Dra. García Alfonso

Jefe de Sección de Oncología Médica

HGU Gregorio Marañón

Inmunoncología en cáncer de colon

Estado del arte

Cáncer Colorrectal

No es sensible

Inmunoterapia

Cáncer Colorrectal

● Inmunoterapia

MSI

3%

Frequency of genetic somatic mutations in cancer

Altered proteins contain new epitopes for

immune recognition,

providing a common denominator for cancer

immunotherapy

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22 20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49 181 231 76 88 35 335 179 121

C→T

C→A

C→G

T→C

T→A

T→G

Lawrence Nature 2013

No at Risk

No MSI

MSI

TCGA CCR: Subtipos

TCGA. Nature 2012

Hipermutado (> 12 mut/106bases): 16%

3/4 MSI, generalmente por hipermetilación del promotor del gen MLH1

1/4 mutaciones somáticas MMR y mutaciones POLE

Diferentes tipos de CCR se correlacionan

con distintos perfiles de expresión génica

Características de los subgrupos

moleculares

Nat Med. 2015 Nov;21(11):1350-6

Overall logrank p= 0.00124*

CMS4 vs. CMS2

HR = 1.7 (1.3 – 2.3)

p = 0.0004*

* Adjusted for stage, MSI, BRAF

mut, adjuvant chemotherapy, and

stratified by dataset.

All follow-up times censored at 72 months

N at risk 2,796 2,253 1,991 1,778 1,526 1,264 938

Overall Survival (n=2,796)

Nat Med. 2015 Nov;21(11):1350-6

• El CSM4 (Mesenquimal) es el de peor pronóstico globalmente

• El CSM1 (MSI inmune) es el de peor pronóstico tras la recaida

• El CSM2 (Canónico) es el de mejor pronóstico tras la recaida

RFS OS Survival after relapse

MSI

Slide 5

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

• Orienta al Consejo Genético

• Marcador pronóstico en estadio II

• Marcador predictivo a la inmunoterapia (Categoría IIB)

● Incidencia

Estadio II (15%); III: 12%; IV: 3%

MSI

*NCCN guidelines validate testing for MSI-H

1. Sargent DJ et al. J Clin Oncol. 2010; 28(20):3219-3226. 2. NCCN Guidelines V.1.2017. 3. Venderbosch S et al. Clin Cancer Res.

2014; 20(20):5322-5330. 4.Richman S. Int J Oncol. 2015; 47(4):1189-1202 9. 5. Van Cutsem E et al. Ann Oncol. 2016; 27(8):1386–

1422.

Slide 6

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

Consejo Genético

Slide 12

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

Slide 13

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

The Value of dMMR/MSI-H as a Predictive Biomarker for

Chemotherapies in mCRC Is Under Investigation

dMMR Status:

Prevalence2 dMMR, n (%) pMMR, n (%) Total, N

CAIRO* 18 (5.6%) 304 (94.4%) 322

CAIRO2* 29 (5.6%) 487 (94.4%) 516

COIN† 65 (4.4%) 1396 (95.6%) 1461

FOCUS‡ 41 (5.4%) 723 (94.6%) 764

Pooled data set 153 (5.0%) 2910 (95.0%) 3063

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

0.2

0.4

0.6

0.8

1.0

Months from randomization

OS

pro

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y

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

0.2

0.4

0.6

0.8

1.0

Months from randomization

PF

S p

rob

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y

pMMR

dMMR

pMMR

dMMR

PFS by MMR status1 OS by MMR status1

1. Koopman M et al. Br J Cancer. 2009;100(2):266-73. 2. Venderbosch S et al. Clin Canc Res. 2014;20(20):5322-5330.

*dMMR testing assessed by IHC with PCR in the absence of MMR protein expression. †dMMR testing assessed by PCR. ‡dMMR testing assessed by IHC.

dMMR, deficient mismatch repair; IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; OS, overall survival; PCR, polymerase chain reaction; PFS, progression-free survival; pMMR, proficient mismatch repair.

Pathologic Features of dMMR CRCs

TIL (linfocitos infiltrantes del tumor) productores de Interferon Gamma PD-1 Células mieloides infiltrantes del tumor PDL-1 +

Cancer Discovery 2015 Doi:10.1158/2159-8290.CD-14-0863

Microambiente en CCR con MSI

Essential role of pre-existing immunity:

The Immune contexture

Pages et al, NEJM 2005; Galon et al, Science 2006; Tosolini et al, Cancer Res 2011

• The nature, functional orientation, density and location of adaptive immune

cells within distinct tumor regions influence the risk of relapse

Slide 29

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

Therapeutic strategies according to immune contexture

Kim and Chen 2016 Ann Oncol; Hedge et al 2016 Clin Cancer Res

Ensayos Clínicos

Ensayos de Inmunoterapia en

CCRm

<br />Study Design: KEYNOTE-164

Pembrolizumab in digestive tumors: dMMR N Engl J Med 2015;372:2509-20. DOI: 10.1056/NEJMoa1500596

Keynote 177<br />first line mCRC MSI-H

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

Nivolumab +/- Ipilimumab (Checkmate

142)Study Design

● Primary endpoint: ORR per investigator assessment

● Secondary endpoint: ORR per blinded independent central review (BICR)

● Other endpoints: PFS, OS, biomarkers, safety and tolerability

Nivolumab

3 mg/kg Q2W

Stage 1a

• Histologically confirmed

metastatic/recurrent CRC

• dMMR/MSI-H per local

laboratory

• ≥ 1 prior line of therapy

Nivolumab

3 mg/kg Q2W

Stage 2b

Patients

Stage 2d Stage 1c

Nivolumab 3 mg/kg

+ ipilimumab 1 mg/kg Q3W for 4

doses

• Then nivolumab 3 mg/kg Q2W

Nivolumab 3 mg/kg

+ ipilimumab 1 mg/kg Q3W

for 4 doses

• Then nivolumab 3 mg/kg

Q2W

Q2W, every 2 weeks; Q3W, every 3 weeks. a Enrollment complete; b Opened based on an adequate ORR (CR + PR) in patients with centrally confirmed MSI-H CRC treated in mStage 1; c Opened despite an adequate ORR in mStage

1 to proceed to mStage2; d Opened based on an adequate ORR in cStage 1.

Modified form Overman MJ, et al. ASCO-GI 2017. Poster oral #519

Presented By Michael Overman at 2016 ASCO Annual Meeting

Phase 2 CheckMate 142 Study Design:

Microsatellite Stable (MSS) Cohort

"Uso experimental no autorizado"

Checkmate 142 (phase II)<br />Anti-PD1 +/- Anti CTLA-4 in MSI-H mCRC

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

Response and Disease Control

Patients, n (%)

dMMR/MSI-H per

Local Laboratory

(N = 74)

dMMR/MSI-H per

Central Laboratory

(n = 53)

Investigator BICR Investigator BICR

ORR, n (%)

95% CI

23 (31.1)

20.8, 42.9

20 (27.0)

17.4, 38.6

19 (35.8)

23.1, 50.2

17 (32.1)

19.9, 46.3

Best overall response, n (%)

CR

PR

SD

PD

Unable to determine

0

23 (31.1)

29 (39.2)

18 (24.3)

4 (5.4)

2 (2.7)

18 (24.3)

28 (37.8)

20 (27.0)

6 (11.1)

0

19 (35.8)

21 (39.6)

10 (18.9)

3 (5.7)

1 (1.9)

16 (30.2)

21 (39.6)

12 (22.6)

3 (5.7)

Disease control for ≥ 12 weeks, n

(%)a 51 (68.9) 46 (62.2) 39 (73.6) 37 (69.8)

BICR, blinded independent central review.

a Patients with CR, PR, or SD for ≥ 12 weeks.

Overman MJ, et al. ASCO-GI 2017. Poster oral #519

NIVOLUMAB en monoterapia

CheckMate 142: MMR-D pts treated with Nivo (74

pts)

Overman ASCO-GI 2017

QOL, quality of life. 1. Osoba D et al. J Clin Oncol. 1998;16:139-44.

Fatigue Appetite Loss

Patients 49 42 39 26 16 11 15 13 12 14 13 11 70

Wo

rse

B

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Patients 49 42 39 26 16 11 15 13 12 14 13 11 70

Bett

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Wo

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Pain

Patients 49 42 39 26 16 11 15 13 12 14 13 11 70

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Fro

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Weeks

-3 0

-2 0

-1 0

0

10

20

30

Weeks

19 25 31 37 43 49 55 61 67 73 79 13 0

-3 0

-2 0

-1 0

0

10

20

30

Global Health Status/

QOL

Bett

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Worse

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e

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-3 0

-2 0

-1 0

0

10

20

30

Weeks

19 25 31 37 43 49 55 61 67 73 79 13 0

Wo

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B

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Mea

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Weeks

-3 0

-2 0

-1 0

0

10

20

30

19 25 31 37 43 49 55 61 67 73 79 13 0 19 25 31 37 43 49 55 61 67 73 79 13 0

● Clinically meaningful (≥ 10-point

change)1 improvements were

reported in QOL, functioning, and

symptoms as early as week 13

Role Functioning

Bett

er

Worse

Mea

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ha

ng

e

Fro

m B

ase

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-3 0

-2 0

-1 0

0

10

20

30

Weeks

19 25 31 37 43 49 55 61 67 73 79 13 0

Patient Reported Outcomes: EORTC QLQ-C30

Overman MJ, et al. ASCO-GI 2017. Poster oral #519

Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of patients (pts) with deficient DNA mismatch

repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC): CheckMate 142

Study

Thierry Andre,1 Sara Lonardi,2 Ka Yeung Mark Wong,3 Michael Morse,4 Ray McDermott,5 Andrew Hill,6 Alain Hendlisz,7 Heinz-Josef Lenz,8 Joseph Leach,9 Rebecca A. Moss,10 Z. Alexander Cao,10

Jean-Marie Ledeine,11 Scott Kopetz,12 Michael Overman12

1Hopital Saint Antoine, Paris, France; 2Istituto Oncologico Veneto IOV-IRCSS, Padova, Italy; 3The University of Sydney, Sydney Medical School,

Sydney, Australia; 4Duke University Office of Research Administration, Durham, NC, USA; 5St Vincent’s University Hospital, Dublin, Ireland; 6Tasman

Oncology Research Pty Ltd, Southport, Queensland, Australia; 7Institut Jules Bordet, Brussels, Belgium; 8University of Southern California Norris

Comprehensive Cancer Center, Los Angeles, CA, USA; 9Allina Health System, Minneapolis, MN, USA; 10Bristol-Myers Squibb, Princeton, NJ, USA; 11Bristol-Myers Squibb, Braine-l’Alleud, Belgium;12MD Anderson Cancer Center, Houston, TX, USA

3531

Andre T., et al. ASCO 2017. Poster oral #3531

• Investigator-assessed response was achieved in 55% of patients and the disease control rate was 79%

DOR, duration of response; NE, not estimable; NR, not reached; TTR, time to response. a Defined as patients with complete response, partial response, or stable disease for ≥ 12 weeks..

Efficacy

Andre T., et al. ASCO 2017. Poster oral #3531

dMMR/MSI-H (N = 84)

ORR, n (%)

[95% CI]

46 (55)

[43.5, 65.7]

Best overall response, n (%)

CR

PR

SD

PD

Not determined/reported

2 (2)

44 (52)

26 (31)

9 (11)

3 (4)

Disease control for ≥ 12 weeks,a n (%)

[95% CI]

66 (79)

[68.3, 86.8]

Median TTR, months (range) 2.8 (1.1–14.0)

Median DOR, months,

[95% CI]

NR

[NE, NE]

No. at Risk 84

1.0

0.9

0.8

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

ba

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Fre

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l

0 3 6 9 12

Time (months)

17 13

15 18 21

65 35 8 1 0

PFS rate (95% CI), %

6 months 77 (66.5, 85.1)

9 months 77 (66.5, 85.1)

Median PFS (95% CI), months NR (11.5, NE)

NE = not estimable; NR = not reached.

• Median time from first dose to death or last known alive date: 8.7 months (range,

0.1 to 20.1) • The 9–month rates of PFS and OS were 77% and 88%, respectively • Medians for PFS and OS had not yet been reached

Andre T., et al. ASCO 2017. Poster oral #3531

PFS per Investigator Assessment with NIVO + IPI

Pro

ba

bil

ity o

f O

ve

rall

Su

rviv

al

No. at Risk 84

NE = not estimable; NR = not reached.

0 3 6 9 12 15 18 21

77 73

Time (months)

40 22 19 13 0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

OS per Investigator Assessment with NIVO + IPI

Andre T., et al. ASCO 2017. Poster oral #3531

a All events (ALT level increase, autoimmune hepatitis, colitis, dyspnea, necrotizing myositis, pneumonitis, immune sarcoidosis, transaminase increase, thrombocytopenia) occurred in one

patient each with the exception of acute kidney injury, which was reported in 2 patients.

• AEs were manageable, with Grade 3/4 TRAEs reported in

29% of patients

• No treatment-related deaths were reported

Safety: Summary of TRAEs with NIVO +

IPI

dMMR/MSI-H (N = 84)

Patients, n (%) Any Grade Grade 3 or 4

Any TRAE 57 (68) 24 (29)

Serious TRAEs 15 (18) 14 (17)

Discontinuation due to TRAEsa 11 (13) 8 (9)

TRAEs reported in ≥ 10% of patients

Diarrhea 20 (24) 1 (1)

Fatigue 14 (17) 1 (1)

Aspartate aminotransferase increase 14 (17) 8 (9)

Pyrexia 13 (16) 0

Pruritus 13 (16) 2 (2)

Alanine aminotransferase increase 12 (14) 7 (8)

Nausea 12 (14) 0

Hyperthyroidism 11 (13) 0

Hypothyroidism 11 (13) 0

Andre T., et al. ASCO 2017. Poster oral #3531

Molecular Information Drug Overview

Compound RG7446

Generic name Atezolizumab

Other names Tecentriq, anti–PD-L1, RO5541267,

MPDL3280A

Molecule type Engineered IgG1 MAb to eliminate

Fc-effector function to avoid killing of

activated T cells

Mechanism

of action

Binds and inhibits PD-L1 to promote

antitumor immune responses

Ongoing clinical

trials

Lung, bladder, renal, prostate,

breast, ovarian, GI, skin, other solid

tumors and hematologic cancers

Development phase Phases I, II, III

Atezolizumab: molecule summary

● References: 1. Herbst R, et al. Nature. 2014;515(7528):563-567. 2. Powles T, et al. Nature. 2014;515(7528):558-562. 3. McDermott DF, et al. J Clin Oncol. 2016;34(8):833-842. 4. Emens L, et al. AACR. 2015 [Oral presentation; abstract 6317]. 5. Gordon M, et al. Chicago Thoracic 2016 [Poster presentation; abstract 84]. 6. Petrylak D, et al. ASCO. 2015 [Oral presentation; abstract 4501]. 7. Wakelee H, et al. Chicago Thoracic 2016 [Oral presentation; abstract Oral01.04]. 8. Fehrenbacher L, et al. Lancet. 2016;387(10030):1837-1846. 9. Rosenberg J, et al. Lancet. 2016;387(10031):1909-1920. 10. Desai J, et al. ESMO. 2016 [Poster presentation; abstract 470P]. 11. Bellmunt J, et al. ESMO. 2016 [Poster presentation; abstract 782PD]. 12. Rosenberg J, et al. ASCO. 2016 [Oral presentation; abstract 104]. 13. Schmid P, et al. ASCO. 2016 [Oral presentation; abstract 11506]. 14. Barlesi F, et al. ESMO. 2016 [Oral presentation; abstract LBA44_PR]. 15. Wallin JJ, et al. Nat Commun. 2016;7:12624. 16. Sequist LV, et al. ESMO 2016 [Poster presentation; abstract 1425PD]. 17. Hwu P, et al. ESMO 2016 [Poster presentation; abstract 1190PD]. 18. Infante J, et al. ESMO 2016 [Poster presentation; abstract #871P]. 19. http://www.biooncology.com/pipeline-molecules/anti-pdl1.

Binds to PD-L1 on tumor cells and tumor- infiltrating immune cells

Cobimetinib + Atezolizumab ● PD-L1 and MEK inhibition: a rational combination

Cobimetinib + Atezolizumab

KRAS

MT

CRC

All

CRC

pts

N=20 N=23

ORR 20% 17%

CR 0 0

PR 20% 17%

SD 20% 22%

PD 50% 52%

NE 10% 9%

mPFS

(mo)

2.3

(1.8-9,5)

2.3

(1.8-9,5)

mOS (mo) NE

(6,5-

NE)

NE

(6,5-

NE)

Bendell ASCO 2016

Estudio fase III multicéntrico, abierto, randomizado, con tres grupos de tratamiento para investigar la

eficacia y seguridad de cobimetinib en combinación con atezolizumab y de atezolizumab en monoterapia,

comparado con regorafenib, en pacientes con adenocarcinoma colorrectal localmente avanzado o

metastásico no resecable tratado previamente

https://clinicaltrials.gov/ct2/show/NCT02788279

Ongoing

Combined chemotherapy plus Bevacizumab may create a

favourable microenvironment for immunotherapy

Presented By Wallin et al at 2016 AACR Annual Meeting

Presented By Wallin et al at 2016 AACR Annual Meeting

Atezolizumab plus Bevacizumab and/or FOLFOX in mCRC:

phase Ib

Slide 32

Presented By Dirk Arnold at 2016 ASCO Annual Meeting

Otras modalidades de Inmunoterapia en CCRm

.- Vacunas: Imprime PGG, GVAX, vacunas basadas en células dendríticas,

vacunas dirigidas frente a diferentes antígenos como CEA, NY-ESO-1, HER-2…

.- Terapia Celular adoptiva dirigida frente a distintos antígenos: NY-ESO-1, MAGE-A3,

MUC-1...

.- Virus oncolíticos: Enadenotucirev, Reolysin…

.- Adyuvantes para otras inmunoterapias: epacadostat, rintatolimod, motolimod…

.- Citokinas: IL-12, AM0010…

.- Lefitolimod (MGN1703): agonista del TLR-9 que estimula la respuesta inmune innata.

En marcha el F III IMPALA que explora su papel como mantenimiento en CCRm

● MGN1703 lefitolimod activates endosomal

TLR-9 on plasmacytoid DCs and B cells

● Broad activation of the innate and adaptive

immune system:

1) Antigen presenting cells (pDCs and B cells)

2) Subsequent activation of various pathways (CTL, NK-cells, ADCC)

Adapted from: B. Wittig et al. / Critical Reviews in Oncology/Hematology 94 (2015) 31–44

Tabernero; ASCO 2017

Tratamiento de pacientes no

subsidiarios de QT intensiva

¡Muchas gracias!