¿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