmunolgica: Regulacin funcin Linfocitos T

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Regulating the T cell immune response T cell responses are regulated through a complex balance of inhibitory (checkpoint) and activating signals Tumours can dysregulate checkpoint and activating pathways, and consequently the immune response Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response PD-1 CTLA-4 Inhibitory receptors Activating receptors TIM-3 LAG-3 Antagonistic (blocking) antibodies Agonistic antibodies T cell stimulation CD28 OX40 CD137 a The image shows only a selection of the receptors/pathways involved. CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 = lymphocyte-activation gene 3; PD-1 = programmed cell death TIM-3 = T-cell immunoglobulin domain and mucin domain 3. Adapted from Mellman I, et al. Nature. 2011:480;481489; Pardoll DM. Nat Rev Cancer. 2012;12:252264.

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Objetivos de la Charla: Revisar los fundamentos cientficos de la inmuno-oncologa en el cncer de pulmn y en qu se diferencia de otras modalidades de tratamiento. Discutir los ltimos avances en inmunoterapia para el tratamiento del cncer de pulmn. Analizar el problema de la identificacin de biomarcadores para las terapias inumono-oncolgicas y su potencial valor predictivo. Valorar el potencial de la inmunoterapia sola o en combinacin con otras modalidades de tratamiento en la prctica clnica.

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Immuno-Oncology: an emerging immunotherapy strategy for NSCLC. EGFR = epidermal growth factor receptor. www.clinicaltrials.gov. Accessed September 2014; NCCN Guidelines. Non-small cell lung cancer. v3.2014; Peters S, et al. Ann Oncol. 2012;23:vii56vii64. Therapeutic vaccines Enhancing immune cell function Adoptive Anti-tumour mAbs Bavituximab EGFR inhibition Adoptive cell transfer Modulate T cell function Cytokines GSK1572932A TG4010 Belagenpumatucel-L Tergenpumatucel-L Racotumomab L-BLP25 CIMAvax Passive (adoptive) Designed to act at tumour; immune-based mechanism Active Designed to act on the immune system itself Immunotherapy Antigen dependent Antigen independent Immuno-Oncology CTLA-4 inhibition PD-1 inhibition PD-L1 inhibition

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Blocking CTL4 and PD-1/PD-L1 Patway Un agente nico es capaz de proporcionar beneficio clnico en mltiples lneas de tratamiento y con largos supervivientes.

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Dose (mg/kg) Died/ Treated ORR, % (n/N) Median OS (95% CI) OS rate, % (95% CI) [patients at risk] 1-year OS2-year OS 126/33 3.0 (1/33) 9.2 (5.3, 11.1) 32 (16, 49) [8] 12 (3, 27) [2] 320/37 24.3 (9/37) 14.9 (7.3, ) 56 (38, 71) [17] 45 (27, 61) [9] 1048/59 20.3 (12/59) 9.2 (5.2, 12.4) 40 (27, 52) [23] 19 (10, 31) [9] 061218243027211593333642485439455157 0.0 0.2 0.4 0.6 0.8 1.0 Overall survival Months since treatment initiation 33 Patients at risk 2185200000015616260000 373 mg/kg26171291111104111321341110 5910 mg/kg35231493220004121629512100 1 mg/kg Anti-PD-1 demonstrates encouraging survival in pre-treated patients: Nivolumab as an example 70% of patients had 35 prior lines of therapy; 46% of these patients had received 1 2 prior lines of therapy and 54% had received 3 5 prior lines of therapy. Gettinger NS et al. J Clin Oncol. 2015; 33 CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy, stage IIIB/IV squamous and non-squamous NSCLC cohort

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Most common treatment-related AE: fatigue 20% 10% experienced 1 grade 3 5 treatment-related AEs Incidence of fatigue, arthralgia and nausea,

Select adverse events (1%) in patients with NSCLC treated with nivolumab Demonstrates a safety profile managed by protocol algorithms No new safety signals emerging; all patients >1 year of follow-up Patients, n (%) [N = 129] Any grade Grade 3 4 Any treatment-related select adverse event*41 (53)5 (6) Skin16 (20)0 Gastrointestinal12 (15)1 (1) Pneumonitis8 (6)3 (2) Pulmonary7 (9)2 (3) Endocrinopathies6 (8)0 Hepatic5 (6)1 (1) Infusion reaction4 (5)1 (1) Renal3 (4)0 *Defined as an event with potential immunological aetiologies that require more frequent monitoring and/or unique intervention. 2/3 cases were fatal. Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).

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Toxicidad clase especfica con un perfil de seguridad manejable Inhibition of CTL4 and PD-1/PD-L1 Patway Un agente nico es capaz de proporcionar beneficio clnico en mltiples lneas de tratamiento y con largos supervivientes. Respuestas rpidas y duraderas independientes del tipo histolgico y de la presencia mutaciones.

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Anti-PD-1 response by histology: nivolumab as an example Responses were durable and occurred early 50% of patients (11/22) with ORs demonstrated response at first assessment (8 weeks) Responses ongoing in 45% of patients (10/22) at time of analysis 38% of responders (6/16) who discontinued for reasons other than PD responded for >30 weeks after last nivolumab dose; responses in 83% of patients (5/6) ongoing at the time of reporting Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112). Time to and duration of response while on treatment Time to response Ongoing response Response duration following latest reported dose of therapy Time, weeks 0163248648096112128144 160 Squamous (n = 9) Non-squamous (n = 13) CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy, stage IIIB/IV NSCLC cohort

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Anti-PD-1 survival rates appear independent of histology: nivolumab as an example Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).

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Response to anti-PD-1 by EGFR or KRAS mutation status: nivolumab as an example Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112). SubgroupORR, % (n/N) [95% CI] EGFR status Mutant17 (2/12) [2.1, 48.4] Wild-type20 (11/56) [10.2, 32.4] Unknown15 (9/61) [7.0, 26.2] KRAS status Mutant14 (3/21) [3.0, 36.3] Wild-type25 (9/36) [12.1, 42.2] Unknown14 (10/72) [6.9, 24.1] Change in tumour size, % -100 -80 -60 -40 120 -20 0 20 40 60 80 100 Patients EGFR mutation status Mutant Unknown Wild-type -100 -80 -60 -40 120 -20 0 20 40 60 80 100 Patients Change in tumour size, % KRAS mutation status Mutant Unknown Wild-type CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy, NSCLC cohort

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Objetivos de la Charla: Revisar los fundamentos cientficos de la inmuno-oncologa en el cncer de pulmn y en qu se diferencia de otras modalidades de tratamiento. Discutir los ltimos avances en inmunoterapia para el tratamiento del cncer de pulmn. Analizar el problema de la identificacin de biomarcadores para las terapias inumono-oncolgicas y su potencial valor predictivo. Valorar el potencial de la inmunoterapia sola o en combinacin con otras modalidades de tratamiento en la prctica clnica.

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Understanding of NSCLC subtyping has evolved in parallel with treatment strategies *Bronchioloalveolar carcinoma 6%, adenosquamous 2%; Of all histologies. 1. Carney DN. N Engl J Med. 2002;346:12628; 2. American Cancer Society. Lung Cancer (Small Cell). Available from http://www.cancer.org/cancer/lungcancer- smallcell/detailedguide/small-cell-lung-cancer-what-is-small-cell-lung-cancer. Accessed September 2014; 3. Chansky K, et al. J Thorac Oncol. 2009;4:792-801; 4. Pao W, et al. Lancet Oncol. 2011;12:175180; 5. Molecular profiling of lung cancer. Available at http://www.mycancergenome.org/content/disease/lung-cancer. Accessed September 2014; 6. American Cancer Society. Lung Cancer (Non-Small Cell); What is non-small cell lung cancer? Available at http://www.cancer.org/cancer/lungcancer-non- smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed September 2014; 7. Kim HS, et al. Lung Cancer. 2013;80:249255; 8. The Cancer Genome Atlas Research Network. Nature. 2012;489:519525. NSCLC >85% SCLC

AgentAssayAnalysisDefinition of positivityPD-L1 expression Nivolumab (anti-PD-1) 1 4 Dako automated IHC assay (28-8 rabbit Ab) Analytically validated Archival FFPE1% and 5% cut-off among >100 evaluable tumour cells 56%: 1% cut-off 49%: 5% cut-off Pembrolizumab (anti-PD-1) 5,6 Dako automated IHC assay (22C3 mouse Ab) New tumour biopsy within 60 days prior to first dose of pembrolizumab Tumour dependent: - Melanoma > 1% - NSCLC PD-L1 (+): Strong (50%) and weak staining (149%) PD-L1 (): no staining ~25%: 50% staining ~4570%: 1% staining MPDL3280A (anti-PD-L1) 7,8,9 Ventana automated clinical research IHC assay Archival FFPEPD-L1 (+): IHC 3 (10%), IHC 2,3 (5%), IHC 1,2,3 (1%) PD-L1 (): IHC 0 (