Presentación de PowerPoint · Cómo seleccionar inmuno vs no inmuno en 2º linea? CHECKMATE 057 :...

Inmunoterapia de segunda línea: largos supervivientes. Biomarcadores y posibles

pautas de selección

Dr. Manuel Cobo, Hospital Regional Universitario de Málaga

Versteven M, Van den Bergh JMJ, Marcq E, et al. Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer. Front Immunol. 2018 Mar 1;9:394

Immunocheckpoints act far beyond the simple synapse Teffector- Tumor cell

Clinical trials in patients previously treated: NIVOLUMAB

Nivolumab – CheckMate 017 (PIII)1

2nd Line, squamous, PD-L1 All-Comer

Nivolumab – CheckMate 057 (PIII)2

2nd Line, non-squamous, PD-L1 All-Comer

1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

Borghaei et al., 2016, ASCO.1Time (Months)

100

80

60

40

20

00 6 30

OS

(%)

1812 24 36

NivolumabDocetaxel

Checkmate 017 (SQ)1

Time (Months)

2-yr OS = 23%2-yr OS = 8%

NivolumabDocetaxel

100

80

60

40

20

00 6 30

OS

(%)

1812 24 36

Checkmate 057 (NSQ)1

2-yr OS = 29%2-yr OS = 16%

5-Year Estimates of OSa

CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

5

Median OS (95% CI), mo

Overall (N = 129) 9.9 (7.8, 12.4)

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8

129 49 27 20 17 16 3 1 0

YearsNo. at Risk

OS

(%)

1 y OS, 42%

2 y OS, 24%

3 y OS, 18% 5 y OS, 16%

aThere were 3 deaths between 3 and 5 years, all due to disease progression; 1 surviving patient was censored for OS prior to 5 years (OS: 58.2+ months)

Pembrolizumab - Keynote 010 (PII/III)3

2nd+ Line, PD-L1 TPS ≥1%

1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

Herbst et al., 2017, ASCO.3Time (Months)

100

80

60

40

20

00 5 10 15 20 25 30 35

OS

(%)

Pembro 2 mg/kgPembro 10 mg/kgDocetaxel

KEYNOTE-010 (≥1% PD-L1)3

30-mo OS = 29.5%30-mo OS = 22.1%30-mo OS = 12.3%

Clinical trials in patients previously treated: Pembrozilumab

Phase III OAK study design

Atezolizumab 1200 mg IV q3w

PD or loss of clinical benefit

Docetaxel 75 mg/m2 q3w

Locally Advanced or Metastatic NSCLC

• 1–2 prior lines of chemo including at least 1 platinum based

• Any PD-L1 status

N = 1,225 enrolleda

PD

R

1:1

Stratification factors• PD-L1 expression

• Histology

• Prior chemotherapy regimens

Primary Endpoints (first 850 enrolled patients):

• OS in the ITT population

• OS in patients with PD-L1 expression on ≥ 1% TC or IC

Secondary Endpoints: ORR, PFS, DoR, Safety

aA prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression). TC, tumor cells; IC, tumor-infiltrating immune cells.

• Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh

Fehrenbacher L, et al. JTO 2018

En el total de los pacientes (1220 pts), Atezolizumab sigue beneficio en SG frente a docetaxel

•Landmark 2-year overall survival in OAK phase III trial.

Atezolizumab vs docetaxel

•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, 2017.•Satouchi, et al. IASLC Tokio 2017

Overall survival (OS) in ITT850• 1–2 prior lines of chemo including at least 1 platinum based

• Any histology

• PDL! Determinates with SP142

Atezolizumab tiene beneficio en SG a largo plazo, con 31 % de pts supervivientes a dos años

• Long-term survival with atezolizumab is associated with extended treatment duration and

is not limited to radiographic responders

•Treatment duration and time to response/progression in

atezolizumab LTS

•Data cutoff: 23 January, 2017.

•Satouchi, et al. WCLC 2017

Be

st R

esp

on

se

TBP in Atezolizumab Arm: By Type of Post-PD Treatment

Gandara DR et al. OAK: Atezolizumab treatment beyond disease progression.

Data cutoff: 7 July, 2016.

18-mo OS

37%

20%

9%

12.7 mo (9.3, 14.9)

8.8 mo (6.0, 12.1)

2.2 mo (1.9, 3.4)

mOS 95% CI

Presented By Solange Peters at 2018 ASCO Annual Meeting

IASLC 2016

Pero, y tras dos años??????

5-Year Estimates of OS <br />Phase 1 nivolumab

Presented By Solange Peters at 2018 ASCO Annual Meeting

Inmunoterapia ca pulmon avanzado Segunda línea para todos los

pacientes ??

Cómo seleccionar inmuno vs no inmuno en 2º linea?

12-month OS

Nivo (n=292) Doc (n=290)

mPFS, months 2.3 4.2

1-year PFS rate, % 19 8HR (95%CI) 0.92 (0.77, 1.11)

p=0.39

CURVESCROSSED

DELAYEDSEPARATION

Borghoei H, et al. NEJM 2015.

CHECKMATE 057 Adenocarcinoma pts: PFS & OS

OS by prespecified PD-L1 expression levels, ITT population (secondary endpoint) after additional follow-up

Secondary endpoint: OS by PD-L1 expression level

18• CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PD-L1, programmed death-ligand 1.

• Borghaei H, et al. N Engl J Med 2015;373:1627–39.

OAK. Atezolizumab vs docetaxel


pacientes ??

Mejores biomarcadores de selección?

Carbone. IASLC 2015

The next frontier: utilising immune profilingfor a patient-driven approach

Adapted from Chen and Mellman. Immunity 2013; Hegde, et al. Clin Cancer Res 2016; Kim and Chen. Ann Oncol 2016; Chen, Herbst et al Nature 2014, and Mellman. Nature 2017

Each immune phenotype requires a personalised immunotherapy approach

to initiate/re-initiate the antitumour immune response

IMMUNE DESERTIMMUNE EXCLUDEDINFLAMED

GENERATEactive, tumour-directed T cells

INFILTRATEtumour

KILLtumour

Essential T cell activity required

Pt CD8+ Density, Invasive Margin Before Treatment

Predicted Probability of Response

Blinded Prediction Clinical Response (RECIST1.1)

1 58 0.35 Progression Progression




5 2120 0.75 Response Stable

6 5466 0.98 Response Progression

7 2211 0.76 Response Response






13 5951 0.99 Response Complete response



Lo ideal:la densidad de infiltración de LT8 junto con expresión de PD-L1

P. C. Tumeh et al., Nature 2014; 515,:568 -71.

La densidad de LT CD8 en el margen de invasión del tumor fue mucho más predictiva de beneficio a Pembrolizumab

que PD-L1. .- Este dato sugiere que expresión de PD-L1 en el tumor es más poderoso como biomarcador cuando se

observa en el contexto de una respuesta de cel T activos.

Types of alterations<br />

Mark Burkard at 2018 ASCO

Tipos de alteraciones genéticas detectadas en NGS

Xiaoliang Wu at ASCO 2018

Chan et al. 2018 ASCO 2018

Novel Clinical Trials: A multi-disciplinary approach to understand response and resistance

Herbs RS. IASLC Tokio 2017

Joshi at 2018 ASCO 2018

¿ Es ya hora de secuenciar Linfocitos y tomar decisiones según la hiperclonalidad de los TCR ??

1 pixel = 0.5 µM

PD-1/PD-L1 INTERACTION SCORE

PD

-L1

PD

-1 C

K D

AP

I

Interaction Score: 4078

Interaction Score: 188

Quantitative Spatial Profiling of PD-1/PD-L1:La interacción PD1-PDL1 captada con esta tecnología y haciendo un “SCORE”Este sería sin duda el biomarcador ideal para una terapia anti Pd1-Pdl1

Vamsidhar Velcheti. IASLC Tokio 2017

identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but

also many new surface receptors. Two new co-inhibitory receptors, activated protein C receptor (PROCR) and

podoplanin (PDPN). co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is

shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module.

Secuenciación Linfocitos usando expresión RNA y proteinas: co-inhibitory receptors

Chihara, et al. Nature. 2018 .Induction and transcriptional regulation of the co-inhibitory gene module in T cells

HAY más checkpoints inhibitoriosAparte de los ya conocios

https://www.ncbi.nlm.nih.gov/pubmed/29899446


pacientes ??

Cómo seleccionar inmuno vs no inmuno en 2º linea?

CHECKMATE 057 : Risk of early death (EPAR)Kaplan-Meier Plot of Overall Survival

European Public Assessment Report , EMA/246304/2016, page 27

Nivolumab 20% early death % vs 15% Docetaxel % at 3 months

CHECKMATE 057 : Waterfall Plots ORR

More and deeper responses with Nivolumab

BUT

Also more and stronger progressions

Borghoei H, et al. NEJM 2015 (Appendix pag. 41-42 )

3-Month Landmark Analysis of OS CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

Nivo(n = 232)

Doc (n = 244)

Median OS, mo

17.4 11.3

Events, n 131 179

HR (95% CI) 0.59 (0.47, 0.74)

Alive at 3 Months − All Patients

ITT Population1

Nivo(n = 292)

Doc (n = 290)

Median OS, mo

12.2 9.4

Events, n 190 223

HR (96% CI) 0.73 (0.59, 0.89)

Based on a March 18, 2015 database lock1. Borghaei H, et al. N Engl J Med 2015;373:1627–1639.

Nivolumab

Docetaxel

OS

(%)

Months

100

90

80

70

60

50

40

30

10

0

20

27211815129630 24

Months

100

90

80

70

60

50

40

30

10

0

20

27211815129630 24

Nivo(n = 82)

Doc(n = 87)

Median OS, mo

14.7 11.4

Events, n 51 62

HR (95% CI) 0.66 (0.45, 0.97)

Alive at 3 Months –Patients With <1% PD-L1 Expression

Months

100

90

80

70

60

50

40

30

10

0

20

27211815129630 24

Definitions & Frequencies

Hiperprogresion

TAC 9-2016(basal)

TAC 11-2016

Aumento lesión +Nódulo satélite

1º evaluación

Aumento de dolor

15-3-2017

TAC 11-2016

PD-L1 local SP 263 < 1%. Se opta por ensayo clínico atezolizumab vs atezolizumab + daratumumab (antiCD38) ( le toca brazo brazo cominación)

27-7-2017

1º evaluación

Progresión recist 1.1

10-10-2017

PD-L1 local SP 263 < 1%. Se opta por ensayo clínico atezolizumab vs atezolizumab + daratumumab (antiCD38) . Se opta por seguir mismo tratamiento y esperar próxima evaluación

2º evaluación

Remisión Parcial

10-10-2017

27-7-201729-11-2017

Predicting hyperprogression

En células Tumorales también hay PD1La conexión PD1-PDL1 inhibe la proliferación en el tumorUn Ac monoclonal antiPD1 podría acelerar el crecimiento del tumor al estimularLa proliferación mediada por la vía PI3K

Ludin, A. Nature 2017

En el modelo in vitro, Aumento viabilidadCelular tras bloqueo con AC antiPD1Disminución crecimiento celular con PD-L1recombinante

En el modelo in vivo, Tumores “inflamados”, la célula tumoral no suele expresar PD1. La terapia inmune: eficaz. Tumores fríos que expresan PD1 en cel tumoral: la terapia inmune produce crecimiento del TUMOR

Inmunoterapia en 2º línea CPNM avanzado con mutación de EGFR: menos eficacia respecto a docetaxel que pts sin mutación

*Data for the pembrolizumab doses were pooled.

CheckMate 057

KEYNOTE-010*

OAK

Nivolumab Docetaxel

Pembrolizumab Docetaxel

Atezolizumab Docetaxel

References in slidenotes.

Pts,

n

Unstratified HR

(95% CI)

82 1.18 (0.69-2.00)

340 0.66 (0.51-0.86)

160 0.74 (0.51-1.06)

Events/Pts, n/N

HR (95% CI)

46/860.88 (0.45-

1.70)

447/8750.66 (0.55-

0.80)

Pts, n (%)

HR (95% CI)

85 (10)1.24 (0.71-

2.18)628 (74)

0.69 (0.57-0.83)

Mutant

Not detected

Not reported

MutantWild type

MutantWild type

1.00.5 2.00.25 4.0

1.00.1 10

1.00.2 2

PDL1 es un factor predictivo que actúa como variable continua: a mayor nivel

de expresión, mayor eficacia de terapias anti PD1 /PDL1

Pero en el intervalo entre PD-L1 1-49, es realmente tan impactante la

variabilidad ?

OS hazard ratios by baseline PD-L1 expression level

51• CI, confidence interval; OS, overall survival; PD-L1, programmed death-ligand 1.

• Opdivo-H-C-3985-II-0002: EPAR – Assessment Report – Variation. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/003985/WC500205973.pdf Accessed 30 January 2017.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/003985/WC500205973.pdf

Kaplan-Meier Plot of Overall Survival by PD-L1 Expression (1 and 10%)


Nivel expresión PDL-1& riesgo muerte precoz

CHECKMATE 057 : Risk of early death (EPAR)

Con PDL1 <1% (negativo), a los 3 m de tto:10% mueren con dctx y 25% con nivolumab (aprox)

Con PDL1 <10%, a los 3 m de tto:12% mueren con dctx y 30% con nivolumab (aprox)

KEYNOTE-001: Efficacy Results

≤1% 1-49% ≥50%

OAK: OS by PD-L1 EXpression

In favor ofdocetaxel

Hazard Ratioa

In favor of atezolizumab

Subgroup

Median OS, moAtezolizumab Docetaxel

n = 425 n = 425

0.2 1 2

TC1/2/3 or IC1/2/3a

TC0 and IC0

ITTa

TC3 or IC3

TC2/3 or IC2/3

13.8 9.6

12.6 8.9

15.7 10.3

16.3 10.8

20.5 8.90.41

0.67

0.74

0.75

0.73

45%

On-study Prevalence

• Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh

16%

31%

55%

100%

TC3 or IC316%

TC2/3 or

IC2/331%

TC1/2/3 or

IC1/2/354%

TC0 and IC045%

Respuesta al tratamiento de primera línea

Intervalo libre progresión del tratamiento 1º línea: tiempo desde inicio 1º línea hasta la necesidad de comenzar nueva línea terapéutica

CHECKMATE 057: OS SUBGROUP ANALYSIS

Borghoei H, et al. NEJM 2015.

CheckMate 057

1st line therapy

Stop 1st lineTherapy

<3 mo, 3-6 mo and >6 mo

Which Is More Important, Choosing Patients Who Will Respond or Identifying Those Who Will Die Early?

Ramos I et al. WCLC 2018 (poster 8300)

0

5

10

15

20

25

30

35

≤4cycles >4cycles

NumberofcyclesofNivolumab

NumberofcyclesofNivolumab

n=22

n=27

Table1-BaselineCharacteristics AllPatients:49 *Rapidsprogressors:22 NonRapids

Progressors:27p-value

Maleno.(%)Femaleno.(%)

36(73,5)13(26,5)

18(81,81)4(18,19) 18(66,66)9(33,3)

0,594

Age-yr(Median,range)Age>75years(%)

62,8(44-77)

8,16

60,9(44-77)

4,54

65,0(48-78)

11,1

0,685

ECOG(%)0-12

91,18,9

90,919,09

92,67,4

0,611

Smokingstatus%-Currentorformer

smokers-NeverSmoked

Cumulativetobaccoconsumption,≥40Tobacco

packs

87,8

10,2

46,9

901040

86,2

3,8

55,6

0,723

0,472

Co-morbidity(%)-Yes-No

40,859,2

38,0961,9

6337

0,407

Histology:-Adenocarcinoma

-Squamous-NSCLCNOS

32,753,112,2

355510

33,351,914,8

0,666

Metastaticlocalitation%-SNC

-Hepatic-Bone

20,416,320,4

19,0433,3342,86

22,211,114,8

0,481

No.ofpriorsystemicregimens(%):

-1-2

-3ormore

69,418,412,2

63,6323,809,5

74,114,811,1

0,959

Bestresponsetomostrecentpriorsystemic-%-Completeorparcial

respones-Stabledisease

-Progressivedisease-UnKnown

30,6

20,416,332,7

19,04

38,0942,854,5

40,7

14,833,311,1

0,059

Timefrompriorchemotherapy(Mean-

Median,days)

329,23-239,0

179,05–163,0

440,48–324,0

0,002

*Rapidprogressors:patientswhohavereceived4cyclesorless

StatisticalanalysesusingthePearson’schi-squaretest,Fisher’sexacttest,andstudent’st-testwereusedtoevaluatetheclinicalcharacteristicsassociatedwiththeefficacyofNivolumab.

Which Is More Important, Choosing Patients Who Will Respond or Identifying Those Who Will Die Early?

Fig.1.Kaplan-Meier survival curveofPFSforpatients who received Nivolumabtreatment

Fig.2.Kaplan-Meier survival curveofOSforpatienss whoreceived Nivolumab treatment

Fig.3.Kaplan-Meier survival curveofPFSaccording to time from prior chemoherapy

(< 6 months vs ≥ 6 months)

Fig.4.Kaplan-Meier survival curveofPFSaccording to time from prior chemoherapy

(< 6 months vs ≥ 6 months)

Ramos I et al. WCLC 2018 (poster 8300)

Further multivariate analyses related to risk of early death


Associations found with

1. PD-L1 expression level (e.g. <1%, <5%, <10%, <50%) and ECOG score (e.g. ECOG PS 1)

2. time since last treatment < 3 months

3. progressive disease as best response to last treatment

Carga tumoral.

Crecimiento rápido: Tiempo duplicación

Mc Farlane F, et al. Bull Math Biol. 4 March 2018

Modelo matemático ratio control proliferacón Cel Tumorales en consonancia con cel inmunitarias

Walker R, et al. Sci Rep. 2018 Jun 21;8(1):9474. Immune interconnectivity of anatomically distant tumors as a potential mediator of systemic responses to local therapy.

El aumento de carga tumoral e incremento de nº de lesiones: menos beneficio de inmunoterapia.Debido a la hiperdiversificación en la distribución de linfocitos con diferentes TCR no compartidos.Y además depende del índice de reclutamiento linfocitario y la ratio de crecimiento de cada lesión


El aumento de carga tumoral e incremento de nº de lesiones: menos beneficio de inmunoterapia.Debido a la hiperdiversificación en la distribución de linfocitos con diferentes TCR no compartidos.Y además depende del índice de reclutamiento linfocitario y la ratio de crecimiento de cada lesión

Varias localizaciones con igual patrón de crecimiento: Si la localización B tiene mayor índice de reclutamiento de linfocitos que localización A, se evidenciará un incremento del crecimiento del tumor de localización A


Sin tratamiento sistémico. Al resecar una lesión tumoral, decrece el crecimiento de la lesión no resecada, y además aumenta el componente de infiltración de células inmunes

PD-L1 < 1%

Expresión PD-L1

PD-L1 1-49% PD-L1 % > 49%

Progresión rápidaDurante 1º línea

Quimioterapia/Quimio-antiangiog Inmunoterapia

PD-L1 < 1%

Expresión PD-L1

PD-L1 1-49%


Quimioterapia óQuimio-antiangiog

Progresión antesDe 3 meses de ultimaDosis de platino

Progresión despuésDe 3 meses de ultimaDosis de platino

Alta cargaTumoral /Progresiónrápida

Baja cargatumoral

Inmunoterapia

PD-L1 1-10% PD-L1 >10%

Baja cargatumoral

Inmunoterapia /Quimio o quimio +antiangiogénicos

Alta cargaTumoral +Progresiónrápida

Quimioterapia óQuimio-antiangiog /Inmunoterapia

Alta cargaTumoral +Progresiónlenta

Inmunoterapia


Quimioterapia óQuimio-antiangiog /inmunoterapia

Progresión antesDe 3 meses de ultimaDosis de platino

Progresión despuésDe 3 meses de ultimaDosis de platino

Alta cargaTumoral /Progresiónrápida

Baja cargatumoral

Inmunoterapia

Baja cargatumoral

Inmunoterapia

Alta cargaTumoral +Progresiónrápida

Inmunoterapia /Quimioterapia óQuimio-antiangiog

Alta cargaTumoral +Progresiónlenta

Inmunoterapia

• The tumor microenvironment contains various immunosuppressive factors from different sources that tumors use as defense mechanisms against the immune system – selected examples are shown

Secreción de factores inmunosupresores

Factor Sourceb Effectb

Transforming growth factor-β Tumor cells, Tregs, and MDSC Suppressive effects on T cells, NK cells, and APCs

IL-10 Tumor cells, tumor-associated macrophages, and TregsDownregulates expression of some co-stimulatory molecules and MHC

VEGFTumor cells and other associated cells

Inhibits DC function

Prostaglandin E24 Tumor cells, tumor-associated macrophages and fibroblasts, other inflammatory cells

Promotes MDSC and Treg development and function; suppresses DC function and antitumor T and NK cell responses

Arginase6 MDSCs, tumor cellsMetabolizes and prevents T cell access to the amino acid arginine; this inhibits T-cell proliferation and global protein synthesis

IDO7 Tumor cells, DCs, fibroblastsMetabolizes tryptophan, inhibiting T-cell proliferation and function and expanding local Treg populations

Adenosine9 Hypoxic tumor cells T-cell suppression and Treg expansion, tumor growth and angiogenesis

iNOS MDSCs MDSC induction, tumor angiogenesis

aInclude enzymes that produce

immunosuppressive factors. bMain

source(s) and key immune effects are

indicated; many factors have multiple

sources and overlapping effects.

IDO = indoleamine 2,3-dioxygenase; iNOS

= inducible nitric oxide synthase; MDSC =

myeloid-derived suppressor cell; VEGF =

vascular endothelial growth factor.1.

Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol 2016;27(8):1492-504.

Palucka AK, Coussens LM. The Basis of Oncoimmunology. Cell 2016;164:1233-47.

Reguladores intrínsecos

Reguladores extrínsecos

Microambiente tumoral

Presentación antigénica

. La adenosina (que es generada por la conversión de ATP gracias a ecto-nucleotidasas CD39 y CD73), inh actividad y expansión de células T a través del receptor de adenosina A2A. Ac que inhiben CD73, aumenta la actividad de anti-PD1

S. Aspeslagh. ANN ONCOL FEB 2018.

Epigenetic modifiers as new immunomodulatory therapies in solid tumours

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