Colorectal Cancer Immunotherapy (IO)

TODAY’S WEBINAR

SPEAKER(S) Dr. Michael Morse from Duke University and Fight CRC’s

Andi Dwyer

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RE

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S

TABOO-TY PODCAST MINI MAGAZINES YOUR GUIDE IN THE FIGHT

FIG

HT

CO

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RE

CTA

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CE

R D

ISC

LA

IME

RThe information and services provided

by Fight Colorectal Cancer are for

general informational purposes only.

The information and services are not

intended to be substitutes for

professional medical advice,

diagnoses or treatment.

If you are ill, or suspect that you are ill,

see a doctor immediately. In an

emergency, call 911 or go to the

nearest emergency room.

Fight Colorectal Cancer never

recommends or endorses any specific

physicians, products or treatments for

any condition.

Dr. M

ich

ae

l M

orse

, M

HS

,FA

CP

Du

ke

U

nive

rsity

Michael Aaron Morse is studying the use of immune therapies to treat various cancers, including gastrointestinal, breast, and lung cancers and melanoma. These therapies include vaccines based on dendritic cells developed in our laboratory as well as vaccines based on peptides, viral vectors, and DNA plasmids. Our group is also a national leader in the development and use of laboratory assays for demonstrating immunologic responses to cancer vaccines. Finally, we are developing immunotherapies based on adoptive transfer of tumor and viral antigen-specific T cells.

Our current clinical trials include phase I and II studies of immunotherapy for: patients with metastatic malignancies expressing CEA, pancreatic cancer, colorectal cancer, breast cancer, and ovarian cancer, and leukemias following HSCT. My clinical area of expertise is in gastrointestinal oncology, in particular, the treatment of hepatic malignancies, and malignant melanoma.

Education and TrainingFellow In Hematology Oncology, Medicine, Duke University, 1993 - 1996Medical Resident, Medicine, University of Washington, 1990 - 1993M.D., Yale University, 1990

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Andrea (Andi) Dwyer is the Co-Director of the Colorado Colorectal Screening Program at the University of Colorado Cancer Center and Program Director at the Colorado School of Public Health. Andi was a key member of the team who developed and implemented patient navigation of the Colorado Colorectal Screening Program (the Program), one of the largest screening and early detection navigation programs in the country.

She has worked for nearly ten years in the area of colorectal cancer prevention and health promotion and authored several papers in the field. Andi is also an instructor for the Colorado Patient Navigation Training. She serves as the Project Director for the Colorado Cancer Prevention and Control Research Network, jointly funded by Centers for Disease Control and Prevention (CDC) and National Cancer Institute (NCI) and is working in the area of dissemination and implementation research. Andi is the out-going chair of the Colorado Colorectal Task Force and Co-Chair of Scientific and Evidence Based Health Interventions of the National Colorectal Cancer Roundtable.

She also serves as the Director of Health Promotion for Fight Colorectal Cancer, focusing on research and patient education.

Colon Cancer Immunotherapy

Michael A. Morse, MD, MHS, FACP

Professor of Medicine

GI Oncology

Duke University Medical Center

Cancer Immunity Cycle and Targets for Immunotherapy

Chen DS, Mellman I. Immunity. 2013;39:1-10.

Therapies to target cancer immunity cycle

Chen DS, Mellman I. Immunity. 2013;39:1-10.

Immune infiltrate and Outcome in CRC

Primary CRC CRC Liver Metastases

(4)-Hi 42%(3)-Hi 27%(1-2)-Hi 27%(0)-Hi 4%

69%

Katz Ann Surg Onc 2013Galon JCO 2006

CD8 high 19%

MSI-H CRC is a unique subgroup

Sargent, et al. ASCO 2008; Tejpar BJC 2009; Koopman BJC 2009

Stage MSI-H

II 22%

III 12%

IV 3.5%

– Clinicopathology: • lymphocytic infiltrate, Crohn’s-like reaction, variegated histology, poor

differentiation, right sided

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

Years

% D

ise

as

e F

ree

HR: 0.51 (0.29-0.89)

p=0.009

Untreated (N=515)

MSI-H 80%MSS 56%

5 yr DFS

Frequency of MSI

decreases by stage

Improved clinical outcome in early stage

MSI CRC is more infiltrated with T cells

Llosa, Cancer Discov. 2015;5:43-51

dMMR / MSI-high CRC: neoantigens and T cell

infiltration

Lord, Nat Rev 2012; Saeterdal I, et al. Proc Natl Acad Sci U

S A. 2001;98(23):13255-13260.dMMR, deficient mismatch

repair; MSI, microsatellite

instable

Mutations or loss of MMR expression results

in MSI, high mutational load, and neoantigens

T cell infiltrate

With Ag-specific

T cells

MSI has higher levels of checkpoint molecules

Llosa, Cancer Discov. 2015;5:43-51

3 6 5 7 3 0

-1 2 5

-1 0 0

-7 5

-5 0

-2 5

0

2 5

5 0

7 5

1 0 0

1 2 5

%C

ha

ng

e fro

m B

as

elin

e S

LD

M M R -d e fic ie n t C R C

M M R -p ro fic ie n t C R C

Anti-PD-1 Ab in dMMR CRC

MMR-

proficient

CRC

0% RR

16% DCR

MMR-

deficient

CRC,

57%RR

89% DCR

a

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0

- 1 0 0

- 7 5

- 5 0

- 2 5

0

2 5

5 0

7 5

1 0 0

W e e k s

Ch

an

ge

in

S

um

o

f T

ar

ge

t L

es

io

ns

S

iz

e (%

)

O n

T r e a t m e n tO f f T r e a t m e n t

C o m p l e t e o r P a r t i a l

R e s o p o n s eF i r s t O c c u r r e n c e o f N e w L e s io n

C h a n g e T r u n c a t e d t o 1 0 0 %

On treatment

Off treatment

CR or PR

First occurrence of new lesion

MMR-

deficient

CRC

31% RR

70% DCR

Pembrolizumab – NCT01876511 Nivolumab – CheckMate-142MMR-proficient CRCMMR-deficient CRC

Le DT, et al. N Engl J Med. 2015;372(26):2509-2520. Le DT, et al. J Clin Oncol. 2016;34(Suppl): Abstract 103. Overman MJ, et al. J Clin Oncol. 2017;35(Suppl 4S): Abstract 519.

BRAF Mutation Status100

-50

-100

50

0

Inve

sti

ga

tor-

As

se

ss

ed

Be

st

Ch

an

ge

in

Ta

rge

t L

es

ion

Siz

e (

%) Mutant

Wild type

+ Confirmed

CR/PR

Clinical History of Lynch

Syndrome100

-50

-100

50

0

Inve

sti

ga

tor-

As

se

ss

ed

Be

st

Ch

an

ge

in T

arg

et

Le

sio

n S

ize

(%

)

Yes

No

+ Confirmed CR/PR

≥ 1%

< 1%

+ Confirmed

CR/PR

Inve

sti

ga

tor-

As

se

ss

ed

Be

st

Ch

an

ge

in

Ta

rge

t L

es

ion

Siz

e (

%)

Tumor PD-L1

Expression100

-50

-100

50

0

Rare

Intermediate

Numerous

+ Confirmed CR/PR

Inve

sti

ga

tor-

As

se

ss

ed

Be

st

Ch

an

ge

in

Ta

rge

t L

es

ion

Siz

e

(%)

Abundance of PD-L1

Expressing Tumor-

Associated Immune Cells

Response Regardless of PD-L1, BRAF Mutation, or Lynch Syndrome

Overman MJ, et al. J Clin Oncol. 2017;35(Suppl 4S): Abstract 519.

Cobimetinib + Atezolizumab in MSS CRC

Bendell JC, et al. J Clin Oncol. 2016;34(Suppl): Abstract 3502.

Confirmed

Response, %

KRAS mutant

CRC

(n = 20)

All CRC Patients

(N = 23)

ORR

PR

20

20

17

17

SD 20 22

PD 50 52

NE 10 9

• Response did not correlate with PD-L1 status: IC0 (n = 2), IC1 (n = 1)

and IC3 (n = 1)

Treatment-related AEs

(> 15% incidence), %

All Grade Grade 3

Diarrhea 70 9

Fatigue 52 4

Dermatitis acneform 44 0

Rash 35 4

Nausea 26 4

Maculopapular rash 26 4

Pruritus 26 0

AST increased 22 4

Blood creatine phosphokinase increased 22 0

Edema peripheral 17 0

Stomatitis 17 0

Vomiting 17 4

Pivotal Studies of Interest in mCRC

NRG-

CR1556

/SWOG-

1610

COMMI

T

MSI-

high

mCRC

mFOLFOX6/Bevacizumab

mFOLFOX6/Bevacizuma

b

+ Atezolizumab

Atezolizumab

KEYNOT

E 177

MSI-high

mCRC

mFOLFOX6/Bevacizumab

Pembrolizumab

1o endpoint: PFSNCT02997228

NCT02563002

Not yet recruiting

GO30182

(COTEZO

)

Mainly

MSS;

> 2 prior

regimens

NCT02788279 Azetolizumab/cobimetinib

Regorafenib

Atezolizumab

1o endpoint: OS1o endpoint: PFS

BACCI:

Refractor

y mCRC

PhII

Cape/Bev/Atezolizumab

Cape/Bev

1o endpoint: PFS

Not yet recruiting

NCT02873195

Early studies of interest

BMS 142 ProCohort 4 Ph II open label trial of

Nivo+Ipi+Cobimetinib in MSS mCRC

MSI status not required to enroll, will be tested

locally, tissue verified prior to tx

Prior cohorts closed to accrual

Macrogenics

MGD007, Dual Affinity Retargeting Protein

for Glycoprotein A33 and CD3. Check for

slots

eFFECTOR Pro00085460

Ph II Open Label, Randomized study of

eFT508 (MNK1 +2 inhibitor) alone and with

Avelumab in MSS Refractory CRC

BMS 142

Cohort 5 Ph II Open label trial of Nivolumab

+ Anti-Lag-3 in previously treated MSI high

mCRC patients

BMS 142

Cohort 6 Ph II Open label trial of Nivolumab

+ Daratumumab in previously treated MSS

mCRC patients

Immunotherapy Efforts and Fight CRC

Immunotherapy Standard of Care

Immunotherapy is rapidly becoming a standard of care for many

cancers.

However, colorectal cancer (CRC) had been generally resistant to

immunotherapy, despite features in common with sensitive tumors.

Observations of substantial clinical activity for checkpoint blockade in

CRCs with defective mismatch repair (microsatellite instability high

[MSI-H] tumors) has re-ignited interest in the search for

immunotherapies that could be extended to the larger microsatellite

stable (MSS) population.

Convening

The Cancer Research Institute and Fight

Colorectal Cancer convened a group of

scientists, clinicians, advocates, and industry

experts in CRC and immunotherapy to compile

ongoing research efforts, identify gaps in

translational and clinical research, and provide a

blueprint to advance immunotherapy.

Main Issues

We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear.

Whether biomarkers with prognostic value, such as the immunoscores and interferon signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with CRC will need to be incorporated into clinical guidelines.

Framework

We have proposed a framework for research to identify immunologic factors

that may be modulated to improve immunotherapy for CRC patients, with the

goal that the biomarkers and treatment strategies identified will become part of

the routine management of CRC.

Major Policy Issue

Testing MSI status of patients at time of diagnosis to help understand the best

treatment for patients.

This is a huge issue and we are working with a multi-stakeholder group to move

ahead…

Keep on Convening

The Immunotherapy Workgroup has requested that Fight CRC continue to host

and convene the group to speak about shared interest and work.

Q

&

A

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