IMUNOTERAPIA NO CÂNCER DE PULMÃO: PRINCÍPIOS

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1 IMUNOTERAPIA NO CÂNCER DE PULMÃO: PRINCÍPIOS Dr. Gilberto de Castro Junior Professor Colaborador Livre-Docente Faculdade de Medicina da USP. Serviço de Oncologia Clínica - Instituto do Câncer do Estado de São Paulo Centro de Oncologia - Hospital Sírio Libanês Grupo Brasileiro de Oncologia Torácica GBOT/LACOG São Paulo - BRASIL

2 Potenciais conflitos de interesses Dr. Gilberto de Castro Junior CRM:84448 Apoio em participação de eventos de cunho científico Roche, AstraZeneca, MSD, BMS, Boehringer-Ingelheim, Novartis, Bayer, Eurofarma Investigador de ensaios clínicos patrocinados Investigador de ensaios clínicos patrocinados Aulas e apresentações Roche, AstraZeneca, BMS, MSD, Merck Serono, Eurofarma, Pfizer Consultorias científicas Roche, AstraZeneca, MSD, Merck Serono, Eurofarma, Boehringer-Ingelheim, Pfizer

3 Mutational landscape across 12 major cancer types Kandoth et al. Nature 2013

4 Pardoll. Nat Rev Cancer 2012

5 Ribas. NEJM 2015 T cell activation in lymph node

6 Ribas. NEJM 2015 T cell activation in tumor milieu

7 A Via do PD-L1 inibindo a Resposta Imune Recognition of tumor by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 up-regulation on tumor Priming and activation of T cells through MHC/antigen & CD28/B7 interactions with antigen-presenting cells IFNγ IFNγR MHC T-cell receptor T-cell receptor MHC Tumor cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 Nivolumab PD-1 Receptor Blocking Ab

8 PD-L1 Expression Associated with Favorable Outcome With Pembrolizumab TPS 50% cutpoint rigorously determined using independent training and validation sets derived from KEYNOTE-0011 PD-L1 IHC 22C3 pharmdx (Dako) approved in the US as a companion diagnostic for pembrolizumab 20x 40x Negative TPS 1% 49% TPS 50% 1. Garon EB et al. N Engl J Med 2015;372:

9 Keynote 010: PD-L1 Expression Correlates with improved OS in Advanced NSCLC

10 Imagens de IHC images de três amostras diagnósticas anti-pdl-1 Marianne J. Ratcliffe et al. Clin Cancer Res 2017;23:

11 PD-L1 expression on tumor cells % Tumor Staining Cases 22C SP142 SP263 Each dot represents the mean score of 3 pathologists Conclusion 1: 3 assays showed similar staining characteristics for PD-L1 staining on tumor cells, but SP142 comparatively showed less tumor cells stained Journal of Thoracic Oncology Vol. 12 No. 2:

12 Phase 3 CheckMate 026 Study Design: Nivolumab vs Chemotherapy in First-line NSCLC Key eligibility criteria: Stage IV or recurrent NSCLC Nivolumab 3 mg/kg IV Q2W n = 271 Disease progression or unacceptable toxicity No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy 1% PD-L1 expression Randomize 1:1 Chemotherapy (histology dependent) Maximum of 6 cycles n = 270 Tumor scans Q6W until week 48 then Q12W Disease progression Crossover nivolumab (optional) Stratification factors at randomization: PD-L1 expression (<5% vs 5%) Histology (squamous vs non-squamous) An exploratory analysis was conducted in CheckMate 026 to test the hypothesis that patients with high TMB may derive enhanced benefit from nivolumab Primary endpoint: PFS per BIRC ( 5% PD-L1+) Secondary endpoints: PFS per BIRC ( 1% PD-L1+) OS ORR Exploratory objective: Predictive biomarkers for outcomes with nivolumab David P Carbone et al. N Engl J Med 2017; 376:

13 Exploratory TMB Methods CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC Tumor DNA Tumor exome data Whole exome sequencing a Somatic missense mutations TMB Germline DNA (blood) Germline exome data a DNA was sequenced on the Illumina HiSeq 2500 using bp paired-end reads; an average of 84 and 89 million reads were sequenced per tumor and germline sample, respectively (average 84.6 and 93 the mean target coverage, respectively) Patients, n (%) Sample size throughout TMB determination N3 Tumor DNA Germline DNA Randomized 541 (100) 541 (100) Samples available for DNA extraction a 485 (90) 452 (84) DNA available for sequencing 408 (75) 452 (84) Successful preparation of next-generation sequencing library Passed internal quality control b Matched tumor-germline exome sequences for TMB analysis c 402 (74) 452 (84) 320 (59) 432 (80) 312 (58) a Samples were not available for various reasons, including but not limited to lack of patient pharmacogenetic consent, samples exhausted for PD-L1 testing, or poor tissue sampling b Internal quality control failure included factors such as discordance between tumor and germline DNA, too few sequence reads, and low or uneven target region coverage c 8 patients with available tumor DNA sequences did not have matched germline DNA sequences David P Carbone et al. N Engl J Med 2017; 376:

14 PFS (%) PFS by Tumor Mutation Burden Tertile CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC Nivolumab Arm Chemotherapy Arm Median PFS, months (95% CI) Low n = (1.5, 5.6) Medium High n = 49 n = (2.7, 6.9) 9.7 (5.1, NR) Median PFS, months (95% CI) Low n = (5.4, NR) Medium High n = 53 n = (4.3, 8.6) 5.8 (4.2, 8.5) High 40 Low Low High 0 Medium 0 Medium Months Months Data for patients with low and medium TMB were pooled in subsequent analyses David P Carbone et al. N Engl J Med 2017; 376:

15 No. of Missense Mutations Baseline Characteristics According to TMB Subgroup- CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC Characteristic High TMB (n = 107) Low/medium TMB (n = 205) 1000 Median age, years (range) 65 (40, 87) 65 (32, 89) Female, % ECOG PS, % 0 1/ / /1.0 Smoking status, % Current smoker Former smoker Never smoker Disease stage, % Stage IV Recurrent Tumor histology, % Squamous Non-squamous PD-L1 expression level, % 5% 25% 50% N Current Former Never Smoking Status Unknown David P Carbone et al. N Engl J Med 2017; 376:

16 Anti-PDL1 + anti-ctla4

17 Anti-PDL1 + anti-ctla4 CTLA-4 inhibition may also induce compensatory signals, including PD-L1 upregulation, that in turn dampen the immune response PD-L1 expression reduces T-cell activation by binding to two important regulatory receptors: - Binding to PD-1 delivers an inhibitory signal that reduces cytokine production and T-cell proliferation N3 - Binding to CD80, further reduces CD28 co-stimulation of T cells PD-L1 blockade may overcome this immune checkpoint, resulting in prolonged T-cell activation

18 Combinação anti-ctla4 & anti-pd1 Inhibition CTLA-4 CD86 Tumour cell MHC Tumour antigen PD-L1 TCR PD-1 CD80 T cell Inhibition Inhibition Activation Activation CD28 TCR PD-L1 Inhibition PD-1 Inhibition CD80 CD80 MHC CD80 PD-L1 Immune cell

19 Combinação anti-ctla4 & anti-pd1 Anti-CTLA4 blocks CTLA-4 binding to CD80 and CD86 Anti-CTLA4 CTLA-4 CD86 Tumour cell MHC Tumour antigen PD-L1 TCR PD-1 CD80 T cell Activation Activation Inhibition CD80 CD28 TCR PD-L1 PD-1 CD80 MHC CD80 PD-L1 Immune cell Anti-PD(L)1 Anti-PD(L)1 Blocking PDL1-PD1 & PDL1-CD80 interaction

20 Combinação anti-ctla4 & anti-pd1 N3 Das et al. J Immunol 2015

21 Indoleamina 2,3-dioxigenase Munn, Mellor. J Clin Invest 2007

22 ECHO-204 trial Epacadostat is an oral inhibitor of IDO1 Phase 1/2 study - Safety and efficacy of oral epacadostat plus IV nivolumab in pts with advanced tumors No DLT was observed in P1 (36 pts) Most common TRAEs ( 15%) in pts treated with E 100 mg (n = 70) and E 300 mg (n = 135) were rash (33% and 22%), fatigue (26% and 31%), and nausea (24% and 19%). For the 23 SCCHN pts treated with E 300 mg, preliminary DCR was 70% (n = 16). Of 30 MEL pts, 8 were treated with E 100 mg and 22 with E 300 mg. ORR 75% (n = 6; all PR) and and DCR 100% (n = 8; 2 SD) (E 100 mg). Perez et al. ASCO 2017

23 Desafios Como identificar os pacientes candidatos? - Biomarcadores preditivos Emergência da resistência ao tratamento - Diagnóstico e tratamento Identificação e tratamento de toxicidades - Educação da equipe e do paciente Custo da medicação e acesso - Farmacoeconomia: custo-efetividade local