¿es el cáncer de mama triple negativo un tumor inmunogénico? · advanced/metastatic triple...
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¿Es el cáncer de mama triple negativo un tumor inmunogénico?
Esther Holgado Martín, MD, PhD
IOB, Complejo Hospitalario Universitario Ruber, Madrid
Valencia, 4 Diciembre, 2019
Cancer-Immunity Cycle
J. M. Kim & D. S. Chen. Annals of Oncology 27. 2016
Cancer and Immunity
Active Immune system
(Host Immunity)
Immune Targets
(Neoantigens)
Mutations TILs Activation Status
Activators Inhibitors(Checkpoints)
Alexandrov L,B. Nature 2013
•Neoantígens
Low Moderate High
Prevalence of somatic mutations per Megabase
0.01 0.1 1.0 10 100 1,0000.001Melanoma
Sq-NSCLC
Non-Sq-NSCLC
Bladder
SCLC
Esophagus
CRC
Cervical
H&N
Stomach
Endometrial
Liver
Clear cell Renal
Papillary Renal
Ovarian
Prostate
Myeloma
B lymphoma
Low grade glioma
Breast cancer
Pancreas
Glioblastoma
Neuroblastoma
CLL
Thyroid
Renal chromophous
LMA
Medulloblastoma
ALL
Pilocytic astrocytoma
▪ Alterations in the DNA replication
and repair mechanisms.
▪ Exposure to endogenous/exogenous
carcinogens.
▪ Enzymatic modifications of the DNA.
Neoantigens-Immunogenicity
Mutational rates in breast cancer
The Cancer Genome Atlas Network, Nature 2012Wang, et al. Nature 2014
Immune system in TNBC
TNBC shows a high mutation rate, estimated to be 13.3x relative to normal cells, and this may produce new antigens that could induce an immune response
CheckMate 141: OS
Nivolumab vs Investigator’s Choice in Recurrent/Metastatic HNSCCCheckMate 141: OS for Nivolumab vs Investigator’s Choice in Recurrent/Metastatic HNSCC
Ferris. Oral Oncol. 2018;81:45. Slide credit: clinicaloptions.com
Median OS, Mos (95% CI) ORR, %
Nivolumab (n = 240) 7.7 (5.7-8.8) 13.3
Investigator’s choice (n = 121) 5.1 (4.0-6.2) 5.8
HR: 0.68 (95% CI: 0.54-0.86)
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27 30 33 36 39
OS
(%)
Mos240 169 132 98 78 57 50 42 37 28 15 10 4 0
121 88 51 32 23 14 10 8 7 4 1 1 0 0
16.9%Nivolumab
6.0%IC
NivolumabIC
Patients at Risk, n
Ferris. Oral Oncol. 2018;81:45.
Three-Year Follow-up From CheckMate 017/057
1. Korn. JCO. 2008;26:527. 2. Long. Lancet Oncol. 2017;18:1202. Slide credit: clinicaloptions.com
Pembrolizumab Plus Reduced-Dose Ipilimumab in Metastatic Melanoma, 2017[2]
Survival data from 42 phase II trials of patients with stage IV melanoma (N = 2100)
OS for Metastatic Melanoma Before 2011[1]
Benefits of ICIs observed in multiple malignancies
Mos
0
20
40
60
80
100
0 12 24 36
OS
(%)
Patients at Risk, n 153 147 140 140 131 97 44 7 0(number censored) (0) (0) (3) (3) (6) (38) (91) (128) (135)
0
20
40
60
80
100
0 6 12 18Mos
OS
(%)
3 9 15 21 24
Los inhibidores inmuno-chkpoint ofrecen un beneficio de supervivencia en comparación con otros tratamiento históricos
1 . Korn. JCO. 2008;26:527. 2. Long. Lancet Oncol. 2017;18:1202.
Inmunoterapia: cambio de paradigma
+ 3 patients recorded as PD appeared to experience pseudo-progression, with durable shrinkage of target and new lesions
Pembrolizumab
(n = 32)
Atezolizumab
(n = 21)
Avelumab (n=58
/9)
Target PD-1 PD-L1 PD-L1
Tumour PD-L1 ≥1% (58%+) ≥5% All / ≥1%
ORR 18.5% 19% + 8.6% / 44.4%
SD 25.9% 27%
(≥24 weeks)22.4%
Immune checkpoint inhibitors in metastatic TNBC
Nanda et al. SABCS 2014 , Emens et al. AACR 2015, Dirix et al SABCS 2015
Immune checkpoint inhibitors have shown durable responses in heavily pretreated patients with metastatic TNBC
Keynote 119: Study design
Primary End Points• OS in patients with PD-L1 positive tumors(CPS ≥10)• OS in patients with PD-L1 positive tumors(CPS ≥1)• OS in all patients
Secondary End Points• PFS in all patients• ORR in all patients• Safety and tolerability• DCR and DOR in all patients and patients with
PD-L1 positive tumors(CPS ≥1 or CPS ≥10 )
Keynote 119: OS
Response to single-agent anti-PD-L1/PD-1
Schmid P, et al. AACR 2017; Adams S, et al ASCO 2017
26%
6.5%
2L+1L
Ob
jec
tive
Res
po
ns
e R
ate
(%
)
10%
20%
30%
0%
23%
4.7%
2L+1L
Pembrolizumab(n =222)
Atezolizumab(n = 115)
CRPR
CRPR
Keynote-086,
Cohort B
Keynote-086,
Cohort A
Anti-PDL1/PD-1 single agent in mTNBC ≥1L, PDL1+/-
Elimination Equilibrium Escape
CTL
NK
CTL
T reg
T cyto
NKT
T reg
T reg
CTL
NK T reg
CTL
Immuno-editing/Immune-selection
Tumor
Antigenicity
Immunocompetence
Immunoediting
Keynote 522: Study design
Keynote 522: Pathological Complete Response at IA1
PFS & Duration of Response to anti-PDL1/anti-PD1
Schmid P, et al. AACR 2017; Adams S, et al ASCO 2017; Adams S et al, SABCS 2017
Median DOR
1.4
21.1
Median PFS
Tim
e f
rom
sta
rt o
f T
x(m
ths)
5
10
15
0
20
Median OS for met TNBC 9-12 months!
Median DOR
2.1
8.4
Median PFS
Tim
e f
rom
sta
rt o
f T
x(m
ths)
5
10
15
0
20
10.4
2L+1LKeynote-086,
Cohort BKeynote-086,
Cohort A
Pembrolizumab(n = 222)
Atezolizumab(n = 115)
Overall Survival by Best Response to anti-PDL1
Schmid P, et al. AACR 2017
Median OS follow-up (range) was 15.2 mo (0.4+ to 36.7) in all patients, 17.0 mo (0.43+ to 36.7) in IC2/3 patients and 12.8 mo (0.8+ to 16.9) in IC0/1
patients.
No. At Risk: CR/PR 15 15 14 14 12 10 6 6 6 4 3 2 1
SD 19 18 17 10 6 5 1PD 55 40 30 28 11 3
3y OS: 100%
1-y OS:
33%
1-y OS:
51%
2y OS: 100%1y OS: 100%
Ove
rall S
urv
iva
l
Time (months)
Response
■ CR/PR■ SD ■ PD
Atezolizumab single agent in mTNBC ≥1L, PDL1+/-
Keynote 119: Duration of response
Poor Outcome of Metastatic TNBC (N=112)
Kassam F, Enright K, Dent et al. Clin Breast Cancer 2009
Initial
therapy
First distantrelapse
Firstline
chemo
Median D.F.I.
Secondline
chemo
Thirdline
chemo
“Time on Treatment”
4 weeks9 weeks12 weeks
Advanced/Metastatic Triple Negative Breast Cancer: SoC
Small group of breast cancer patients with transformative benefit but unable to define subgroup
Strategies going forward concentrating
on combinations
Combining immunotherapy and conventional therapy
Time
Surv
ival
(%
)
Chemotherapy
Genomically targeted therapy
Immune checkpoint therapy
Immunotherapy combination
Chemotherapy Induces Multiple Immunomodulatory Changes in the Tumor Microenvironment That May Influence the Effectiveness of Immunotherapy
M1, tumor-associated macrophage; MHC, major histocompatibility complex; TNF-ɑ, tumor necrosis factor alpha
1. Daly ME, et al. J Thorac Oncol. 2015;10(12):1685-1693. 2. Kaur P, et al. Front Oncol. 2012;2:191; 3. Deng L, et al. J Clin Invest. 2014;124(2):687-695.
Luen, The Breast, 2016
Tumor Mutational Burden & TIL correlation
Immune system in TNBC
TNBC shows the highest rate of T-cell infiltration among BC subtypes
LPBC, lymphocyte-predominant breast cáncer; Lum, luminal; TILs, tumor-infiltrating lymphocytes
[1] Denkert et al, SABCS 2016; [2] Loi et al, J Clin Oncol 2013.
Immune system in TNBC
1. Chen and Mellman. Immunity 2013; 2. Lehmann, et al. J Clin Invest 2011; 3. Cimino-Matthews, et al. Hum Pathol 2013; 4. Loi, et al. Ann Oncol 2014; 5. Adams, et al. J Clin Oncol 2014
TNBC shows T cell infiltration, an essential precursor to an antitumour immune response
• Primary TNBC tumours show increased levels of tumour-infiltrating T cells compared with other BC subtypes2–4
• T cell infiltration in TNBC is associated with improved prognosis for patients
• For each 10% increase in the level of stromal tumour-infiltrating T cells:
Reduction in risk of death5
19%
Reduction in risk of distant recurrence4,5
13–18%
Reduction in risk of recurrence or death5
14%
Active T cell
TUMOUR MICROENVIRONMENT
Apoptotic TCAntigens
Immune system in TNBC
PD-L1 expression in TNBC
Scoring of PD-L1 expression can vary between studies due to a number of factors including the cell types included for analysis (TCs or tumor-infiltrating immune cells), the proportion of stained cellsrequired for a simple to be considered PD-L1 positive and variability between immunohistochemistry detection antibodies
[1]. TCGA, The Cancer Genome Atlas. [1] Nanda et al, J Clin Oncol, 2016; [2] Mittendorf et al, Cancer Immunol Res 2014.
Immune system in TNBC
IC, tumour-infiltrating immune cell; TFI, treatment-free interval. a ClinicalTrials.gov: NCT02425891. b Locally evaluated per ASCO–College of American Pathologists (CAP) guidelines. c Centrally evaluated per VENTANA SP142 IHC assay (double blinded
for PD-L1 status). d Radiological endpoints were investigator assessed (per RECIST v1.1).
Schmid P, et al. IMpassion130 . ESMO 2018 (LBA1_PR) http://bit.ly/2DMhayg
• Co-primary endpoints: PFS and OS in the ITT and PD-L1+ populationsd
• Key secondary efficacy endpoints (ORR and DOR) and safety
IMpassion130 study design
Key IMpassion130 eligibility criteriaa:
• Metastatic or inoperable locally advanced TNBC
‒ Histologically documentedb
• No prior therapy for advanced TNBC
‒ Prior chemo in the curative setting, including
taxanes, allowed if TFI ≥ 12 mo
• ECOG PS 0-1
Stratification factors:
• Prior taxane use (yes vs no)
• Liver metastases (yes vs no)
• PD-L1 status on IC (positive [≥ 1%] vs negative [< 1%])c
Atezo + nab-P arm:
Atezolizumab 840 mg IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Plac + nab-P arm:
Placebo IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Double blind; no crossover permittedRECIST v1.1
PD or toxicityR1:1
IMpassion130: Primary PFS analysis
Primary PFS analysis: ITT population
NE, not estimable. Data cutoff: 17 April 2018. Median PFS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months.
0 3 6 9 12 15 18 21 24 27 30 33 Months
No. at risk: Atezo + nab-P 451 360 226 164 77 34 20 11 6 1 NE NE
Plac + nab-P 451 327 183 130 57 29 13 5 1 NE NE NE
Atezo + nab-P
(N = 451)
Plac + nab-P
(N = 451)
PFS events, n 358 378
1-year PFS
(95% CI), %
24%
(20, 28)
18%
(14, 21)
7.2 mo (5.6, 7.5)
5.5 mo (5.3, 5.6)
100
80
60
40
20
0
Pro
gre
ss
ion
-fre
e s
urv
iva
l Stratified HR = 0.80
(95% CI: 0.69, 0.92) P = 0.0025
Schmid P, et al. IMpassion130
ESMO 2018 (LBA1_PR)
http://bit.ly/2DMhayg
NE, not estimable. Data cutoff: 17 April 2018. Median PFS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months. Schmid P, et al. IMpassion130 ESMO 2018 (LBA1_PR) http://bit.ly/2DMhayg
A 1.7 month significant median PFS benefit was observed with the addition of TECENTRIQ to
nab-paclitaxel
Primary PFS analysis: PD-L1+ population
Data cutoff: 17 April 2018.
0 3 6 9 12 15 18 21 24 27 30 33 Months
No. at risk: Atezo + nab-P 185 146 104 75 38 19 10 6 2 1 NE NE
Plac + nab-P 184 127 62 44 22 11 5 5 1 NE NE NE
7.5 mo (6.7, 9.2)
5.0 mo (3.8, 5.6)
100
80
60
40
20
0
Pro
gre
ss
ion
-fre
e s
urv
ival Stratified HR = 0.62
(95% CI: 0.49, 0.78)
P < 0.0001
Atezo + nab-P
(n = 185)
Plac + nab-P
(n = 184)
PFS events, n 138 157
1-year PFS
(95% CI), %
29%
(22, 36)
16%
(11, 22)
Schmid P, et al. IMpassion130
ESMO 2018 (LBA1_PR)
http://bit.ly/2DMhayg
The PFS benefit with TECENTRIQ + nab-paclitaxel was more
pronounced (2.5 months) in patients with PD-
L1+ TNBC than in the ITT population
ITT population PD-L1+ population
IMpassion130 Update: OS in ITT Population
Schmid. ASCO 2019. Abstr 1003.
Atezolizumab+ nab-Paclitaxel
(n = 451)
Placebo+ nab-Paclitaxel
(n = 451)Median OS, mos (95% CI) 21.0 (19.0-22.6) 18.7 (16.9-20.3)
24-Mo OS, % (95% CI) 42 (37-47) 39 (34-44)
HR: 0.86 (95% CI: 0.72-1.02; P = .0777)
Patients at Risk, n
Atezo + nab-Pac 451 426 389 342 312 270 235 162 88 56 35 19 8 3 NE Pbo + nab-Pac 451 420 376 329 291 252 216 145 87 51 33 17 4 1 NE
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42Mos
IMpassion130 Update: OS in PD-L1+ Subgroup
Schmid. ASCO 2019. Abstr 1003.
Atezolizumab+ nab-Paclitaxel
(n = 185)
Placebo+ nab-Paclitaxel
(n = 184)Median OS, mos (95% CI) 25.0 (19.6-30.7) 18.0 (13.6-20.1)
24-mo OS, % (95% CI) 51 (43-59) 37 (29-45)
Not formally tested due to prespecified hierarchical statistical design for trial. *
HR: 0.71 (95% CI: 0.54-0.93)*
Patients at Risk, n
Atezo + nab-Pac 185 177 160 145 135 121 106 69 43 28 21 10 6 3 NEPbo + nab-Pac 184 170 147 129 111 93 81 47 26 20 15 10 1 NE NE
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42Mos
IMpassion130: secondary efficacy endpoints
– Numerically higher and more durable responses
were seen in the TECENTRIQ +
nab-paclitaxel arm
– The CR rate was higher in the
TECENTRIQ + nab-paclitaxel arm vs the placebo
+
nab-paclitaxel arm
• ITT population: 7% vs 2%
• PD-L1+ patients: 10% vs 1%
Data cutoff: 17 April 2018. Objective response-evaluable patients: *450 in TECENTRIQ + nab-paclitaxel and 449 in placebo +
nab-paclitaxel arm. §185 in TECENTRIQ + nab-paclitaxel and 183 in placebo + nab-paclitaxel arm. ¶No death or PD.
Schmid et al. ESMO 2018 (Abstract 2056); Schmid, et al. N Engl J Med 2018
0
10
20
30
40
50
60
70
ITT A-nabPx
ITT P-nabPx
PD-L1+ A-nabPx
PD-L1+ P-nabPx
OR
R (
%)
ITT* PD-L1+§
56%
46%
59%
43%
49%
44%
49%
42%
1%2%7%10%
TECENTRIQ +
nab-paclitaxel
Placebo +
nab-paclitaxel
TECENTRIQ +
nab-paclitaxel
Placebo +
nab-paclitaxel
DOR, median(95% CI), months
7.4(6.9–9.0)
5.6(5.5–6.9)
8.5(7.3–9.7)
5.5(3.7–7.1)
No. of ongoing responses, n (%)¶ 78 (31) 52 (25) 39 (36) 19 (24)
CR:
PR:
IMpassion130 Update: Safety
• Updated safety analysis revealed a profile consistent with primary analysis
• No difference in patient-reported outcomes (HRQoL) between treatment arms
Schmid. ASCO 2019. Abstr 1003. Schmid. NEJM. 2018;379:2108. Schneeweiss. ASCO 2019. Abstr 1068. Adams. ASCO 2019. Abstr 1067.
Median follow-up: 15.6 mos (4.5 mos after primary PFS analysis)
All-cause AEs
Treatment-related AEs
Serious AEs
AEs leading to any treatment withdrawal
AESI
AEs leading to Atezo or Pbo withdrawal
AESI requiring systemic corticosteroids
Atezolizumab+ nab-Paclitaxel
(n = 453)
Placebo+ nab-Paclitaxel
(n = 437)
Grade 1/2Grade 3/4Grade 5Any grade
020Incidence (%)
20 404060 60 8080100 100
Marzo 2019: FDA
Septiembre 2019: EMA
Aprobación de la combinación de Atezolizumab más Abraxane para el tratamiento de pacientes con cáncer de mama localmente avanzado irresecable
o metastásico, en tumores con expresión PD-L1 (≥1%), que no hayan recibido tratamiento previo con quimioterapia para la enfermedad metastásica
Keytruda 200mg IV q3w+ chemotherapy
(nab-paclitaxel or paclitaxel or gemcitabine / carboplatin)
Placebo + chemotherapy(nab-paclitaxel or paclitaxel or gemcitabine /
carboplatin)
KEYNOTE-355: phase III 1L Keytruda study in inoperable or mTNBC
NCT02819518
Keytruda 200mg IV q3w+ chemotherapy
(nab-paclitaxel or paclitaxel or gemcitabine / carboplatin)
Primary endpoints:
• Proportion of patients with AEs
• Discontinuations due to AEs
1L inoperable locally
recurrent or mTNBCn=858
Part 1* safety n=30
R
Part 2 efficacy n=828
2:1
Primary endpoints:
• PFS (ITT and PD-L1+ patients)
• OS (ITT and PD-L1+ patients)
Secondary endpoints include:
• ORR (ITT and PD-L1+ patients)
• DoR (ITT and PD-L1+ patients)
• DCR (ITT and PD-L1+ patients)
• Proportion of patients with AEs
• Discontinuations due to AEs
Courtesy of Prof Schmid
mTNBC: treatment algorithm
Management of TNBC primarily consists of single-agent chemotherapy and chemotherapy combinations
Triple-Negative Breast Cancer - Current Management
Primary breast
cancer
Adjuvant chemo
(after surgery)
MBC 1st line
Taxanes
(if DFI >1a)
Platinum
Combinations
(CarboTax, GC)
Taxanes +
Bevacizumab
MBC 2nd line
Capecitabine
Platinum
Combinations
(CarboTax, GC)
Eribulin
Neoadjuvant CT
(before surgery)
Accelerated approval?
50% 3 year-recurrence
pCR(30-40%)
Non
pCR
Post NACT
adjuvant studies?
MBC >2nd line
Eribulin
BSC
Median OS for met TNBC 9-12 months!
PARPi(BRCA1/2) #
PARPi(BRCA1/2)#
PARPi(BRCA1/2) #
Atzo + Chemo/ PDL1+
TNBC Subtypes: (Some) Research Strategies
Heterogeneity of TNBC and Treament Strategies
Personalised immunotherapy
TILs – linked with CD8 T cells/IFNγ, PDL1/checkpoints
Single-agent immune checkpoint inhibitors
(or combination with chemotherapy)
Low T cells,Low MHC class I,Proliferating tumours
Immunologically ignorant “cold tumours”
PD-L1/checkpointsCD8 T cells/IFNγMutational loadTILs
Pre-existing tumours“inflamed” or “hot” tumours”
Angiogenesis, MDSCs,Reactive stroma,
Mutational load
Excluded infiltrate
Priming & activation(e.g. CTLA-4, OX40)
Influence infiltration? (e.g. VEGF, MEKi)
Priming, activation & infiltration
Neoantigen expression?(e.g. epigenetic modulation)
Adoptive Cell Therapy? Vaccination
Bring T cells into tumours
Generate T cells
1. Wang, et al. Nature 2014; 2. Stephens, et al. Nature 2009; 3. Banerji, et al. Nature 2012; 4. Lehmann, et al. J Clin Invest 2011; 5. Cimino-Matthews, et al. Hum Pathol 2013; 6. Loi, et al. Ann Oncol 2014; 7. Chen and Mellman. Immunity 2013; 8. Mittendorf, et al. Cancer Immunol Res 2014; 9. Nanda et al. J Clin Oncol 2016
TNBC is more immungenic compared with other BC subtypes
A higher mutation rate (large differences in mutations and biology even within tumours)1-3
Higher PD-L1 expression7-9
A higher rate of T-cell infiltration4-6
Compared with other BC subtypes, patients with TNBC have:
TNBC ER+
Mea
n ±
SD o
f P
D-L
1
mR
NA
exp
ress
ion
Non-TNBC
TNBC
12
10
8
6
4
45 36 19
29 41 30
44 37 19
56 3213
20% 40% 60% 80% 100%
All
TNBC
HER2+
0%
% of tumors
Low(0–10% TILs)
Intermediate(11–59% TILs)
High(≥60% TILs)Lum/HER2–
Immune system in TNBC
• Is there a rational for immune-based therapy in TNBC?
• Evidences from clinical data?
• Can you enhance immunogenicity?
YES
YES
YES
CONCLUSION
Baseline 9-Month Follow-Up CT 20-Month Follow-Up
Target 1
MUCHAS GRACIAS!!!!
Esther Holgado Martín, MD, PhD
IOB, Complejo Hospitalario Universitario Ruber, Madrid