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ES/ONCO/1118/0300
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Advances in Lung Cancer Inmunotherapy
Luis Paz-Ares
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Disclosures (5 years) Honoraria (self/family)– Scientific advice, speaker: Lilly, MSD, BMS, Roche, Pharmamar, Merck, Astra-Zeneca, Novartis, Boehringer, Celgene, Servier, Sysmex, Celgene, Amgen, Incyte, Pfizer Board – Genómica Research grants to Institution – MSD, BMS, Astra-Zeneca
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The cancer-immunity cycle
Chen DS, et al. Immunity. 2013;39(1):1-10.
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T cell targets for modulating activity
Balance between inhibitory and stimulatory receptors dictates T-cell priming Tumour cell or APC T cell 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 T cell stimulation Agonistic Antibodies Blocking Antibodies B7.1 MHC I PD-L1 CDI37-L OX40-L CD40-L CD70 Light CTLA-4 CD28 TCR PD-1 CDI37 OX40 CD40R CD27 HVEM Mellman I, et al. Nature. 2011;480(7378):480-9. Pardoll DM. Nat Rev Cancer. 2012;12(4):
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Targeting CTLA-4 and PD-1 pathways
Periphery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) TCR TCR MHC MHC B7 + + Dendritic cell CD28 T cell T cell PD-1 PD-L1 Tumour cell - - - - B7 CTLA-4 Anti-PD-1/PD-L1 Anti-CTLA-4 PD-1 PD-L2 - - - Anti-PD-1 CTLA-4 pathway PD-1 pathway Wolchock J, et al. J Clin Oncol 2013;31(Issue 15_suppl); abstr 9012
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Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies Future perspectives 7
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Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies Future perspectives 8
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PD-1/PD-L1 Inhibitors in pretreated NSCLC
<1% 1-49% ≥50% Pembrolizumab - OS by PD-L1 expression Garon EB, et al. N Engl J Med. 2015;372(21):
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Summary of phase III studies of immunotherapy in previously treated patients
CheckMate 0171 Nivolumab vs docetaxel CheckMate 0571 Nivolumab vs docetaxel KEYNOTE-0102 Pembrolizumab (2mg/kg or 10mg/kg) vs docetaxel OAK3 Atezolizumab vs docetaxel Phase of study III II/III PD-L1 selected No Yes (TPS* ≥1%) Study size, n 272 (135 vs 137) 582 (292 vs 290) 1,033 (344 vs 346 vs 343) 1,225 (425 vs 425)* Histology Squamous Non-squamous All-comers Line of therapy, % 2L 3L >3L Other/unknown 100 88 11 <1 69 20 9 75 25 Subsequent CIT (immunotherapy arm vs chemo arm), % <1 vs 2 1 vs 2 0.6 vs 1.7 vs 13.1 4.5 vs 17.2 Crossover from chemo arm to study immunotherapy, % 4 6 Not permitted Median OS, months HR vs docetaxel (p value) 9.2 vs 6.0 0.62 (p=0.0004) 12.2 vs 9.5 0.75 (p<0.001) 10.4 vs 12.7 vs 8.5 2mg/kg: 0.71 (p=0.0008) 10mg/kg: 0.61 (p<0.0001) 13.8 vs 9.6 0.73 (p=0.0003) Borghaei H, et al. J Clin Oncol. 2016;34(15_suppl):9025 Herbst RS, et al. Lancet. 2016;387(10027): Rittmeyer A, et al. Lancet. 2017;389(10066):
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Inmunotherapy in pre-treated patients!
PD-L1 expression was predictive of benefit with nivolumab ≥1% PD-L1 expression level HR (95% CI)=0.59 (0.43, 0.82) <1% PD-L1 expression level HR (95% CI)=0.90 (0.66, 1.24) Nivo Doc 100 90 80 70 60 50 40 30 10 20 24 21 18 15 12 9 6 3 27 Median OS (mo) Nivo 17.2 Doc 9.0 Median OS (mo) Nivo 10.4 Doc 10.1 OS (%) OS (%) Time (months) Time (months) PD-L1 expression level Median OS (mo) HR Nivolumab Docetaxel ≥5% <5% 18.2 9.7 8.1 10.1 HR (95% CI) = 0.43 (0.30, 0.63) HR (95% CI) = 1.01 (0.77, 1.34) ≥10% <10% 19.4 9.9 8.0 10.3 HR (95% CI) = 0.40 (0.26, 0.59) HR (95% CI) = 1.00 (0.76, 1.31) Paz-Ares L, et al. J Clin Oncol. 2015;33(Suppl):Abstract LBA109. . Borghaei H, et al. N Engl J Med. 2015;373(17):
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KEYNOTE 024 Trial: Pembro v Chemo First Line treatment in PD-L1 > 50% NSCLC
1.0 0.8 0.6 0.4 0.2 Time (months) PFS estimate 6 3 9 18 15 12 Pembrolizumab Chemotherapy HR=0.50 (95% Cl 0.37–0.68) p<0.001 6.0 10.3 CheckMate-026 PFS3 Reck M, et al. ESMO. 2016:Abstract LBA8_PR. Reck M, et al. N Engl J Med. 2016;375(19):
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KeyNote 024 Trial – Updated OS
Brahmer JR, et al. WCLC :OA
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Presented By Gilberto Lopes at 2018 ASCO Annual Meeting
KEYNOTE-042 Trial: Pembro v QT First Line treatment in PD-L1 > 1% NSCLC Presented By Gilberto Lopes at 2018 ASCO Annual Meeting G Lopes etLopes G, et al. J Clin Oncol. 2018;36(suppl):abstract LBA4. al. ASCO 2018
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Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies Future perspectives 15
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Combining Inmunotherapy plus Chemotherapy
Immunotherapy can modify tumor micro-environment increasing sensitivity to chemotherapy Reduced support to cancer cells (effect on MDSC and macrophages) Reprogrammed tumor vasculature Chemotherapy can boost the immune response Immunogenic cell death Depletion of myeloid cells & Tregs, influx of TILs, inflammation Emens L. et al. Cancer Immunol Res 2015;3: Galluzzi L, et al. Cancer Immunol Res. 2016;4(11):
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RENCA Tumor-bearing Mouse models suggest a benefit for anti-PD-1 combined with paltinum-based chemotherapy A presented by Gandhi L. AACR 2018
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Front-line therapy: anti-PDL1/PD1 agents in combination with chemotherapy
GP phase Ib solid tumours (incl. first-line NSCLC) Atezolizumab + chemotherapy KEYNOTE phase I/II first-line NSCLC Pembrolizumab + chemotherapy CheckMate 0123 phase I first-line NSCLC Nivolumab (N) + chemotherapy Atezo + carbo + pac Atezo + carbo + pem Atezo + carbo + nab-pac Pembro + carbo + pac Pembro + carbo + pac + bev Pembro + carbo + pem N10 + cis + gem N10 + cis + pem N10 + carbo + pac N5 + carbo + pac N 8* 17* 16* 25 24 12 15 14 ORR, % 77 71 56 52 50 48 47 47 43 33 1. Giaccone, et al. ECC 2015; 2. Gadgeel, et al. ASCO 2016; 3. Rizvi, et al. J Clin Oncol 2016
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KEYNOTE-021, cohort G - Efficacy
Langer CJ, et al. Lancet Oncol. 2016;17(11): Borghaei H, et al. Annals Oncol. 2017;28(suppl_5):mdx
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Chemo ± Pembrolizumab in Non-SCC NSCLC KeyNote 189 Trial
Gandhi L, et al. N Engl J Med. 2018;378(22):
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Chemo ± Pembrolizumab in Non-SCC NSCLC KeyNote 189 Trial Benefit according to PD-L1 expression
Gandhi L, et al. N Engl J Med. 2018;378(22):
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Platin/Pem + Atezo in Non-SCC NSCLC Impower 132 Trial
5.2 mo (95% CI: 4.3, 5.6) 7.6 mo (95% CI: 6.6, 8.5) HR 0.60 (95% CI: 0.49, 0.72) P < Minimum follow-up, 11.7 mo Median follow-up, 14.8 mo HR: 0.81 (95% CI: 0.64, 1.03) P = Minimum follow-up: 11.7 mo Median follow-up: 14.8 mo 18.1 mo (95% CI: 13.0, NE) 13.6 mo (95% CI: 11.4, 15.5) Papadimitrakopoulou V, et al. IASLC :Abstract OA05.7
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CnP + Pembrolizumab in Non-SCC NSCLC Impower 130 Trial
Cappuzzo F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA53
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Carbo-Nab-paclitaxel + Atezolizumab in Non-SCC NSCLC - Impower 130 Trial
Conclusions In the ITT-WT population atezolizumab + chemotherapy showed benefit in PFS and OS, which was maintained across all PD-L1 subgroups No new safety signals were observed with the combination of atezolizumab + chemotherapy Cappuzzo F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA53
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Chemo+ Beva + Atezolizumab in Non-SCC NSCLC IMPower 150 Trial
Socinski MA, et al. N Engl J Med. 2018;378(24):
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Chemo+ Beva ± Atezolizumab in Non-SCC NSCLC IMPower 150 Trial – Overall Survival
Socinski MA, et al. N Engl J Med. 2018;378(24):
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Chemo+ Beva v Chemo ± Atezolizumab in Non-SCC NSCLC IMPower 150 Trial – Overall Survival
Socinski MA, et al. N Engl J Med. 2018;378(24):
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Chemo ± Atezolizumab in SCC NSCLC IMPower 131 Trial – Overall Survival
Jotte RM, et al. J Clin Oncol. 2018;36(suppl):Abstract LBA9000.
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Chemo ± Atezolizumab in SCC NSCLC IMPower 131 Trial – Overall Survival
Minimum follow-up: 9.8 mo Median follow-up: 17.1 mo Time (months) 12.0% 24.7% 12-month PFS Jotte RM, et al. J Clin Oncol. 2018;36(suppl):Abstract LBA9000.
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Chemo ± Pembrolizumab in SCC NSCLC KeyNote 407 Trial
Paz-Ares L, et al. N Engl J Med. 2018: doi: /NEJMoa
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Chemo ± Pembrolizumab in SCC NSCLC KeyNote 407 Trial
Paz-Ares L, et al. N Engl J Med. 2018: doi: /NEJMoa
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Chemo ± Pembrolizumab in SCC NSCLC KeyNote 407 Trial – Benefit by PD-L1 expression
Paz-Ares L, et al. N Engl J Med. 2018: doi: /NEJMoa
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Chemo ± Nivolumab in NSCLC PD-L1 Negative CheckMate 227 Trial
Borghaei H, et al. J Clin Oncol. 2018;36(suppl):Abstract 9001.
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Chemo ± Nivolumab in NSCLC PD-L1 Negative CheckMate 227 Trial- PFS
Borghaei H, et al. J Clin Oncol. 2018;36(suppl):Abstract 9001.
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Nivo + Chemo in 1L NSCLC High TMB (≥10 mut/MB)
TMB ≥10 mut/Mb: ORR was 60.5% with nivo + chemo and 20.8% with chemo TMB <10 mut/Mb: ORR was 27.8% with nivo + chemo and 22.0% with chemo Borghaei H, et al. J Clin Oncol. 2018;36(suppl):Abstract 9001.
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Chemo ± Atezolizumab in SCLC
Impower 133 Trial Atezolizumab (N=201) Placebo (N=202) Median OS, months (95% CI) 12.3 (10.8, 15.9) 10.3 (9.3, 11.3) HR (95% CI) 0.70 (0.54, 0.91) P = 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months 100 90 80 70 60 50 40 30 Overall Survival (%) 51.7% 38.2% 12-month OS Atezolizumab Placebo Censored + Paz-Ares L, et al. N Engl J Med. 2018 doi: /NEJMoa
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Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies Future perspectives 37
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CheckMate 227 Part 1 Study Designa
Database lock: January 24, 2018; minimum follow-up: 11.2 months N = 1189 <1% PD-L1 expression N = 550 Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W n = 396 Histology-based chemotherapyb n = 397 Nivolumab 240 mg Q2W n = 187 n = 186 Nivolumab 360 mg Q3W + histology-based chemotherapyb n = 177 R 1:1:1 Key Eligibility Criteria Stage IV or recurrent NSCLC No prior systemic therapy No known sensitizing EGFR/ALK alterations ECOG PS 0–1 Stratified by SQ vs NSQ ≥1% PD-L1 expression Nivolumab + ipilimumab n = 396 Chemotherapyb Patients for PD-L1 co-primary analysis Co-primary endpoints: Nivolumab + ipilimumab vs chemotherapy OS in PD-L1–selected populations PFS in TMB-selected populations Nivolumab + ipilimumab n = 139 n = 160 Patients for TMB co-primary analysisc Hellmann MD, et al. N Engl J Med. 2018;378(22):
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Checkmate 227: TMB as predictor of response with nivo+ipi
Hellmann MD, et al. N Engl J Med. 2018;378(22):
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Checkmate 227: TMB as predictor of response with nivo+ipi
Hellmann MD, et al. N Engl J Med. 2018;378(22):
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TMB and Tumor PD-L1 Expression Identify Distinct and Independent Populations of NSCLC
Hellmann MD, et al. N Engl J Med. 2018;378(22):
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What do I do? 1st Line TMB high TMB low Other Charact. PDL1 Neg Chemo
Chemo-IO / IO-IO Chemo-IO ? PDL1 ≥ 1% IO Unfit for chemo PDL1 ≥ 50% Agressive disease? Hellmann MD,…Paz-Ares L. New Eng J Med 2018
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What would I do? 1st Line TMB high TMB low Other Charact. PDL1 Neg
Chemo Chemo-IO / IO-IO Chemo-IO ? PDL1 ≥ 1% IO Unfit for chemo PDL1 ≥ 50% Agressive disease? Hellmann MD,…Paz-Ares L. New Eng J Med 2018
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Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies Future perspectives 44
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Stage III: PACIFIC TRIAL PFS and OS
Antonia SJ, et al. N Engl J Med. 2017;377(20):
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IO may be part Neoadjuvant Therapy
Nadim Trial N % Major Pathologhical response1 Complete response 24 18 80.0 75.0 Less < 90% 6 20.0 Total 30 100.0 Median patient follow-up = 4.1 months, range months. None of the patients have suffered recurrence. One pt with stage IIIA NSCLC was not resectable at the time of surgery due to tracheal invasion – this pt is not included in the pathologic response exploratory analysis graph 95% CI for MPR calculated using a modified Wald calculation Provencio M, et al. IASLC : Abstract OA01.5.
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Stratification factors PIs: M O´Brien & L Paz-Ares
PEARLS Adjuvant EORTC-ETOP Trial (KeyNote 091) Randomized Phase III Trial Stage IB, II-IIIA NSCLC Radically resected (R0) Standard of care as adjuvant CT Pembrolizumab 2mg q21d for 18 injections R Placebo q21d for 18 injections Stratification factors Stage (IB versus II versus IIIA) Histology (non-squamous versus squamous) PDL-1 IHC expression (0 versus 1-49% versus > 50%) No chemotherapy versus adjuvant platinum-based chemotherapy PIs: M O´Brien & L Paz-Ares
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Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies Future perspectives 48
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Cancer Genotypes shapes the immune landscape
Borghaei H, et al. J Clin Oncol. 2018;36(suppl):Abstract 9001.
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Underlying Genomic Aberrations KRAS and LKB1
Skoulidis F, et al. Cancer Discov. 2018;8(7):
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Relevance of a specific genomic aberration on the immune landscape
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MEDI9447+Anti-PD1: demonstration of synergistic effect
Hay CM, et al. Oncoimmunology. 2016;5(8):e
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Get Cold Tumors Inflammed Adenosine Receptor Inhibitors
Adenosine Suppresses Immunity and is a Potential Mechanism of Resistance to Anti-PD-(L)1 Therapy Fong L, et al. J Clin Oncol. 2017;35(suppl):Abstract 3004.
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Adenosine Receptor Inhibitors CPI-444 + Atezo
Fong L, et al. J Clin Oncol. 2017;35(suppl):Abstract 3004.
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Presence of Tregs and expression of PD-L1 and IDO are associated with a CD8+ T cell infiltrate
Spranger et al. Sci Transl Med. 2013;5(200):200ra116 as shown by Gajedski at ASCO 2016
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PD-1 + IDO Inhibition Gangadhar T, et al. J Clin Oncol. 2017;35(suppl):Abstract 9014.
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11/14/2019 Targeted agent not directed against a genomic aberration: IO Agents + Antiangiogenics Pembrolizumab+ramucirumab is not in the label of ramucirumab in The Netherlands Herbst et al. ESMO 2016
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All doses: ORR overall patient population 21.5%
High dose: ORR 37% and 86% for PD-L1+ and PD-L1 high, respectively Adults with recurrent NSCLC, who progressed following 1L standard-of-care systemic treatment (chemotherapy or targeted therapy), and who had no prior immunotherapy, were randomized to receive M mg Q2W (n=40) or 1200 mg Q2W (n=40) until disease progression, unacceptable toxicity, or trial withdrawal • The primary objective of this expansion cohort study is to assess BOR per RECIST v1.1 Paz-Ares L, et al. J Clin Oncol. 2018;36(Suppl):Abstract 9017.
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Get Cold Tumors Inflammed Microbiota
Commensal microbiota: Bifidobacterium species can improve anti-tumor immunity and response to anti-PD-L1 antibody in vivo Sivan A, et al. Science. 2015;350(6264):
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Patients who had received antibiotics showed decreased PFS and OS following anti-PD-1/PD-L1 treatment Routy B, et al. Science. 2018;359(6371):91-7.
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Adoptive T-Cell Therapy
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Gracias lpazaresr@seom.org
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How to treat patients tomorrow
How to treat patients tomorrow? Do all patients with PD-L1 >50% tumors need chemo? Pembrolizumab+platinum+pemetrexed combination is not in the label of pemetrexed in The Netherlands
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Pembrolizumab in MSI-High Tumors
RR=53% Le DT, et al. Science. 2017;357(6349):
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How to treat patients tomorrow
How to treat patients tomorrow? Do all patients with PD-L1 =0 tumors need pembro? Pembrolizumab+platinum+pemetrexed combination is not in the label of pemetrexed in The Netherlands
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Rational Combinations At present!!
1º Line TMB high TMB low Other Charact. PDL1 Neg Chemo Chemo-IO / IO-IO Chemo-IO ? PDL1 ≥1% PDL1 ≥ 50% IO Agressive Disease ?
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One size does not fit all!! Personalized treatments require:
Agenda One size does not fit all!! Personalized treatments require: Biomarkers Tailored treatments 69
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Multiparametric Immune Characterization
Bulk immune content Immune Contexture IHC tGE (eg reactive stroma) IF/DP Composite Molecular Features Mutational load (F-One) Prognostic Predictive for CIT Predictive for specific therapy/regimen Clinical outcomes Modified from Hegde, Karanikas, Evers. Clin Cancer Res 2016; Herbst et. al. Nature 2014
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Different Immune Phenotypes indicate distinct cancer immunity blockades
ACTIVATE (central) Non-inflamed RECRUIT/ INFILTRATE (vasculature) Excluded EXCLUDED CD8+ T cells present but have not efficiently infiltrated IMMUNE DESERT CD8+ T cells are absent from tumor and its periphery INFLAMED CD8+ T cells infiltrated, but are inhibited KILL CANCER CELLS (tumor) Inflamed Sources: Modified from Chen DS, Mellman I. Immunity. 2013; Herbst et. al. Nature 2014; Hegde, Karanikas, Evers. Clin Cancer Res 2016
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Mutational Burden Predictor for Pembrolizumab Benefit
Rizvi NA, et al. Science. 2015;348(6230):124-8.
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TMB & Clonal Neoantigens Predictor for anti-PD-1Treatment Benefit
McGranahan N, et al. Science. 2016;351(6280):
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Progression-Free Survival – OAK
Increasing Atezolizumab benefit with higher bTMB cut-points in OAK Trial Progression-Free Survival – OAK Overall Survival – OAK Enrichment of PFS benefit was observed in the bTMB ≥16 subgroup, while OS was consistent between the bTMB ≥16 subgroup and the BEP Gandara DR, et al. Nat Med. 2018;24(9):
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