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
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
Slide 17
Presented By Sameek Roychowdhury at 2015 ASCO Annual Meeting
11ORAL 16.07 – Q Zhang
Cancer Research UK
Stratified Medicine Program
12ORAL 16.07 – Q Zhang
13ORAL 16.07 – Q Zhang
14ORAL 16.07 – Q Zhang
15ORAL 16.07 – Q Zhang
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
ORAL 16.07 – Q Zhang
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
ORAL 16.07 – Q Zhang
Temas1.- Medicina Personalizada2.- Agentes dirigidos a DIANAS Específicas3.- INMUNOterapia4.- Desarrollo de nuevos fármacos y EECC
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).
ORAL 16.07 – Q Zhang
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)
Oral 17.07 – GR Oxnard
EGFR mutant lung cancer – T. Mitsudomi
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
EGFR mutant lung cancer – T. Mitsudomi
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
Oral 17.07 – GR Oxnard
EGFR mutant lung cancer – T. Mitsudomi
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
Oral 17.07 – GR Oxnard
EGFR mutant lung cancer – T. Mitsudomi
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
ORAL 16.07 – Q Zhang
Temas1.- Medicina Personalizada2.- Agentes dirigidos a DIANAS Específicas3.- INMUNOterapia4.- Desarrollo de nuevos fármacos y EECC
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
Goldberg SB et al. ORAL31.07
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
Nivo 3 Q2W + Ipi 1 Q12W
–100–80–60–40–20
020406080
100
Time Since First Dose (Months)
Per
cen
t ch
ang
efr
om
bas
elin
e
Nivo 1 Q2W + Ipi 1 Q6W
0–100–80–60–40–20
020406080
100
Time Since First Dose (Months)
Per
cen
t ch
ang
efr
om
bas
elin
e
Nivo 3 Q2W + Ipi 1 Q6W
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
EGFR mutant lung cancer – T. Mitsudomi
- 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)
Oral 18.01 – E Quoix
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)
Oral 18.01 – E Quoix
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
Temas1.- Medicina Personalizada2.- Agentes dirigidos a DIANAS Específicas3.- INMUNOterapia4.- Desarrollo de nuevos fármacos y EECC
R► m
Eduational – T Mok
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
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