1. ES/ONCO/1118/0300

2. Advances in Lung Cancer Inmunotherapy
Luis Paz-Ares

3. 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

4. The cancer-immunity cycle
Chen DS, et al. Immunity. 2013;39(1):1-10.

5. 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):

6. 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

7. Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies
Future perspectives 7

8. Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies
Future perspectives 8

9. 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):

10. 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):

11. 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):

12. 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):

13. KeyNote 024 Trial – Updated OS
Brahmer JR, et al. WCLC :OA

14. 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

15. Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies
Future perspectives 15

16. 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):

17. RENCA Tumor-bearing Mouse models suggest a benefit for anti-PD-1 combined with paltinum-based chemotherapy
A presented by Gandhi L. AACR 2018

18. 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

19. 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

20. Chemo ± Pembrolizumab in Non-SCC NSCLC KeyNote 189 Trial
Gandhi L, et al. N Engl J Med. 2018;378(22):

21. 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):

22. 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

23. CnP + Pembrolizumab in Non-SCC NSCLC Impower 130 Trial
Cappuzzo F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA53

24. 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

25. Chemo+ Beva + Atezolizumab in Non-SCC NSCLC IMPower 150 Trial
Socinski MA, et al. N Engl J Med. 2018;378(24):

26. Chemo+ Beva ± Atezolizumab in Non-SCC NSCLC IMPower 150 Trial – Overall Survival
Socinski MA, et al. N Engl J Med. 2018;378(24):

27. 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):

28. Chemo ± Atezolizumab in SCC NSCLC IMPower 131 Trial – Overall Survival
Jotte RM, et al. J Clin Oncol. 2018;36(suppl):Abstract LBA9000.

29. 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.

30. Chemo ± Pembrolizumab in SCC NSCLC KeyNote 407 Trial
Paz-Ares L, et al. N Engl J Med. 2018: doi: /NEJMoa

31. Chemo ± Pembrolizumab in SCC NSCLC KeyNote 407 Trial
Paz-Ares L, et al. N Engl J Med. 2018: doi: /NEJMoa

32. 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

33. Chemo ± Nivolumab in NSCLC PD-L1 Negative CheckMate 227 Trial
Borghaei H, et al. J Clin Oncol. 2018;36(suppl):Abstract 9001.

34. Chemo ± Nivolumab in NSCLC PD-L1 Negative CheckMate 227 Trial- PFS
Borghaei H, et al. J Clin Oncol. 2018;36(suppl):Abstract 9001.

35. 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.

36. 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

37. Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies
Future perspectives 37

38. 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):

39. Checkmate 227: TMB as predictor of response with nivo+ipi
Hellmann MD, et al. N Engl J Med. 2018;378(22):

40. Checkmate 227: TMB as predictor of response with nivo+ipi
Hellmann MD, et al. N Engl J Med. 2018;378(22):

41. TMB and Tumor PD-L1 Expression Identify Distinct and Independent Populations of NSCLC
Hellmann MD, et al. N Engl J Med. 2018;378(22):

42. 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

43. 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

44. Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies
Future perspectives 44

45. Stage III: PACIFIC TRIAL PFS and OS
Antonia SJ, et al. N Engl J Med. 2017;377(20):

46. 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.

47. 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

48. Agenda Monotherapy Combos with chemo IO + IO combos
IO in multimodality strategies
Future perspectives 48

49. Cancer Genotypes shapes the immune landscape
Borghaei H, et al. J Clin Oncol. 2018;36(suppl):Abstract 9001.

50. Underlying Genomic Aberrations KRAS and LKB1
Skoulidis F, et al. Cancer Discov. 2018;8(7):

51. Relevance of a specific genomic aberration on the immune landscape

52. MEDI9447+Anti-PD1: demonstration of synergistic effect
Hay CM, et al. Oncoimmunology. 2016;5(8):e

53. 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.

54. Adenosine Receptor Inhibitors CPI-444 + Atezo
Fong L, et al. J Clin Oncol. 2017;35(suppl):Abstract 3004.

55. 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

56. PD-1 + IDO Inhibition
Gangadhar T, et al. J Clin Oncol. 2017;35(suppl):Abstract 9014.

57. 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

58. 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.

59. 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):

60. 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.

61. Adoptive T-Cell Therapy

62. Gracias lpazaresr@seom.org

64. 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

65. Pembrolizumab in MSI-High Tumors
RR=53%
Le DT, et al. Science. 2017;357(6349):

66. 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

67. 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 ?

68. One size does not fit all!! Personalized treatments require:
Agenda
One size does not fit all!!
Personalized treatments require:
Biomarkers
Tailored treatments 69

69. 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

70. 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

71. Mutational Burden Predictor for Pembrolizumab Benefit
Rizvi NA, et al. Science. 2015;348(6230):124-8.

72. TMB & Clonal Neoantigens Predictor for anti-PD-1Treatment Benefit
McGranahan N, et al. Science. 2016;351(6280):

73. 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):