Cáncer de Pulmón Avanzado Futuro del Tratamiento · 2015-05-08 · Cáncer de Pulmón Avanzado...

Cáncer de Pulmón Avanzado Futuro del Tratamiento

L. Paz-AresHospital Universitario Doce de Octubre,

Madrid, Spain

Temas1.- Medicina Personalizada2.- Agentes dirigidos a DIANAS Específicas3.- INMUNOterapia4.- Desarrollo de nuevos fármacos y EECC

• Multidisciplinary teams

• Uncovering of molecular aberrations

– Novel targets

– Predictive biomarkers

• Technology acquisition

– Tumor profiling

– Effective targeting

Drivers of Lung Cancer treatment Evolution

Magnitude of Genomic Derangement is greatest in Lung Cancer

From The Cancer Genome Atlas Project: Govindan R. J Clin Oncol. 2012 (Proc ASCO Annual Meeting);30 (suppl): abstr 7006.

1 / Mb

10 / Mb

100 / Mb

0.1 / Mb

81 64 38 316 100 17 82 28n=109 119 21 40 20

Hematologic & Childhood Cancers

Carcinogen-induced Cancers

??

Aden

oca

Squa

mou

s

Ovarian, Breast, Prostate Cancers

MutationsPer Mb DNA

Oncogenic Drivers &Targeted Therapy

Kris et al., JAMA 2015.

Tumor Profiling EvolutionThe Example of NGS

ØClinical implementation of precision oncologyØDealing with tumor heterogeneity and resistance ØPrioritizing targets ØLow frequency aberrations - innovative trials ØPredictive biomarkers for immune-based therapiesØDrug combinations: emerging and limiting toxicities

Some Challenges

• Expert teams • Tumor matherial• Technology• Bioinformatics• Adequate time-frame• Quality assurance programs• Link to a innovative clinical trials program

Clinical Implementation

Presented By Sameek Roychowdhury at 2015 ASCO Annual Meeting

11ORAL 16.07 – Q Zhang

Cancer Research UK

Stratified Medicine Program


Cancer Research UK

Stratified Medicine Program

Plataforma de Biomarcadores en Cáncer SEAP-SEOM 16

WP1

: Coo

rdin

aon

, Gen

omic

s and

Bio

info

rma

cs

WP3: Biomarkers in exosomes

WP4: Valida on in clinical cohorts

WP5: Implementa on of new technologies

WP6: Na onal pla orm

Research Ins tutes/Groups

Groups: 7, 1, 3, 4, 9, 12, 13

Groups: 10, 1, 11, 12, 13

Groups: 2, 1, 5, 6, 7, 8, 10,

11, 12, 13

Groups: 5, 1, 2, 4, 6, 7, 8,

9, 10, 11, 12

Groups: 6, 1, 2, 4, 5, 7, 8, 10,

11, 12, 13

Gro

up

s: 1

, 4,

5, 6

, 7,

10, 1

2

PIE 2015 – L Paz-Ares (IP)

Intratumor Heterogeneity of EGFR Activating Mutations

Nested-PCR efficiency and allele drop-out rate in single H1975 cells

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

nested-PCR efficiency allele drop-out rate

96.2%

7.0%

► 104 single H1975 cells were isolated to analyse EGFR 21 exon L858R mutation.

► The efficiency of nested PCR showed 96.2% (100/104) detected by 2% agarose gel electrophoresis.

► According to the result of derectsequence, 4 cells showed L858R homogeneous mutation instead of heterogeous mutation and 3 cells showed wild type, which meant the rate of allele drop-out (ADO) was only 7.0%(7/100).

ORAL 16.07 – Q Zhang

The clinicopathologic feature of six patients

Patient HistologyEGFRstatus

TKI treatment

stage

TKI-PFS（months）

Best response

3647 adenocarcinoma L858R First-line 19 PR

2715 adenocarcinoma L858R Second-line 22 SD

4128 adenocarcinoma L858R Second-line 15 PR

3669 adenocarcinoma L858R First-line 5 SD

1813 adenocarcinoma L858R Second-line 3 PD

Group A:PFS>14

Group B:PFS<6


0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

nested-PCR efficiency mutational rate

Group AGroup B

The efficiency of single-cell nested PCR and EGFRmutational rate of EGFR-21exon between two groups

84.3%

93.8%86.4%

68.9%• The intratumoral heterogeneity of

EGFR activating mutation in lungadenocarcinoma does exist basedon the analysis in single cancercells and the abundance of EGFRactivating mutation is relevant tothe benefit from EGFR-TKIstreatment.

P=0.077 P=0.021


Targeted AgentsNuevas dianas y conceptos

Nuevos tratamientos sin biomarcador

Nuevos análogos (de inhibidores)

DLL3 is a dominant inhibitor of Notch signaling

• Normally expressed during development in the Golgi

• Aberrantly expressed in SCLC tumor-initiating cells

• Interacts with and inhibits Notch1 in cis

• May mediate Notch inhibition downstream of ASCL1

Kume et al., J Angiogen Res 2009

Drug-to-Antibody Ratio (DAR) = 2

Cathepsin-B Cleavable Linker

PBD Dimer Toxin

Rovaltizumab: best response data in evaluable patients 0.2 mg/kg q3w and 0.3 mg/kg q6w cohorts

* LCNEC-60

-40

-20

0

20

40

60

80

Be

st

Re

spo

nse

(RE

CIS

T)

**

*

*

***

• 20% ORR• 57% Anti-Tumor Activity• 70% Clinical Benefit Rate

-60

-40

-20

0

20

40

Be

st

Re

sp

on

se

(RE

CIS

T)

• 39% ORR• 71% Anti-Tumor Activity• 75% Clinical Benefit Rate^

DLL3+ = H-score ≥ 180 on scale of 300

evaluable DLL3+ patients (n=28)

All patients (n=60)

NSCLC Models with Activated KRAS

B. Human Xenograft NSCLC Model

Abemaciclib mesylate dose:KRAS Status

H212

2

H838

H441

H358

A549

H143

7

H197

5

H23

H460

H222

8

H165

0

H522

H661

IC50 (µM) 0.17

0.44

0.60

0.61

0.65

0.81

1.68

2.02

2.36

3.41

5.25

5.54

7.86

KRAS (G12) Activation Y N Y Y Y N N Y N N N N NCDKN2A Loss Y Y N N Y Y Y N Y Y Y N Y

RB Loss N N N N N N N N N N N N NMean = 0.61µM

Mean = 2.4µM

A. Growth Inhibition in vitro @ 96 Hours

Monotherapy Phase I trialBest Response NSCLC Cohort

Each bar represents one evaluable patient

% C

hang

e fr

om

Bas

elin

e

80

60

40

20

0

-20

-40

-60

-80

-100

Disease Control Rate (DCR=CR + PR + SD)

All NSCLC (n=57) = 49.1% KRAS Mutanta (n=29) = 55.2%

KRAS Wild-typea (n=24) = 37.5%

† SQ SQ SQ

SQ

Goldman et al. ASCO 2015

Kim et al. ASCO 2015

Abemaciclib Combos in NSCLCPhase I results

Sequist L et al. J Clin Oncol 2010

3 best responses (by far) with neratinib in patients

with exon 18 mut+

Yang CH et al. Lancet Oncol 2015

Afatinib

EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Sensitivity to Afatinib or Neratinib but Not to Other EGFR-TKIs

Kobayashi Y et al. ORAL 03.01

Philip J et al. ORAL 03.02

Type of exon 20 mutation

Proportion of pts(n=20)

Median OS mos. (range)

S768I 7 (35%) 6.0 ( 0-16.3)

INSGGT 4 (20%) 12.0 (0.2-23.98)

INS9 5 (25%) 2.0 (1.1-2.9)

T790M 4 (20%) 5.0 ( 1.2-8.8)

Is EGFR Exon20 Mutation a Prognostic/Predictive Biomarker in Our Lung Cancer Patients?

Yang CH et al. Lancet Oncol 2015

Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions

Piotrowska Z et al. MINI 30.06

• AUY922 is a Heat Shock Protein 90 (Hsp90) inhibitor • The starting dose of AUY922 was 70 mg/m2 IV weekly for all patients• 21 patients with EGFR in20 were treated• Toxicities: grade 1-2 visual changes (86%), diarrhea (86%), fatigue (71%); grade 3

hypertension (1%), and AST elevation (0.5%)• ORR 24%• Median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7)

CNS efficacy of Next generation ALK inhibitors in Crizotinib Pre-treated patients

Drug Reference N Dose CNS activityORR PFS

G3/4 Side effect

Ceritinib Liu G ORAL 33.02

Phase I (N=163/246)

50-750 mg 18% ORR(n=75)

* 44% crizotinib naïve

6.9m Diarrhea 5.9%, Nausea 5.9%, Vomiting 5.9%

ASCEND-2(N=140)

750 mg 39.4% ORR(n=33)

*58.8% crizotinib naïve

5.4m Diarrhea 6.4%, Nausea 6.4%, Vomiting 4.3%ALT elevation 17.1%

Alectinib Gadgel S ORAL 33.05

Pooled analysis(n=136/225)

600 mg bid 64% ORR(n=50)

DOR 10.8m

Rash 2%Neutropenia 4%

Brigatinib Gettinger SNORAL 33.06

Phase I/II(N=65/137)

30-300 mg 53% ORR(n=15)

DOR18.9 m

pulmonary symptoms 9%

Lorlatinib Bauer TM ORAL 33.07

Phase I(n=30/50)

10-400 mg 33% ORR(n=30)

DOR NA

Hypercholesterolemia 10%Hypertriglyceridemia 4%CNS effects 2%

Intratumor Heterogeneity of EGFR Activating Mutations

Nested-PCR efficiency and allele drop-out rate in single H1975 cells

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

nested-PCR efficiency allele drop-out rate

96.2%

7.0%

► 104 single H1975 cells were isolated to analyse EGFR 21 exon L858R mutation.

► The efficiency of nested PCR showed 96.2% (100/104) detected by 2% agarose gel electrophoresis.

► According to the result of derectsequence, 4 cells showed L858R homogeneous mutation instead of heterogeous mutation and 3 cells showed wild type, which meant the rate of allele drop-out (ADO) was only 7.0%(7/100).


Mechanisms of acquired resistance to AZD9291 in EGFR T790M positive lung cancer

Geoffrey R. Oxnard1, Kenneth S. Thress2, Cloud P. Paweletz1, Daniel Stetson2,

Brian Dougherty2, Zhongwu Lai2, Aleksandra Markovets2, Enriqueta Felip3, Ana Vivancos3, Yanan Kuang1, Lynette Sholl4, Amanda J. Redig1,

Mireille Cantarini5, J. Carl Barrett2, Rathi N. Pillai6, Byoung Chul Cho7, David Planchard8, Jean-Charles Soria8, Pasi A. Jänne1

1Dana-Farber Cancer Institute, Boston, MA, USA; 2AstraZeneca, Gatehouse Park, Waltham, MA, USA;3Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain;

4Brigham and Women’s Hospital, Boston, MA, USA; 5AstraZeneca, Alderley Park, Macclesfield, UK;6Winship Cancer Institute, Emory University, Atlanta, GA, USA;

7Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea;8Gustave Roussy, Paris, France

Oral 17.07 – GR Oxnard

EGFR mutant lung cancer – T. Mitsudomi

Results: C797Sn 67 patients met the following two eligibility criteria for acquired resistance analysis:

l T790M positive on plasma or tumor genotypingat enrollment

l Detectable EGFR-TKI-sensitizing mutation in plasma at progression on AZD9291

nOf those, 15 (22%) had detectable C797S onddPCR, all with detectable T790M

nC797S was more common with EGFR exon 19 del (13/43, 30%) vs those with L858R(2/24, 8%, p=0.06)



Results: T790M loss

n32 of 67 (48%) had no detectable T790M in plasma despite presence of the EGFR-TKI-sensitizing mutation, suggesting overgrowth of an alternate resistance mechanism

Data source: G. Oxnard, C. Paweletz, R. Alden, K. ThressOral 17.07 – GR Oxnard


Results: HER2 amplificationn15 cases completed plasma NGS after

resistance to AZD9291 (4 showing C797S)nOne patient treated at 80 mg had an initial

unconfirmed PR (-38%) followed by new liver metastasisnWhole genome sequencing of resistance

cfDNA found high level HER2 amplificationBaseline 12 weeks

(PD) 21 weeks

(off tx)

L858R 85% 79% 82%

T790M 42% 0% 1%

EGFR CNV 6 5 6

ERBB2 CNV 6 11 32

Chromosome 17

log2

Rat

io

3 Mb region on chromosome 17

log2

Rat

io

HER2

NEUROD2, PPP1R1B, STARD3, TCAP, PNMT, PGAP3,

ERBB2, MIR4728, MIEN1, GRB7, IKZF3, ZPBP2

21 weeks

12 weeks (PD)

Baseline

Data source: D. Stetson, A. Markovets, B. Dougherty, Z. Lai, C. Barrett, K. ThressCNV, copy number variation; PD, progressive disease; PR, partial response; tx, treatment



Results: MET amplificationn 69-year-old female with EGFR-mutant NSCLC metastatic to liver, adrenal, bones who had progression after first-

line chemotherapy and subsequent erlotinib

n Resistance biopsy was inadequate for genotyping, but plasma genotyping positive for L858R (26%) and T790M (4%)

n Initiated AZD9291 and responded on the first scan (-40%) but progressed after 24 weeks

n Resistance biopsy undergone for targeted NGS:

l Positive for L858R, negative for T790M, positive for MET amplification

l MET protein overexpression also seen on IHC

Pre-AZD9291plasma genotype:

L858R (26%)T790M (4%)

4 months

Progressiontumor genotype:

L858RT790M negativeMET amplified

6 monthsBaseline



Results: BRAF V600En 49-year-old male with metastatic NSCLC positive for EGFR exon 19 deletion

n Developed resistance to first-line erlotinib after 11 months, T790M positive biopsy

n Had a confirmed PR to AZD9291 but growth of lung mass, effusion after 5 months

n Targeted NGS of progression biopsy shows exon 19 deletion (8% of reads), no T790M, BRAF V600E (6% of reads)l A patient-derived xenograft is in developmentPre-AZD9291

Ex19del/T790M2 months 6 months

Ex19del/BRAF V600E PDX genotype by PCR

Data source: P.A. Jänne, A.J. RedigOral 17.07 – GR Oxnard

39

Long-Hua Guo, Xu-Chao Zhang, Zhi-Hong Chen, Jian Su, Jin-Ji Yang, Chong-Rui Xu, Zhi Xie, Wei-Bang Guo, Hong-

Hong Yan, Xue-Ning Yang, Wen-Zhao Zhong, Qiu-Yi Zhang, Yi-Long Wu*, Qing Zhou*

Intratumor Heterogeneity of EGFR Activating Mutations Analyzed in Single Cancer Cells in

Advanced NSCLC Patients

Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou/China


OS by PD-L1 expression: CheckMate 057

41

• PD-L1 expression was predictive of benefit with nivolumab

NivoDoc

10090807060504030

100

20

Time (months)24211815129630 27

Median OS(mo)

Nivo 10.4Doc 10.1

Median OS (mo)

Nivo 17.2Doc 9.0

≥1% PD-L1 expression level

HR (95% CI)=0.59 (0.43, 0.82)

<1% PD-L1 expression level

OS

(%

)

HR (95% CI)=0.90 (0.66, 1.24)

OS

(%

)

24211815129630 27

10090807060504030

100

20

NivoDoc

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

≥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)

POPLAR: OS by PD-L1 Expression

aUnstratified HR.Data cut-off May 8, 2015.

42

Atezolizumab Docetaxel Censored+

HRa = 0.59 (0.40, 0.85)P value = 0.005n = 195

HRa = 1.04 (0.62, 1.75)P value = 0.871n = 92

Median 9.7 mo(6.7, 12.0)

Median 9.7 mo(8.6, 12.0)

Median 15.5 mo(11.0, NE)Median 9.2 mo

(7.3, 12.8)

Select phase 3 studies with immune checkpoint inhibitors in 1st-line advanced NSCLC

43

Pembrolizumab

MEDI4736

SOC=standard of care. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed August 2015.

Atezolizumab

Ipilimumab

An

ti-P

D-1

/PD

-L1

An

ti-

CT

LA

-4

KEYNOTE-042Pembrolizumab

SOC chemotherapy Primary endpoint: OSPD-L1+ NSCLC

N=1240

Nivolumab Primary endpoints: OS, PFS

CheckMate 227

Nivolumab

Nivolumab + ipilimumab

Platinum-based chemotherapy

Treatment-naïve or recurrent NSCLCN=1980

Primary endpoint: PFSCheckMate 026Nivolumab

Investigator’s choice chemotherapyTreatment-naïve or recurrent PD-L1+

NSCLC N=535

KEYNOTE-024Pembrolizumab

Platinum-based chemotherapy Primary endpoint: PFSPD-L1 strong NSCLC

N=300

IMpower 111Atezolizumab

Gemcitabine + cisplatin or carboplatin Primary endpoint: PFSStage IV squamous PD-L1+ NSCLC

N=400

IMpower 150

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatinPrimary endpoint: PFS

Atezolizumab + bevacizumab + paclitaxel + carboplatin

Stage IV non-squamous NSCLCN=1200

IMpower 130Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxelPrimary endpoint: PFS

Stage IV non-squamous NSCLCN=550

IMpower 110Atezolizumab

Carboplatin or carboplatin + pemetrexed Primary endpoint: PFSStage IV non-squamous PD-L1+

NSCLC N=400

IMpower 131

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxelPrimary endpoint: PFSAtezolizumab + carboplatin + paclitaxelStage IV squamous NSCLC

N=1200

Primary endpoint: PFSMYSTIC

MEDI4736

MEDI4736 + tremelimumab

SOC chemotherapy

Advanced NSCLCN=675

CA184-104

Ipilimumab + paclitaxel/carboplatinàipilimumab

Placebo + paclitaxel/carboplatin à placebo Primary endpoint: OSSquamous NSCLC

N=920

CA184-153Ipilimumab + paclitaxel/carboplatinà ipilimumab

Placebo+ paclitaxel/carboplatin à placebo Primary endpoint: OSSquamous NSCLC

N=867

http://www.clinicaltrials.gov/

Goldberg SB et al. ORAL31.07

Vansteenkiste J. et al., atezolizumab in NSCLC (POPLAR)

ORAL11.03: Single-Agent Pembrolizumab for Patients with Malignant Pleural Mesothelioma (MPM) – Alley EW et al• Key results

o Median PFS was 5.8 months (95%CI 3.4, 8.2) and 6-month PFS rate was 50.0%

o There was no relationship between higher PD-L1 expression on tumour and inflammatory cells and frequency of response

• Conclusiono Single-agent pembrolizumab showed significant clinical activity in patients with

PD-L1–positive MPM but further evaluation is required

Best overall response n % 95%CI

Complete responsea 0 0 0.0, 13.7

Partial responsea 7 28.0 12.1, 49.4

Stable disease 12 48.0 27.8, 68.7

Progressive disease 4 16.0 4.5, 36.1

No assessmentb 2 8.0 1.0, 26.0Objective response ratea: 28.0% (95%CI 12.1, 49.4)Disease control ratea: 76.0% (95%CI 54.9, 90.6)

Alley et al. J Thorac Oncol 2015; 10 (suppl 2): ORAL11.03

I-O agents have a unique mechanism of action, offering the opportunity for combination with other agents

47

I-O

Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J. 2011;17:351–358; Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013;25:291–296.

Immune checkpoint inhibitors: Potential as part of a combination regimen

48

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 cell

MHC TCR

CD28

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

- - -

- - -

Anti-PD-1 plus anti-CTLA-4 tumor response and survival outcomes: Nivolumab plus ipilimumab as an example

CheckMate 012: Phase 1 study, non-squamous/squamous stage IIIB/IV NSCLC

49

Nivo 1+ Ipi 1 Q3W

(n = 31)

Nivo 1 Q2W + Ipi 1 Q6W

(n = 40)

Nivo 3 Q2W+ Ipi 1 Q12W

(n = 38)

Nivo 3 Q2W+ Ipi 1 Q6W

(n = 39)Nivo 3 Q2Wa

(n = 52)

Confirmed ORR, % 13 25 39 31 23

Confirmed DCR, % 55 58 74 51 50

Best overall response, %

Complete response 0 0 0 0 8

Partial response 13 25 39 31 15

Unconfirmed partial response 3 3 5 8 0

Stable disease 42 33 34 21 27

Median PFS, mos 10.6 4.9 8.0 8.3 3.6

Median OS, mos NR NR NR NR 22.6

Median follow-up, mos 16.6 6.2 8.4 7.7 14.3

Treatment-related AEs grade 3–4, % 29 35 29 28 19

Treatment-related AEs (any grade) leading to discontinuation, % 13 8 5 10 10

NR = not reported due to the high percentage of ongoing response of insufficient number of events and/or follow-upaResults for Nivo 3 Q2W are reported based on a March 2015 DBL.

Hellmann MD et al. Presented at ECC 2015, P349. Rizvi N, et al. Presented at WCLC 2015, Abstract 786.

Anti-PD-1 plus anti-CTLA-4 tumor response and survival outcomes: Nivolumab plus ipilimumab as an example

CheckMate 012: Percent change in target lesions from baseline

50

Includes all patients with baseline target lesion and ≥1 post-baseline assessment of target lesion.Horizontal lines denote 30% decrease, no change, and 20% increase.

Hellmann MD et al. Presented at ECC 2015, P349.

Nivo 1 + Ipi 1 Q3W

0–100–80–60–40–20

020406080

100

Time Since First Dose (Months)

Per

cen

t ch

ang

efr

om

bas

elin

e


–100–80–60–40–20

020406080

100


Per

cen

t ch

ang

efr

om

bas

elin

e


0–100–80–60–40–20

020406080

100


Per

cen

t ch

ang

efr

om

bas

elin

e


Time Since First Dose (Months)P

erce

nt

chan

ge

fro

m b

asel

ine

First occurrence of new lesion % change truncated to 100%

1 2 4 7 8 9 10 11 12 14 15 17 18 19 2013 163 5 6 211 2 4 7 8 9 10 11 12 14 15 17 18 19 2013 163 5 6 21

0 1 2 4 7 8 9 10 11 12 14 15 17 18 19 2013 163 5 6 21 0–100–80–60–40–20

020406080

100

1 2 4 7 8 9 10 11 12 14 15 17 18 19 2013 163 5 6 21


- Stage IV NSCLC- ECOG PS 0-1

- No prior treatment for advanced

disease- MUC1 + tumors

(IHC)- No brain mets

- Not EGFR mutated

*TrPAL≤ ULN

(N=170)

TrPAL*> ULN

(N=52)

1:1

1st Line Therapy + TG4010

1st Line Therapy + Placebo

*TrPAL: CD6+, CD56+, CD69+

• Randomization 1:1 in each cohort according to level of TrPAL • Randomization for TrPAL based on a cut-off value obtained from 369 healthy volunteers: 95th percentile of the

upper limit of normal (ULN)• Stratification by minimization in each cohort on Chemotherapy, Histology and Center

TIME study: Randomized, placebo-controlled, double-blind study

1st Line Therapy + TG4010

1st Line Therapy + Placebo

TG4010 (1.0 x 108 PFU) or Placebo:

SC injection weekly for 6 weeks and then once every 3 weeks until progression

1st Line Therapy:Carboplatin + paclitaxel, or

Cisplatin + gemcitabine (for squamous), orCisplatin + pemetrexed (for non-squamous)

Up to 6 cyclesBevacizumab at investigator’s discretion

Maintenance therapy (pemetrexed or erlotinib) if eligible at investigator’s discretion

RANDOMI ZE

Oral 18.01 – E Quoix

EGFR mutant lung cancer – T. MitsudomiPresentation Number: Presentation Title – Presenting Author

PFS in Patients according to level of TrPAL (Q3)High TrPAL >Q3 (N=75)Low TrPAL <Q3 (N=147)


EGFR mutant lung cancer – T. MitsudomiPresentation Number: Presentation Title – Presenting Author

OS in Patients according to level of TrPAL (Q3)High TrPAL >Q3 (N=75)Low TrPAL <Q3 (N=147)


Presentation Number: 18.06, A. Kotsakis

Chemotherapy has no effect on the different subpopulations of MDSCs; however, there is a trend towards a statistical reduction of the percentage of the G-MDSC in pts treated with Bev.

Bevacizumab based (n=13pts) Non-Bevacizumab based (n=33pts)Cell type Pre-treatment

(mean ± SEM)Post 3rd cycle

(mean ± SEM)p Pre-treatment

(mean ± SEM)Post 3rd cycle

(mean ± SEM)p

CD15(+) M-MDSC’s 3,35±0,86 5,27±2,40 0,84 2,7±0,7 2,5±0,6 0,97

CD15(-) M-MDSC’s 3,98±1,0 3,71±0,97 0,89 5,7±1,1 3,8±0,6 0,16

G-MDSC’s 5,1±2,5 4,42±2,51 0,06 0,7±0,1 1,4±0,3 0,68DC’s 67,68±6,79 58,58±7,11 0,057 51,7±4,4 56,5±3,9 0,61

Bevacizumab-based chemotherapy significantly reduced the percentages of the G-MDSC subpopulation when compared to the effect of non-bevacizumab-based therapy

Mean change after 3 cycles of therapyCell type Bevacizumab based

(n=13pts)Non-bevacizumab based

(n=33pts)p-value

CD15(+) M-MDSC’s 1,92±2,34 -0,23±0,91 0,82CD15(-) M-MDSC’s -0,27±1,18 -2±1,24 0,47G-MDSC’s -0,68±0,34 0,69±0,38 0,02DC’s -9,10±8,52 4,76±5,42 0,12

R► m

Eduational – T Mok

Futuro

1.- Se impone el tratamiento personalizado

2.- Mas targets (DDL3, MET,…) y fármacos

3.- INMUNOterapia “para muchos”

4.- Desplazamiento de los EECC al ESTE

Cáncer de Pulmón Avanzado Futuro del Tratamiento · 2015-05-08 · Cáncer de Pulmón Avanzado...

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