clinical development of lung cancer...

Clinical development of lung cancer

immunotherapy

Luis Paz-Ares

Hospital Universitario Doce de Octubre,

Madrid, Spain

Michel-Ange 1500

Different views of Cancer

TRADITIONAL

ONCOLOGY

A CANCER

IMMUNO-

ONCOLOGY

A BODY THAT

LET A CANCER

CD8 T cells B cells CD4 T cells

Confirmed by Djenidi et al., J Immunol 2015 and Donnem et al., Clin Cancer Res 2015

Positive prognostic value of tumor infiltrating lymphocytes in NSCLC patients

Schalper et al., J Natl Cancer Inst 2015

Immune checkpoint inhibitors

1. Sharma P, et al. Science. 2015;348:56–66. 2. Wolchock J, et al. J Clin Oncol. 2013;31(15 suppl):abstract 9012.

T cell Tumor cell

MHC TCR

PD-L1 PD-1 T cell Dendritic

MHC TCR

B7 CTLA-4 - - -

Activation (cytokines, lysis, proliferation,

migration to tumor)

B7 + + +

CTLA-4 pathway PD-1 pathway

Anti-CTLA-4

Anti-PD-1/PD-L1

Periphery Tumor microenvironment

PD-L2 PD-1

Anti-PD-1

• Pre-treated patients

• First line and earlier stages

• Further patient selection

• The future

Agenda

• The future

Agenda

PD-1/PD-L1 Inhibitors in pretreated NSCLC

Hirsch et al. Lancet 2015

PD-1/PD-L1 Inhibitors in pretreated NSCLC

Most responses occurred early and were

durable 50% of responders (11/22) demonstrated

response at the first tumor assessment

(8 weeks)

Responses were ongoing in 41% of

patients (9/22) at the time of analysis

Time to response is short

Nivo & Avelumab monotherapy in ≥2nd-line

Gettinger SN, et al. J Clin Oncol. 2015;33:2004–2012.

Versraegen et al., ESMO 2016

96 weeks

0 6 12 18 24 30 36 42

Time Since Treatment Initiation (months)

Time to and

duration of

response

discontinuati

of therapy

Time to

response

Ongoing

response

Duration of

response

discontinuati

of therapy

Garon NEJM 2015

<1% 1-49% ≥50%

PD-L1 Expression Matters

Pembrolizumab - OS by PD-L1 expression

Summary of phase III studies of

immunotherapy in previously treated patients

*850 in primary population

NR = not reached 1. Borghaei, et al. ASCO 2016

2. Herbst, et al. Lancet 2015; 3. Barlesi, et al. ESMO 2016

CheckMate 0171

Nivolumab

vs docetaxel

CheckMate 0571

Nivolumab

vs docetaxel

KEYNOTE-0102

Pembrolizumab (2mg/kg or

10mg/kg) vs docetaxel

Atezolizumab

vs docetaxel

Phase of study III III II/III III

PD-L1 selected No No Yes (TPS* ≥1%) No

Study size, n 272

(135 vs 137)

(292 vs 290)

(344 vs 346 vs 343)

(425 vs 425)*

Histology Squamous Non-squamous All-comers All-comers

Line of therapy, %

Other/unknown

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 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)

OS by PD-L1 expression: CheckMate 057

Nivolumab

• PD-L1 expression was predictive of benefit with nivolumab

Time (months)

24 21 18 15 12 9 6 3 0 27

Median OS(mo)

Nivo 10.4

Doc 10.1

Median OS (mo)

Nivo 17.2

Doc 9.0

≥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)

24 21 18 15 12 9 6 3 0 27

aPD-L1 expression was measured in pretreatment tumor biopsies (DAKO automated IHC assay).2

CI=confidence interval; Doc=docetaxel; IHC=immunohistochemistry; Nivo=nivolumab;

1. Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109. 2. Rizvi NA, et al. Lancet Oncol 2015;16:257–265.

PD-L1 expression level

Median OS (mo) HR

Nivolumab Docetaxel

HR (95% CI) = 0.43 (0.30, 0.63)

HR (95% CI) = 1.01 (0.77, 1.34)

≥10%

HR (95% CI) = 0.40 (0.26, 0.59)

HR (95% CI) = 1.00 (0.76, 1.31)

Keynote 010: OS by PD-L1 Expression

Pembrolizumab

HR: 0.53

HR: 0.76

R Herbst et al. Lancet 2016

Keynote 010: OS by by Subgroups

Pembrolizumab

R Herbst et al., Lancet 2016

OAK Trial: OS by PD-L1 Expression Atezoluzumab

• Barlesi, et al. ESMO 2016

Comparability among five assays on tumor cell staining

MS Tsao et al, WLCC 2017

The immune system has memory

Long term benefit from IO?

Goldberg SB et al., WLCC 2015

Brain Metastases - Pembro Phase II Trial

CheckMate 153: Continuous vs 1-Year Nivolumab

Patient Flow and Analysis Populations

Stop nivolumab

Continuous nivolumab

1,245 patients treateda

220 patients on

treatment at

1 year

76 had response or SD

at randomizationc

87 had response or SD

at randomizationd

Efficacy analyses

13% 18%

Spigel DR et al, ESMO 2017

CheckMate 153: Continuous vs 1-Year Nivolumab

PFS From Randomizationa

Median, months (95% CI)

PFS rate, %

6-month 1-year

Continuous tx NR (NR) 80 65

1-year txb 10.3 (6.4, 15.2) 69 40

HR: 0.42 (95% CI: 0.25, 0.71)

No. at risk

1-year tx

Continuous tx

87 50 43 33 21 16 5 1 0

76 60 53 49 35 22 10 3 0

No. at risk

1-year tx

Continuous tx

87 50 43 33 21 16 5 1 0

76 60 53 49 35 22 10 3 0

Time post-randomization (months)

0 3 6 9 12 15 18 21 24

CheckMate 153:

OS From Randomization

Median, months (95% CI)

OS rate, %

6-month 1-year

Continuous tx NR (NR) 97 88

1-year txb 23.2 (23.2, NA) 95 81

HR: 0.63 (95% CI: 0.33, 1.20)

74 72 67 62 41 29 7 2 0

79 74 70 61 38 23 4 0 0

No. at risk

1-year tx

Continuous tx

Time post-randomization (months)

0 3 6 9 12 15 18 21 24 27

Tumor burden change

in target lesions

following retreatment

● Start of retreatment

% change truncated

to 100%

Days since randomization

−100

0 100 200 300 400 500

PD-1/PD-L1

Inhibitor

First/SecondLine

Disease

Progression

Cohort 1

Pembrolizumab

Second line

N=24/55

Cohort 2

Platinum

Chemotherapy

Second line

Cohort 2

Pembrolizumab

Third line

N=24/55

Tumor and

collection

Rechallenge study - SLCG

PI: L Paz-Ares

• The future

Agenda

KEYNOTE-024 and CheckMate 026: PFS

Time (months)

6 3 9 18 15 12

Pembrolizumab

Chemotherapy

HR=0.50 (95% Cl 0.37–0.68)

p<0.001

KEYNOTE-024 PFS1,2 (PD-L1 >50% of cells) CheckMate-026 PFS3 (PD-L1 >5% of cells)

6.0 10.3

1. Reck, et al. N Engl J Med 2016;

2. Reck, et al. ESMO 2016; 3. Socinski, et al. ESMO 2016

Brahmer et al. WLCC 2017

EMA approval December 2016

30% of 1ºL patients

KeyNote 024 Trial – Updated OS

Overall Survival: TPS ≥1%

Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

KEYNOTE-042 Trial: Pembro v QT

First Line treatment in PD-L1 > 1% NSCLC

Chemo + Pembrolizumab in Non-SCC NSCLC

KeyNote 189 Trial

Ghandi et al., NEJM 2018

Gandhi et al., NEJM 2018

Chemo + Pembrolizumab in Non-SCC NSCLC

KeyNote 189 Trial

Benefit according to PD-L1 expression

Chemo+ Beva + Atezolizumab in Non-SCC NSCLC

IMPower 150 Trial

Socinski et al, NEJM, 2018

Chemo+ Beva + Atezolizumab in Non-SCC NSCLC

IMPower 150 Trial – Overall Survival

Socinski et al, NEJM, 2018

Chemo + Atezolizumab in SCC NSCLC

Presented By Robert Jotte at 2018 ASCO Annual Meeting

Chemo + Atezolizumab in SCC NSCLC

Minimum follow-up: 9.8

Median follow-up: 17.1

Time (months)

12-month PFS

Presented By Robert Jotte at 2018 ASCO Annual Meeting

Chemo + Pembrolizumab in SCC NSCLC

KeyNote 407 Trial

Paz-Ares eta al., ASCO2018

KeyNote 407 Trial

Paz-Ares et al., ASCO 2018

KeyNote 407 Trial – Benefit by PD-L1 expression

Paz-Ares et al., ASCO 2018

PACIFIC: Study Design

• Patients with stage III, locally

advanced, unresectable NSCLC

who have not progressed following

definitive platinum-based cCRT

(≥2 cycles)

• 18 years or older

• WHO PS score 0 or 1

• Estimated life expectancy of ≥12

All-comers population

(i.e. any PD-L1 status)

Durvalumab

10 mg/kg q2w for

up to 12 months

Placebo

10 mg/kg q2w for

up to 12 months

2:1 randomization,

stratified by age, sex,

and smoking history

Secondary endpoints

• Proportion of patients alive and

progression-free at 12 and 18

months (per BICR)

• ORR (per BICR)

• DoR (per BICR)

• OS at 24 months

• Safety and tolerability

• PROs

• Pharmacokinetics

• Immunogenicity

Co-primary endpoints

• PFS by BICR using RECIST v1.1*

• OS

1–42 days

post-cCRT

Paz-Ares L et al, ESMO 2017 Antonia S et al., NEJM 2017

PFS by BICR (Primary Endpoint; ITT) P

0 3 6 9 12 15 18 21 24 27

Time from randomization (months)

Placebo

Durvalumab

476 377 301 264 159 86 44 21 4 237 163 106 87 52 28 15 4 3

No. At Risk Durvalumab

Placebo

Durvalumab

(N=476) Placebo

(N=237)

Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)

12-month PFS rate (95% CI) 55.9% (51.0–60.4) 35.3% (29.0–41.7)

18-month PFS rate (95% CI) 44.2% (37.7–50.5) 27.0% (19.9–34.5)

Stratified hazard ratio, 0.52 (95% CI, 0.42–0.65) Two-sided P<0.0001

28,4 16,0 0

Durvalumab(N=443)*

Placebo(N=213)*

Confirmed Objective Response

Durvalumab

(N=475)

Placebo

(N=234)

Any-grade all-causality AEs, n (%) 460 (96.8) 222 (94.9)

Grade 3/4 142 (29.9) 61 (26.1)

Grade 5 21 (4.4) 13 (5.6)

Leading to discontinuation 73 (15.4) 23 (9.8)

Any-grade treatment-related AEs, n (%) 322 (67.8) 125 (53.4)

Any-grade all-causality AESIs, n (%) 311 (65.5) 114 (48.7)

Grade 3/4 39 (8.2) 9 (3.8)

Grade 5 4 (0.8) 4 (1.7)

Requiring concomitant treatment 200 (42.1) 40 (17.1)

Any-grade immune-mediated AEs, n (%) 115 (24.2) 19 (8.1)

Grade 3/4 16 (3.4) 6 (2.6)

Grade 5 4 (0.8) 3 (1.3)

PACIFIC: AEs Profile

PEARLS Adjuvant ETOP-EORTC 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

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: L Paz-Ares & M O´Brien

Radiographic

response (N=20)

RECIST 1.1

Partial Response 2 (10%)

Stable Disease 18 (85%)

Progressive

Disease

1 (5%)

Tumor pathologic response after

neoadjuvant anti-PD-1 (N=20)

39% (95% CI 20-61% ) of per protocol

patients, 7 of 18, had <10% residual viable

tumor at resection

1 patient had a pathologic complete response

0 10 20 30 40 50 60 70 80 90 100

Percent Pathologic Response

Major pathologic response

Minor or no response

Neo-Adjuvant Nivolumab – WOO trial

Forde et al., ESMO 2016; Chaft et al. ASCO 2017

<10% residual viable tumor cells

defines major pathologic response per

Pataer et al. JTO 2012

Radiographic

response (N=20)

RECIST 1.1

Partial Response 2 (10%)

Stable Disease 18 (85%)

Progressive

Disease

1 (5%)

Tumor pathologic response after

neoadjuvant anti-PD-1 (N=20)

39% (95% CI 20-61% ) of per protocol

patients, 7 of 18, had <10% residual viable

tumor at resection

1 patient had a pathologic complete response

0 10 20 30 40 50 60 70 80 90 100

Percent Pathologic Response

Major pathologic response

Minor or no response

Neo-Adjuvant Nivolumab – WOO trial

Forde et al., ESMO 2016; Chaft et al. ASCO 2017

<10% residual viable tumor cells

defines major pathologic response per

Pataer et al. JTO 2012

• The future

Agenda

APC, antigen-presenting cell; CTL, cytotoxic T cell; IFN-γ, interferon gamma; M2, M2 macrophage; MDSC, myeloid derived suppressor cell; MHC, major histocompatibility complex;

PD-1, programmed death protein 1; PD-L1, programmed death ligand 1; TCR, T cell receptor; TH1, T helper 1; TIL, tumour infiltrating lymphocyte; Treg, regulatory T cell.

Teng MWL et al. Cancer Res. 2015;75(11):2139-2145.

Tumour Microenvironment Types Based on TILs and PD-L1

PD-L1+

Type I

PD-L1-

Type II

PD-L1-

Type IV

PD-L1+

Type III

EGFR mutant NSCLC

ALK rearranged NSCLC

Non–PD-1/PD-L1 suppression

pathways

Tolerance (other suppressors?)

1. Antigen recognition

MHC-peptide

IFN-γ

3. Induction of PD-L1

Blood vessel

CTL TH1

Blood vessel

Macrophage

Macrophage APC

Macrophage

Adaptive immune resistance

Immunological ignorance

Intrinsic induction

Oncogenic pathway induction

of PD-L1

TUMOUR CELLS

Tumour microenvironment across solid tumors

IV: PD-L1↓ CD8A↑

III: PD-L1↑ CD8A↓

II: PD-L1↓ CD8A ↓

I: PD-L1↑ CD8A↑

denocarc

nocort

ical cancer

inosarc

hepato

ultiform

mophobe

Pheochro

mocyto

ganglio

Uveal m

Ovaria

denocarc

l adenocarc

thelia

l carc

ast cancer

Mesoth

Pancre

atic a

denocarc

Esophageal carc

neous m

sticula

r germ

mach a

denocarc

ical cancer

Head &

neck s

Lung s

Lung a

denocarc

Ock CY et al. Clin Cancer Res. 2016;22(9):2261-2270.

Atezolizumab-treated NSCLC patient benefit

by pretreatment IFNγ mRNA signature

Fehrenbacher et al., Lancet oncol 2016

Overall survival in bTMB subgroups in OAK

BEP, biomarker-evaluable population; HR, hazard ratio; ITT, intention-to-treat.

1. Gandara DR, et al. ASCO 2017 48

Interaction P = 0.75

Months Months

bTMB ≥16 bTMB <16

Atezolizumab (N = 216) Docetaxel (N = 209)

+ Censored

Atezolizumab (N = 77) Docetaxel (N = 81)

+ Censored

• The OS benefit observed was consistent between the bTMB ≥16 population and the BEP

• This result may reflect the impact of subsequent therapies post-PD1

• Median OS for the bTMB ≥16 subgroup was 13.5 months in the atezolizumab arm

and 6.8 months in the docetaxel arm

Increasing Atezolizumab benefit with higher bTMB cut-points

in OAK Trial

BEP, biomarker-evaluable population; ITT, intention-to-treat. 49

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

CHICAGO, IL 2018

CheckMate 227

Nivolumab + Ipilimumab vs Platinum-Doublet Chemotherapy as First-line Treatment for Advanced

Non-Small Cell Lung Cancer: Initial Results From CheckMate 227

Matthew D. Hellmann,1 Tudor-Eliade Ciuleanu,2 Adam Pluzanski,3 Jong Seok Lee,4 Gregory A. Otterson,5

Clarisse Audigier-Valette,6 Elisa Minenza,7 Helena Linardou,8 Sjaak Burgers,9 Pamela Salman,10

Hossein Borghaei,11 Suresh S. Ramalingam,12 Julie Brahmer,13 Martin Reck,14 Kenneth J. O’Byrne,15

William J. Geese,16 George Green,16 Han Chang,16 Joseph Szustakowski,16 Prabhu Bhagavatheeswaran,16

Diane Healey,16 Yali Fu,16 Faith Nathan,16 Luis Paz-Ares17

1Memorial Sloan Kettering Cancer Center Hospital, New York, NY, USA; 2Prof. Dr. Ion Chiricuta Institute of Oncology and Universitatea de Medicina si Farmacie Iuliu Hatieganu, Cluj-napoca, Romania; 3Centrum Onkologii–Instytut im. Marii Sklodowskiej-Curie, Warsaw, Poland;

4Seoul National University Bundang Hospital, Seoul, South Korea; 5The Ohio State University, Columbus, OH, USA; 6Hôpital Sainte Musse, Toulon, France; 7Ospedale Santa Maria della Misericordia, Perugia, Italy; 8First Department of Oncology, Metropolitan Hospital, Athens,

Greece; 9Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands; 10Fundación Arturo López Pérez, Santiago, Chile; 11Fox Chase Cancer Center, Philadelphia, PA, USA; 12Winship Cancer Institute, Emory University, Atlanta, GA, USA; 13Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins, Baltimore, MD, USA; 14LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 15Princess Alexandra Hospital, Brisbane, QLD, Australia; 16Bristol-Myers Squibb, Princeton, NJ, USA;

17Hospital Universitario 12 de Octubre, Centro Nacional de Investigaciones Oncológicas, Universidad Complutense, & CiberOnc, Madrid, Spain

CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)

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 = 396

Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W

n = 187

Histology-based chemotherapyb

n = 186

Nivolumab 360 mg Q3W + histology-based chemotherapyb

n = 177

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

aNCT02477826 bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivolumab + pemetrexed maintenance following nivolumab + chemotherapy; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles; cThe TMB co-primary analysis was conducted in the subset of patients randomized to nivolumab + ipilimumab or chemotherapy who had evaluable TMB ≥10 mut/Mb

≥1% PD-L1 expression

Nivolumab + ipilimumab n = 396

Chemotherapyb

n = 397

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

Chemotherapyb n = 160

Patients for TMB co-primary analysisc

TMB and Tumor PD-L1 Expression Identify Distinct and Independent Populations of NSCLC

Tumor PD-L1 expression

11 aSymbols (dots) in the scatterplot may represent multiple data points, especially for patients with <1% tumor PD-L1 expression. The black line shows the relationship between TMB and PD-L1

expression as described by a linear regression model; bAmong patients in the nivolumab +ipilimumab and chemotherapy arms; TMB ≥10 mut/Mb, n = 299; TMB <10 mut/Mb, n = 380

TMB and tumor PD-L1 expressiona

PD-L1 expression (%)

0 20 40 60 80 100

TMB ≥10 mut/Mbb

TMB <10 mut/Mbb

29% ≥1%

Poor (inverse?) of correlation between TMB and PD-L1 expression

111 94 47 60 n =

Co-primary Endpoint: PFS With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)a

Nivo + ipi 139 85 66 55 36 24 11 3 0

Chemo 160 103 51 17 7 6 4 0 0

Nivo + ipi

(n = 139)

(n = 160)

Median PFS,b mo 7.2 5.4

97.5% CI

0.41, 0.81

P = 0.0002

Months

0 6 12 18 3 9 15 21 24

Chemotherapy

Nivolumab + ipilimumab

1-y PFS = 43%

1-y PFS = 13%

aPer blinded independent central review (BICR); median (range) of follow-up in the co-primary analysis population was 13.6 mo (0.4, 25.1) for nivo + ipi and 13.2 mo (0.2, 26.0) for chemo;

b95% CI: nivo + ipi (5.5, 13.2 mo), chemo (4.4, 5.8 mo); c95% CI: 0.43, 0.77 mo; dThe P-value for the treatment interaction was 0.0018

No. at risk

• In patients with TMB <10 mut/Mb treated with nivo + ipi vs chemo, the HR was 1.07 (95% CI: 0.84, 1.35)d

Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

Nivolumab +

Chemotherapy

• 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

43 36 21 14 9 5 2 0 No. at risk

48 30 16 4 1 1 1 0 Chemo

Nivo + chemo

(n = 43)

(n = 48)

Median PFS,a mo 6.2 5.3

(95% CI)

(0.35, 0.91)

Nivolumab +

chemotherapy

Months

Chemotherapy

0 6 12 18 3 9 15 21

TMB ≥10 mut/Mb and <1% Tumor PD-L1 Expression

1-y PFS = 27%

1-y PFS = 8%

Months

TMB <10 mut/Mb and <1% Tumor PD-L1 Expression

Nivo + chemo

(n = 54)

(n = 59)

Median PFS,b mo 4.7 4.7

(95% CI)

(0.57, 1.33)

0 6 12 18 3 9 15 21

1-y PFS = 18%

1-y PFS = 16%

54 38 19 13 6 3 0 0 59 39 16 6 6 3 1 0

Nivo + chemo

No. at risk

Nivo + chemo

Relevance of a specific genomic aberration on the immune landscape

Kras + LKB1 mutation LKB1 co-mutation determines the microinviroment and response to PD-1/PD-L1 agents in Kras mutant Advanced NSCLC

Skoulidis et al. Cancer Discovery 2015

& ASCO 2017

• The future

Agenda

New Combinations

ORR=30%; DCR=85%

N=34 (Non-Sq NSCLC)

ORR=29,4%

DCR=67,6%

PFS=6,9 m

N=40 (Non-Sq NSCLC)

ORR=35%

DCR=63%

PFS=6,9 m

Pembrolizumab-

Ramurizumab

Herbst R & Paz-Ares L.

ESMO 2016

Pembrolizumab-

Necitumumab

Gil M, et al. IASCL 2016

Pembro+Epacadostat

Gangadhar TC, et al.

ASCO 2017

Balance between inhibitory and stimulatory

receptors dictates T-cell activity

CDI37-L

OX40-L

CD40-L

CTLA-4

Tumour cell or APC T cell

CTLA-4

T cell targets for modulating activity

Activating

Receptors

Inhibitory

Receptors

T cell

stimulation

Agonistic

Antibodies

Blocking

Antibodies

Mellman Nature 2011; Pardoll Nat Rev Cancer 2012

CD73 and driver oncogene

• 642 resected

NSCLC tissue

microarray

• CD73 and A2AR

expression by IHC

• CD73 high

expression is more

common in EGFR

mutant protein

expression and ALK

+ NSCLC

Inoue et al Oncotarget 2017

High CD73 as poor prognostic biomarker

Inoue et al., Oncotarget 2017

Should we investigate the combination of MEDI9447 + Durvalumab in EGFR mutation

positive/T790M negative/CD73 high expression tumor after failing first line EGFR TKI?

CEA-TCB induces potent T-cell–mediated killing of tumor cells, with enhanced activity in combination with atezolizumab

Commensal microbiota: Bifidobacterium species

can improve anti-tumor immunity and response to

anti-PD-L1 antibody in vivo

Get Cold Tumors Inflammed

Microbiota

Sivan et al., Science 2015

Patients who had received antibiotics showed decreased PFS and OS following anti-PD-1/PD-L1 treatment

Derosa et al., Science 2018

Targeting CD19+ CLL with CAR-Modified T cells

• Gene transfer (lentiviral

vector) to stably express

CAR on T cells confers

novel antigen specificity

• CAR modified T cells can

now recognize and kill

CD19+ cells

CAR, chimeric antigen receptor; TCR, T-cell receptor.

Lentiviral vector

T cell

Native TCR

Tumor cell

CTL019 cell

Dead tumor cell

Anti-CD19

CAR construct

Blank CU et al. Science 2016; 352:658

Conclusions

• We are at the beginning of the IO revolution in lung cancer

• PD-1/PD-L1 inhibitors have proven a role on the treatment of advanced

tumors

• Pretreated: Nivo, Atezo, Pembro (PD-L1 +)

• Front-line:

• Pembro Monotherapy (PD-L1 high) & combo with chemo (all comers)

• Following Chemo-radiation (Stage III): Durva

• New options and combinations of IO are in the horizon (IO-IO, …)

• Personalized strategies for IO therapeutics will be developed

Gracias

lpazaresr@seom.org

clinical development of lung cancer...

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