IMMUNE CHECKPOINT BLOCKADE FOR NSCLC. Marina Chiara Garassino

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1 IMMUNE CHECKPOINT BLOCKADE FOR NSCLC Marina Chiara Garassino

2 Cells of the Immune System Innate immune system: Involving proteins (chemokines and cytokines) and cells, is considered to be the first line of immune defense and does not generate an antigen-specific response 1,2 Mast cell B cell Adaptive immune system: Mediated by B and T cells is highly specific and capable of generating an antigen-specific response 1,2 Macrophage NK cell DC Basophil γδ T cell Antibodies Induction requires presentation of antigens by cells of the innate immune system Complement protein Eosinophil T cell Neutrophil NKT cell Granulocytes CD4 + cell CD8 + cell Innate Immunity (rapid response) Adaptive Immunity (slow response, memory) Adapted from Dranoff G. 1 DC, dendritic cell; NK, natural killer. 1. Dranoff G. Nat Rev Cancer. 2004;4(1): Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004.

3 The cycle of cancer immunity Chen D & Mellman I, Immunity ,1

4 Mutational Load Creates Neoantigens Stephens PJ, et al. Nature. 2012;486(7403): Fritsch EF, et al. Oncoimmunology. 2014;3:e29311

5 Explanation of the Molecular Mechanisms of Checkpoint Inhibitors and Other Key Emerging Immunologic Strategies Chen L, et al. Nat Rev Immunol. 2013;13(4):

6 Chen L, et al. Nat Rev Immunol. 2013;13(4): Co-Signalling in T cells

7 Anti-cancer immunity in humans is segregated into three main phenotypes Immune-excluded Immune-desert Inflamed

8 Anti-cancer immunity in humans is segregated into three main phenotypes Immune-excluded Clinical responses to immunotherapy uncommon Immune-desert Non-inflamed tumor, will not respond to immunotherapy Inflamed Tumors most likely to respond to immunotherapy Can we increase the patient population that responds to Immunotherapy?

9 What is a PDL1 Positive Tumor? Atezolizumab Durvalumab 25% / 90%

10 Blueprint PD-L1 IHC Assay Comparison Project Partnership between industry and academia to provide information on analytical correlation of 4 PD-L1assays. Aim: compare analytical staining factors reported as percentages of stained cells TC and IC between four PD-L1 IHC systems (22 C3, 28-8, SP142, SP263). Results and Conclusions Mean Tumour Proportion score (TPS per case based on three readers Data points represent the mean score from three pathologist for each assay on each case 3 (22C3, 28-8 and SP 263) of 4 assay are analitically similar for tumour cel, staining Methods: assessment 39 sample of NSCLC stained with all four investigational use only assays and assessed by 3 trained pathologists from the two diagnostic companies (2 Ventana/Roche and 1 Dako/Agilent).

11 Multicentric French harmonization study for PD-L1 IHC testing in non-small cell lung cancer Aim: To evaluate the analytical correlation between 28-8, 22C3 and SP263 PD-L1 assays across various centers Results and Conclusions To determine if laboratory developed tests (LDT) can achieve an analytical performance close to PD-L1 assays in a set of NSCLC cases 22C3, 28-8 and SP263 assays highly concordant (51.8%) LDTs concordant as compared to reference assays for tumor cell staining Methods: 41 resected NSCLC selected to have various expression levels of PD-L1 IHC performed in 7 centers (3 with Dako AS Link 48, 2 with Ventana Benchmark Ultra and 2 with Leica Bond III) 22C3, 28-8, E1L3N, SP142, SP263 clones used in each center either as assays on dedicated platform (22C3, 28-8, SP263) or LDT

12 First Line treatment

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19 CA : nivolumab monotherapy in chemotherapy-naïve patients CheckMate 026: Nivolumab monotherapy N=1325 Key Inclusion Criteria Stage IV or recurrent NSCLC No prior systemic anticancer therapy Measurable disease per RECIST 1.1 Tumor PD-L1+ ( 1% by IHC) ECOG PS 1 No known EGFR/ALK mutations sensitive to available targeted inhibitor therapy No untreated CNS metastases No autoimmune disease R Nivolumab 3 mg/kg IV Q2W Optional Crossover* Squamous NSCLC Gemcitabine + Cisplatin Gemcitabine + Carboplatin Paclitaxel + Carboplatin Non-Squamous NSCLC Pemetrexed + Cisplatin Pemetrexed + Carboplatin Until disease progression or unacceptable toxicity Start Date: March 2014 Estimated Study Completion Date: January 2018 Primary Completion Date: July 2016 Status: Ongoing, not recruiting Study Sponsor: Bristol-Myers Squibb Primary Outcome Measures: PFS in subjects with strong (ie, 5%) PD-L1 expression Secondary Outcome Measures: OS, PFS, disease-related symptom improvement: in all subjects with any PD-L1 tumor expression; OS, ORR, DOR and TTR: in subjects with strong (ie, 5%) PD-L1 expression * Permitted if crossover eligibility criteria met, including progression confirmed by independent radiology review Investigator s choice of chemotherapy administered in 3-week cycles up to a maximum of 6 cycles of IV injection until disease progression, unacceptable toxicity, or completion of 6 cycles, whichever comes first. Please refer to the Oncology Clinical Trials Platform for the most up-to-date clinical trial information. Abbreviations and references can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES.

20 CA : nivolumab monotherapy in chemotherapy-naïve patients OS (%) PFS (%) OS and PFS (in Patients With 5% PD-L1+) % in the chemotherapy arm had subsequent nivolumab therapy 43.6% in the nivolumab arm had subsequent systemic therapy Chemotherapy All randomized patients ( 1% PD-L1+): HR=1.07 (95% CI: 0.86, 1.33) Nivolumab No. of patients at risk: Months Nivolumab Chemotherapy Nivolumab Chemotherapy Months Nivolumab (n = 211) LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. Chemotherapy (n = 212) Median PFS, months (95% CI) 4.2 (3.0, 5.6) 5.9 (5.4, 6.9) 1-year PFS rate, % HR=1.15 (95% CI: 0.91, 1.45), P= Median OS, months (95% CI) 14.4 (11.7, 17.4) 13.2 (10.7, 17.1) 1-year OS rate, % Adapted from Socinski M, et al. Oral presentation at ESMO Abstract LBA7. Abbreviations, references and additional footnotes can be found in the speaker notes HR=1.02 (95% CI: 0.80, 1.30)

21 CA : nivolumab monotherapy in chemotherapy-naïve patients OS (%) PFS (%) OS and PFS (in Patients With 5% PD-L1+) % in the chemotherapy arm had subsequent nivolumab therapy 43.6% in the nivolumab arm had subsequent systemic therapy Chemotherapy All randomized patients ( 1% PD-L1+): HR=1.07 (95% CI: 0.86, 1.33) Nivolumab No. of patients at risk: Months Nivolumab Chemotherapy Nivolumab Chemotherapy Months Nivolumab (n = 211) Chemotherapy (n = 212) Median PFS, months (95% CI) 4.2 (3.0, 5.6) 5.9 (5.4, 6.9) 1-year PFS rate, % HR=1.15 (95% CI: 0.91, 1.45), P= Median OS, months (95% CI) 14.4 (11.7, 17.4) 13.2 (10.7, 17.1) 1-year OS rate, % HR=1.02 (95% CI: 0.80, 1.30) Adapted from Socinski M, et al. Oral presentation at ESMO Abstract LBA7. Abbreviations, references and additional footnotes can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. 75

22 Total exome mutations (mutations/mb) CA : nivolumab monotherapy in chemotherapy-naïve patients exploratory TMB analysis Total Exome Mutations vs Genes in FoundationOne Panel* FoundationOne panel* (mutations/mb) Samples from the TMB analysis in CheckMate 026 were not tested at Foundation Medicine; however, an exploratory in silico analysis (i.e. virtual bioinformatic approach) evaluating 315 genes in the FoundationOne panel suggested a correlation with total exome mutations *Based on in silico analysis filtering on 315 genes in FoundationOne comprehensive genomic profile (Foundation Medicine, Inc, Cambridge, MA, USA) Adapted from Peters S, et al. Oral presentation at AACR. 2017_CT082. Abbreviations, references and additional footnotes can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. 87

23 CA : nivolumab monotherapy in chemotherapy-naïve patients exploratory TMB analysis Progression-free survival (%) PFS by Tumor Mutation Burden Subgroup High TMB Low/medium TMB Median PFS, months (95% CI) Nivolumab n = (5.1, NR) Chemotherapy n = (4.2, 8.5) HR = 0.62 (95% CI: 0.38, 1.00) Median PFS, months (95% CI) Nivolumab n = (2.8, 5.4) Chemotherapy n = (5.5, 8.6) HR = 1.82 (95% CI: 1.30, 2.55) Nivolumab Months No. at Risk Nivolumab Chemotherapy Chemotherapy Chemotherapy Nivolumab Months Adapted from Peters S, et al. Oral presentation at AACR. 2017_CT082. Abbreviations, references and additional footnotes can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. 93

24 CA : nivolumab monotherapy in chemotherapy-naïve patients exploratory TMB analysis OS (%) OS by Tumor Mutation Burden Subgroup High TMB Low/medium TMB Nivolumab n = 47 Chemotherapy n = 60 Nivolumab n = 111 Chemotherapy n = No. at Risk Nivolumab Chemotherapy 0 Median OS, months (95% CI) 68% received nivolumab as crossover and/or post-study treatment 18.3 (11.4, NR) 18.8 (11.3, NR) HR = 1.10 (95% CI: 0.64, 1.88) 1-y OS rate = 64% vs 60% Chemotherapy Nivolumab Months Median OS, months (95% CI) 55% received nivolumab as crossover and/or post-study treatment 12.7 (9.9, 16.1) 13.2 (9.5, 15.2) HR = 0.99 (95% CI: 0.71, 1.40) 1-y OS rate = 54% vs 53% Months Chemotherapy Nivolumab Adapted from Peters S, et al. Oral presentation at AACR. 2017_CT082. Abbreviations, references and additional footnotes can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. 95

25 CA : nivolumab monotherapy in chemotherapy-naïve patients exploratory TMB analysis PFS (%) PFS by TMB Subgroup and PD-L1 Expression 100 Nivolumab Arm 100 Chemotherapy Arm 75 High TMB, PD-L1 50% No. at Risk High TMB, PD-L1 50% High TMB, PD-L1 1 49% 25 Low/medium TMB, PD-L1 50% 0 Low/medium TMB, PD-L1 50% High TMB, PD-L1 1 49% Low/medium TMB, PD-L1 1 49% Months Low/medium TMB, PD-L1 1 49% High TMB, PD-L1 1 49% Low/medium TMB, PD-L1 50% Months Low/medium TMB, PD-L1 1 49% High TMB, PD-L1 50% Adapted from Peters S, et al. Oral presentation at AACR. 2017_CT082. Abbreviations, references and additional footnotes can be found in the speaker notes. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES. 99

26 CheckMate 227: Nivolumab monotherapy or in combination with ipilimumab or chemotherapy A Phase 3 Study of Nivolumab and Nivolumab in Combination with Ipilimumab or Chemotherapy Versus Chemotherapy in Subjects With Stage IV NSCLC N=2220 Key Inclusion Criteria Stage IV or recurrent NSCLC No prior systemic therapy for advanced disease PD-L1 IHC testing with results ECOG PS 1 EGFR WT and ALK negative CNS metastases permitted if adequately treated 2 weeks prior to randomization Stratification Factor Histology (SQ versus NSQ) PD-L1+ ( 1%) Randomize 1:1:1 PD-L1- (<1%) Nivolumab monotherapy 240 mg Q2W Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W Chemotherapy Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W Nivolumab 360 mg Q3W + Chemotherapy Start Date: August 2015 Estimated Completion Date: December 2020 Estimated Primary Completion Date: January 2018 Status: Recruiting Sponsor: Bristol-Myers Squibb Chemotherapy Primary Endpoint: OS and PFS Secondary Endpoints: ORR, disease-related symptom improvement by week 12 Adapted from Socinski, et al. Presentation at ESMO. 2016_LBA7. Please refer to the Oncology Clinical Trials Platform for the most up-to-date clinical trial information. Abbreviations, references and additional footnotes can be found in the speaker notes. 107 LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES.

27 Chemotherapy Enhances Anti-Cancer Immune Response: Rational Partner for Immunotherapy Increasing T-cell penetrance in the tumor Eliminating immunosuppressive cells: T-regulatory cells Enhancing effector T-cell function Enhancing maturation and activation of dendritic cells toward antigen presentation Improving recognition of tumor antigens by T-cell Inducing immunogenic cell death Eliminating immunosuppressive cells: T-regs, myeloid-derived suppressor cells, M2 macrophages

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36 O S, % O S, % Plus chemotherapy in NSCLC Keynote -024 Keynote -021 G All NSCLC Histologies PD-L1 TPS 50% Median OS Pembro: 30 months Chemo: 14.2 months HR 0.63 (95%CI, ) Non-squamous NSCLC Any PD-L1 TPS Median OS Pembro +PC: NR Chemo: 20.9 months HR 0.59 (95%CI, ) % 54.8% 51.5% 34.5% N o. a t ris k T im e, m o n th s P em bro C h e m o N o. a t r is k Median (95% CI) NR (22.8 mo NR) 20.9 mo (14.9 NR) T im e, m o n th s 18-mo rate 70% 56%

37 Survival follow-up IMpower150 study design Maintenance therapy (no crossover permitted) Stage IV or recurrent metastatic non-squamous NSCLC Chemotherapy-naive a Tumour tissue available for biomarker testing Any PD-L1 IHC status Stratification factors: Sex PD-L1 IHC expression Liver metastases N = 1202 R 1:1:1 Arm A Atezolizumab b + Carboplatin c + Paclitaxel d 4 or 6 cycles Arm B Atezolizumab b + Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Arm C (control) Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Atezolizumab b Atezolizumab b + Bevacizumab e Bevacizumab e Treated with atezolizumab until PD by RECIST v1.1 or loss of clinical benefit AND/OR Treated with bevacizumab until PD by RECIST v1.1 The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m 2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w. Reck M, et al. IMpower150 PFS analysis Presented at ESMO IO 2017

38 INV-assessed PFS in ITT-WT (Arm B vs Arm C) Arm B: atezo + bev + CP Arm C: bev + CP HR, (95% CI: 0.517, 0.737) P < Minimum follow-up: 9.5 mo Median follow-up: ~15 mo 6.8 mo (95% CI: 6.0, 7.1) 8.3 mo (95% CI: 7.7, 9.8) INV, investigator. Data cutoff: September 15, 2017 Reck M, et al. IMpower150 PFS analysis Presented at ESMO IO 2017

39 INV-assessed PFS in ITT-WT (Arm B vs Arm C) Arm B: atezo + bev + CP Arm C: bev + CP 67% 56% 37% Minimum follow-up: 9.5 mo Median follow-up: ~15 mo 18% INV, investigator. Data cutoff: September 15, 2017 Reck M, et al. IMpower150 PFS analysis Presented at ESMO IO 2017

40 INV-assessed PFS in Teff-high WT (Arm B vs Arm C) Landmark PFS, % Arm B: atezo + bev + CP Arm C: bev + CP 6-month 72% 57% 12-month 46% 18% HR, (95% CI: 0.377, 0.675) P < Minimum follow-up: 9.5 mo 6.8 mo (95% CI: 5.9, 7.4) 11.3 mo (95% CI: 9.1, 13.0) INV, investigator. Data cutoff: September 15, 2017 Reck 50 M, et al. IMpower150 PFS analysis Presented at ESMO IO 2017

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44 Conclusions 1 line For PD-L1>50% pembro is the standard of care For PD-L1<50% chemo is the standard of care The use of TMB COULD be important for defining a further subset Starting with IO seems the better strategy First line could rapidly change in the next months in combination with anti CTLA4 and chemotherapy We will have a problem in sequencing the right treatment for the right patients Patient empowerment will be crucial

45 Second line

46 Three drugs approved Nivolumab Pembrolizumab (PD-L1>1%) Atezolizumab

47 KEYNOTE-010: Pembrolizumab vs docetaxel Herbst RS, Presented December 20, 2015

48 KEYNOTE-010: Pembrolizumab vs docetaxel: OS Time (months) Grade 3 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel: 13% of patients given 2 mg/kg, 16% given10 mg/kg, and 35% of patients given docetaxel). Herbst RS, Lancet 2016; 387:

49 OS (%) OS (%) Nivolumab VERSO docetaxel OS (3 anni di follow-up) CheckMate 017 (SQ NSCLC) Nivolumab (n = 135) Docetaxel (n = 137) HR (95% CI): 0.62 (0.48, 0.80) CheckMate 057 (non-sq NSCLC) Nivolumab (n = 292) Docetaxel (n = 290) HR (95% CI): 0.73 (0.62, 0.88) y OS = 24% 2-y OS = 8% 3-y OS = 6% Months No. of patients at risk 1-y OS = 42% Δ18% 2-y OS = 23% Δ15% Nivolumab Docetaxel CI = confidence interval; HR = hazard ratio 3-y OS = 16% Δ10% Months No. of patients at risk Nivolumab Docetaxel Δ12% 1-y OS = 39% y OS = 51% 2-y OS = 16% 2-y OS = 29% Δ13% 3-y OS = 9% 3-y OS = 18% Δ9%

50 Overall survival (%) Overall survival (%) Overall survival (%) CHECKMATE-057 study: OS Nivolumab vs docetaxel 100 1% PD-L1 expression 100 5% PD-L1 expression % PD-L1 expression 90 mos (mo) 90 mos (mo) 90 mos (mo) Nivolumab Docetaxel Nivolumab Docetaxel Nivolumab 19.9 Docetaxel Nivolumab Docetaxel Nivolumab Docetaxel Nivolumab Docetaxel 10 0 HR (95% CI) (0.43, 0.79) Time (months) 10 0 HR (95% CI) (0.30, 0.62) Time (months) 10 0 HR (95% CI) (0.27, 0.58) Time (months) Borghaei H, et al. N Engl J Med 2015;373: (suppl appendix)

51 Barlesi F et al, Annals of Oncology (2016) 27 (6): /annonc/mdw435; adapted from ESMO 2016 presentation available at ; last access 7/11/2016

52 Barlesi F et al, Annals of Oncology (2016) 27 (6): /annonc/mdw435; adapted from ESMO 2016 presentation available at ; last access 7/11/2016

53 Barlesi F et al, Annals of Oncology (2016) 27 (6): /annonc/mdw435; adapted from ESMO 2016 presentation available at ; last access 7/11/2016

54 Barlesi F et al, Annals of Oncology (2016) 27 (6): /annonc/mdw435; adapted from ESMO 2016 presentation available at ; last access 7/11/2016

55 Barlesi F et al, Annals of Oncology (2016) 27 (6): /annonc/mdw435; adapted from ESMO 2016 presentation available at ; last access 7/11/2016

56 Landmark 2-year overall survival in OAK Overall survival (OS) in ITT850 LTS, long-term survivors. a 27 atezolizumab- and 49 docetaxel-arm patients were censored prior to 24 months and excluded from this analysis. Data cutoff: 23 January, Satouchi, et al. WCLC 2017

57 OS (%) OS (%) Chechmate 057 (Nivolumab) Niv o Doc 1% PD-L1 expression level Median OS (mo) Nivo 17.2 Doc HR (95% CI)=0.59 (0.43, 0.82) OS by PD-L1 expression: <1% PD-L1 expression level Median OS(mo) Nivo 10.4 Doc Niv o 20 Doc HR 10(95% CI)=0.90 (0.66, 1.24) Time (months) > % 1 PD-L1 HR 0.59 < % 1 PD-L1 HR 0.90 Keynote 10 (Pembrolizumab).Rizvi NA, et al. Lancet Oncol 2015 R Herbst et al. Lancet 2016 Barlesi, et al. ESMO 2016 OAK Trial (Atezolizumab) TC3 or IC3 HR: 0.41 TC0 and IC0% HR: 0.75 PD-L1 > 50% HR: 0.53 PD-L1 < 1% HR: 0.76 In the II line setting, do we really select patients according a more favorable HR? Courtesy of C. Bennati

58 Duration

59 PFS (%) CM 152- PFS From Randomization a Median, months (95% CI) PFS rate, % 6-month 1-year Continuous tx NR (NR) year tx b 10.3 (6.4, 15.2) HR: 0.42 (95% CI: 0.25, 0.71) No. at risk Continuous tx 1-year tx Time post-randomization (months) a Patients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months b With optional retreatment allowed at PD NR = not reached; tx = treatment

60 PFS (%) PFS (%) Same for RP and SD 100 CR/PR Continuous tx 1-year tx b,c Median, months (95% CI) NR (NR) 10.6 (4.8, NA) HR: 0.45 (95% CI: 0.24, 0.85) 100 SD Continuous tx Median, months (95% CI) NR (5.6, NA) 1-year tx b 9.6 (4.5, 12.6) HR: 0.44 (95% CI: 0.17, 1.09) No. at risk Time post-randomization (months) Continuous tx year tx Time post-randomization (months)

61 OS (%) Do not stop the treatment OS Median, months (95% CI) 6-month OS rate, % 1-year Continuous tx NR (NR) year tx b 23.2 (23.2, NA) HR: 0.63 (95% CI: 0.33, 1.20) No. at risk Continuous tx 1-year tx Time post-randomization (months) a Patients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months b With optional retreatment allowed at PD

62 Change in target lesion size from randomization (%) Tumor Burden Change of Target Lesions in Retreated Patients Tumor burden change in target lesions following retreatment a,b 100 Type of PD n (%) Target lesions only 12 (35) Non-target lesions only 1 (3) New lesions only 14 (41) 0 Target lesions and new lesions 4 (12) 20 Non-target lesions and new lesions 1 (3) 40 Target lesions, non-target lesions, and new lesions 2 (6) Start of retreatment % change truncated to 100% Days since randomization a Patients with PD in target lesions only; b n = 11: 1 patient without further assessment after retreatment start was excluded 75

63 FUTURE

64 Resistances Innate resistance: non responders from the beginning Adaptative resistance Progressing during the treatment

65 Innate resistance Low mutational burden Associated genes to MHC I (es. B2 microglobulina) e MHC II HLA-loss IPRES (innate anti PD-1 resistance) signature trascrittomica correlate alla EMT JAK1/2 mutations IFNγ IFNγ signalling alterations PTEN loss/ PI3K

66 Tumors Use Complex, Overlapping Mechanisms to Evade and Suppress the Immune System 3 2 Priming and Activation CD28/B7.1, CD137/CD137L OX40/OX40L, CD27/CD70 HVEM, GITR, IL-2, IL-12 CTLA4/B7.1 PD-L1/PD-1 PD-L1/B7.1 Prostaglandins Cancer antigen presentation TNF-, IL-1 IFN-, CD40L/CD40 CDN, ATP HMGB1, TLR IL-10, IL-4, IL-13 Lymph node Tumour Stimulatory factors Blood vessel Trafficking of T cells to tumours CX3CL1, CXCL9, CXCL1 CCL5 Infiltration of T cells into tumours LFA1/ICAM1 Selectins VEGF Endothelin-B receptor Recognition of cancer cells by T cells T cell receptor Reduced pmhc on cancer cells Release of cancer cell antigens Immunogenic cell death Tolergenic cell death Inhibitors Killing of cancer cells IFN-, T-cell granule content TIM-3/phospholipids PD-L1/PD-1 PD-L1/B7.1 IDO TGF- BTLA VISTA LAG-3 Arginase MICA/MICB B7-H4 7 Chen DS and Mellman I. Immunity Jul 25;39(1):1-10.

67 Kynurenine Pathway IFNgamma AHR (Anche il recettore della diossina) Routy JP, et al. Int J Tryptophan Res. 2016;9:67-77.

68 Kynurenine Pathway IFNgamma AHR (Anche il recettore della diossina) Routy JP, et al. Int J Tryptophan Res. 2016;9:67-77.

69 Percentage Change in Target Lesions Epacadostat Plus Pembrolizumab Phase 1/2 Advanced NSCLC (Patients With 0 2 Prior Lines of Treatment) ORR=14/36 (39%): 2 CRs (6%), 12 PRs (33%) TPS, tumor proportion score Gangadhar TC, et al. J Clin Oncol. 2017;35(Suppl 4): Abstract 9014.

70 Practical conclusions 1. Test for PD-L1 (with the right antibody) 2. For patients PD-L1 (TPS)>50% pembro represents the standard of care (INFLAMED) for first line treatment 3. Stay tuned for 1 lines (look KN189, CM226, Mystic, IMPOWER 150) and critically «think» to the right sequence 4. Combinations could be the future for IMMUNE EXCLUDED and IMMUNE DESERT 5. For second line IO represents «a» standard of care 6. Kanyurenine pathway seem to be promising in the treatment of NSCLC 7. Multiple other targets are now under investigation

71 Thank you very grazie