Colon Cancer: State of the Art...2018/09/12 · 0.006 *Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary,

Colon Cancer: State of the Art

Heinz-Josef Lenz

Professor of Medicine and Preventive Medicine

Associate Director, Clinical Research

J Terrence Lanni Chair in Cancer Research

Co-Director, USC Center for Molecular Pathways and Drug

Discovery

USC/Norris Comprehensive Cancer Center

Los Angeles, California

HEINZ-JOSEF LENZ COLORECTAL CANCER: STATE OF THE ART

ADVISORY BOARDS: BAYER, BOEHRINGER-INGELHEIM, MERCKSERONO, ROCHE, GENENTECH, BMS

CLINICAL TRIAL SUPPORT: ROCHE, BAYER, TAIHO, DAICHI, INCYTE, BOEHRINGER-INGELHEIM, BMS, PFIZER,

MERCK, MERCKSERONO, SWOG, NCI, NIH

THE SPEAKER WILL DIRECTLY DISCLOSURE THE USE OF PRODUCTS FOR WHICH ARE NOT LABELED (E.G., OFF LABEL USE) OR IF THE

PRODUCT IS STILL INVESTIGATIONAL.

14th Annual California Cancer Conference Consortium

August 10-12, 2018

The Colorectal Cancer Subtyping Consortium

(CRCSC) identifies a network of molecular subtypes

Dienstmann R, et al. ASCO 2014 (Abstract No. 3511)

Group A

Group B

Group C

Group D

Group E

Group F

Subtype 1.3

D

E CCS3

Subtype 1.1

C4 Stem-like

C_score

CMS4

C2

C

Inflammatory

CCS2 A_score

Subtype 1.2 CMS1

Subtype 2.1

C3

Goblet-like

A

CMS3

CMS2

CCS1

Enterocyte

B_score

B

C5

TA

C1

Subtype 2.2

Presented by: Heinz Josef Lenz

0 12 24 36 48 60 72

Months From Randomization

0.00

0.25

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0 12 24 36 48 60 72


0.00

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Logrank P-value:


0 12 24 36 48 60 72


0.00

0.25

0.50

0.75

1.00P

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0 12 24 36 48 60 72


0.00

0.25

0.50

0.75

1.00P

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ou

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ve

nt

Logrank P-value: 0.0290

11.7 (10.9-18.0)49/55Cetuximab

22.5 (15.9-32.6)36/49Bevacizumab

Median (95% CI)Events/TotalArm

OS – CMS1 Patients by Arm


0 12 24 36 48 60 72


0.00

0.25

0.50

0.75

1.00P

ro

po

rtio

n W

ith

ou

t E

ve

nt

0 12 24 36 48 60 72


0.00

0.25

0.50

0.75

1.00P

ro

po

rtio

n W

ith

ou

t E

ve

nt

Logrank P-value: 0.0484

42.0 (39.3-54.4)79/119Cetuximab

36.0 (33.5-42.3)94/123Bevacizumab

Median (95% CI)Events/TotalArm

OS – CMS2 Patients by Arm

● Ding et al., Nature 2010

● Mutations present in 5–90% of

sequencing reads from one tumor

● Navin et al., Nature 2011

● Independent subclones coexisting

in a single anatomic site in breast

● Gerlinger et al., NEJM 2012

● Two-thirds of mutations in single

biopsies were not uniformly

detectable throughout all sampled

regions

● Both sensitive and resistant RNA

expression patterns

Heterogeneity also exists within

individual tumors

Intra-tumor copy number heterogeneity in CRC at the single gland level

C. Curtis & colleagues

Liquid Biopsies

Circulating

Tumor

Cells (CTC)

http://www.inostics.com/

Tumor specific change (e.g. Mutation)

Tumor

Tumor cell

release DNA and RNA Circulating

tumor DNA

Normal DNA

CTC

Blood Vessel

Circulating

tumor RNA

MGH GI Cancer Center Liquid Biopsy Program

Routine liquid biopsy

assessment can effectively

identify mechanisms of

resistance across different

tumor types and treatments

Mechanism of resistance identified in 80%

36% with multiple resistance mechanisms

(range 2-12; median 3)

In patients with matched tumor biopsies, ctDNA

identified additional resistance mechanisms in 64%

RAS WT CRC (n=21)

54%

BRAF mCRC (n=5) 13%

FGFR2 biliary (n=8) 21%

FGFR2 gastric (n=1)

2%

MET amp gastric (n=2)

5%

HER2 amp CRC (n=2)

5%

N=39

no mechanism identified (n=8)

21%

multiple mechansims identified (n=14)

36%

single mechanism identifed (n=17)

43%

EGFR antibodies in RAS-WT CRC

Anti-EGFR antibodies

RAS

CRAF

ARAF

BRAF

ERK

MEK

PROLIFERATION AND SURVIVAL

KRAS

NRAS

HRAS

EGFR RTK

• 10 distinct resistance alterations

identified across 21 patients

• KRAS mutations

• KRAS amplification

• EGFR ECD mutations

• MET amplification

• ERBB2 amplification

• Novel MEK1 mutation

• Some patients with 5 or more

alterations present in ctDNA

A Bertotti et al. Nature 000, 1-5 (2015) doi:10.1038/nature14969

Therapeutic intervention in preclinical trials to

overcomeresistance to anti-EGFR antibody

blockade.

Interesting Findings

14

1. In a small series of 10 patients who all had mt ras in tissue

and liquid biopsy treated with bev based chemotherapy.

5/10 changed to wt Ras under chemotherapy ) Gazzaniga

et al Annals of Oncology (2017) 28 (suppl_5): v573-v594)

2. Case report in JCO Precision Oncology from same group

reported PR in one of this patient treated with cetuximab

CALGB/SWOG 80405

Chemo + Cetuximab

Chemo + Bevacizumab

1ST LINE

MET / ADVANCED

COLORECTAL

KRAS wt Codons 12 & 13

FOLFIRI or

FOLFOX

MD choice

ASCO, JUNE, 2014 Chemo + Cetuximab

OS = 29.9 mos

PFS = 10.4 mos

Chemo + Bevacizumab

OS = 29.0 mos

PFS = 10.8 mos N = 1137

: NO DIFFERENCE

All RAS

wt

OS = 32.0 mos

PFS =11.4 mos

OS = 31.2 mos

PFS = 11.3 mos

ESMO, SEP, 2014

N = 526

ESMO, 2016

N = 474 *

OS = 32.5 mos

OS = 31.2 mos

* Right or left-sided primary

Included in sidedness analysis

80405: Overall Survival by Sidedness (all RAS wt)

Side N

(Events)

Median

(95% CI)

HR

(95% CI) p

Left 325

(238)

35.2

(32.1-39.0) 0.72

(0.56-0.92) 0.009

Right 149

(114)

21.9

(16.3-29.0)

80405: OS by Sidedness (Bevacizumab)

Side

N

(Events)

Median

(95% CI)

HR

(95% CI)

Adjusted

p

Left 152

(119)

32.6

(28.3-36.2) 0.88

(0.62-1.25) .50

Right 78

(58)

29.2

(22.4-36.9)

80405: OS by Sidedness (Cetuximab)

Side N

(Events)

Median

(95% CI)

HR

(95% CI)

Adjuste

d P

Left 173

(119)

39.3

(32.9-42.9) 0.55

(0.39-0.79) 0.001

Right 71

(56)

13.6

(11.3-19.0)

80405: Sidedness Predictive for Biologics

Biologic by 1° Side Interaction BIOLOGIC SIDE OF PRIMARY HAZARD RATIO

95% CI

P (adjusted*)

Any biologic

OS

Cetux v Bev; left

Cetux v Bev; right

1.81

(1.15, 2.84)

Pint = 0.009

PFS 1.94

(1.28, 2.95)

Pint = 0.001

Cetux v Bev

OS

Left 0.77

(0.59, 0.99)

0.04

PFS 0.84

(0.66, 1.06)

0.15

Cetux v Bev

OS

Right 1.36

(0.93, 1.99)

0.10

PFS 1.64

(1.15, 2.36)

0.006

*Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary,

liver metastases

Numbers at

Risk

Cetuximab + FOLFIRI

38

10 0 0

0 0 0

Bevacizumab +

FOLFIRI

5

0

16 1 0 0 0 0

Cetuximab + FOLFIRI

38

24 10 4 1 1 0

Bevacizumab +

FOLFIRI

50

37 16 7 1 0 0

Progression-free survival

Overall survival

FIRE-3: Right-sided tumors

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity o

f P

FS

7.6

9.0

HR = 1.44 (95% CI: 0.92–

2.26)

p = 0.11

Right-sided mCRC

Bevacizumab + FOLFIRI (n=50)

0 12 60 72 24 36

48

Months

Numbers at Risk

0.0

0.2

0.4

0.6

0.8

1.0 Right-sided mCRC

Pro

ba

bil

ity o

f O

S

HR = 1.31 (95% CI:

0.81–2.11)

p = 0.28

Cetuximab + FOLFIRI (n=38)


18.3 23.0

0 12 60 72 24 36 48

Months


Numbers at

Risk

Cetuximab + FOLFIRI

157

60 17 10 6 4 0

Bevacizumab +

FOLFIRI

149

56 13 7 2 0 0

0.0

0.2

0.4

0.6

0.8

1.0 Left-sided mCRC

Pro

ba

bil

ity o

f P

FS

10.7

10.7

HR = 0.90 (95% CI:

0.71–1.14)

p=.38



0 12 24 36

Months

60 72 48

A

0.0

0.2

0.4

0.6

0.8

1.0 Left-sided mCRC

Pro

ba

bil

ity o

f O

S

0 12

HR = 0.63 (95% CI:

0.48–0.85)

p = 0.002



60 72

24 36 48

Months

B

Cetuximab + FOLFIRI

157

131 77 38 23 6 0

Bevacizumab +

FOLFIRI

149

120 76 31 11 3 0

Progression-free survival

Overall survival

FIRE-3: Left-sided tumors

28.0 38.3

Numbers at

Risk

BRAF mut

MSI

KRAS

PIK3CA

Mucinous

differentiation

Right

Left

18q loss

20q Gain

EREG expression

EGFR gain

HER2 gain

Poor

Prognosis

Sensitive to

Cetuximab

Good

Prognosis

High mutation

Frequency

Distinct Biology of R v. L CRC

Analysis of PETACC-3 samples (n=2849)

Missiaglia, ASCO 2013

LEFTy Organization

HR for OS According to Primary Tumor Location

Loree JM,.... Kopetz S; Clin Cancer Res 2018

T + EGFR-i

if ORR is a

primary goal

D + Bev

if EGFR-i are not

accepted/tolerated

RAS wt

Left-sided

Treatment options based on Location: My Take

D + EGFR-i

if OS is a

primary goal

Right-sided

D/T + Bev

if OS is a

primary goal

default

recommendation

default

recommendation D: chemo doublet

T: chemo triplet

Microsatellite Instability

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

Le DT, et al.

NEJM 2015

and ASCO

2016

-1 0 0

-5 0

0

5 0

1 0 0

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

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

% C

ha

ng

e fro

m B

as

elin

e S

LD

MMR-deficient CRC, N=28

MMR-proficient CRC, N=25

Response Rate 57% 0%

Disease Control Rate 89% 16%

Pembrolizumab

MSI-high CRC: Nivolumab Monotherapy

Overman et al. Lancet Oncology 2017

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

Disease Control ≥12weeks in 69%

RR 31% SD 39% PD 24%

Reduction in Target Lesions Regardless of PD-L1 Expression, BRAF or Lynch History

≥ 1% < 1% + Confirmed CR/PR

Inve

stig

ato

r-A

sses

sed

Be

st C

han

ge in

Tar

get

Lesi

on

Siz

e (

%)

Tumor PD-L1 Expression

100

-50

-100

50

0

BRAF Mutation Status 100

-50

-100

50

0

Inve

stig

ato

r-A

sses

sed

Bes

t C

han

ge in

Tar

get

Lesi

on

Si

ze (

%)

Mutant Wild type + Confirmed CR/PR

Clinical History of Lynch Syndrome 100

-50

-100

50

0

Inve

stig

ato

r-A

sses

sed

Bes

t C

han

ge in

Tar

get

Lesi

on

Si

ze (

%)

Yes No + Confirmed CR/PR

Overman et al. Lancet Oncology 2017

World Congress On Gastrointestinal Cancer, 2018 Bendell J, et al. IMblaze370

IMblaze370: randomised, Phase III, multicentre, open-label study in mCRC

Atezo, atezolizumab; cobi, cobimetinib; INV, investigator; rego, regorafenib. a Two-sided type I error rate of 0.05 was controlled by hierarchical testing (testing atezo vs rego only if atezo + cobi vs rego

was positive). NCT02788279.

32

• Unresectable locally

advanced or metastatic

CRC

• Received ≥ 2 prior

regimens of cytotoxic

chemotherapy for

metastatic disease

• ECOG PS 0-1

• MSI-H capped at 5%

Regorafenib 160 mg oral 21/7 days

Atezolizumab 840 mg IV q2w

+ cobimetinib 60 mg oral 21/7 days

Atezolizumab 1200 mg IV q3w R

2:1:1

N=363 Lo

ss o

f

clin

ical

ben

efi

t

Primary endpoint

• OSa

– Atezo + cobi vs rego

– Atezo vs rego

INV-assessed key secondary endpoints

• PFS

• ORR

• DOR

Stratification

• Extended RAS mutation status (≥ 50% patients in each arm)

• Time since diagnosis of first metastasis (< 18 months vs ≥ 18 months)

• Data cutoff date: March 9, 2018

World Congress On Gastrointestinal Cancer, 2018 Bendell J, et al. IMblaze370

Overall survival

N/A, not applicable. HRs are from stratified log-rank tests.

Data cutoff: March 9, 2018. a For descriptive purposes only.

33

Atezo + cobi

(n = 183)

Atezo

(n = 90)

Rego

(n = 90)

Median OS, mo

(95% CI)

8.9

(7.00, 10.61)

7.1

(6.05, 10.05)

8.5

(6.41, 10.71)

HR vs rego

(95% CI)

1.00

(0.73, 1.38)

1.19

(0.83, 1.71) N/A

P value 0.9871 0.3360a N/A

12-mo OS, % 38.5% 27.2% 36.6%

HER2 Overexpression

HER2/neu 3+ (2+)

Trastuzumab + Lapatinib in HER2+ / KRAS-wt pts refractory to ani-EGFR AK

Siena, et al. ASCO 2015

HERACLES Trial

849 patients screened, 46 patients (5.4%) HER2+ (2+/3+); 23 patients evaluable for response

ORR 35%, DCR 78%

Optimal treatment of mCRC in

the presence of braf

Clinical Efforts in BRAFmut

37

BRAFi+ EGFRi

BRAFi+ EGFRi

+ PI3Ki

BRAFi+ EGFRi

+ MEKi

Roche/Genentech

GSK Novartis

BRAFi+ EGFRi

+ chemo

US Cooperative Groups

Study Design

Presented by: Scott Kopetz, MD, PhD

R

E

G

I

S

T

R

A

T

I

O

N

Local

BRAF

testing

No local

BRAF

testing

BRAF

V600E

Mutation

Central

Testing

Performed

Wild-type

(off study)

R

A

N

D

O

M

I

Z

A

T

I

O

N

ARM 1:

Cetuximab +

Irinotecan

ARM 2:

Vemurafenib +

Cetuximab +

Irinotecan

STEP 3: Cross-

over to add

Vemurafenib

Progression

Off Study

Progression Off Study

Vemurafenib 960mg PO bid continuous

Cetuximab 500mg/m2 IV q2weeks

Irinotecan 180mg/m2 IV q2weeks

Primary Endpoint: Progression-free survival


N Events Median 95% Conf Int

Cetuximab + Irinotecan 50 46 2.0 (1.8 – 2.1)

Vemurafenib + Cetuximab 49 36 4.3 (3.6 – 5.7)

+ Irinotecan

HR = 0.48 (95% CI 0.31 – 0.75)

P=0.001

0 3 6 8 10 12 14

Months after randomization

80%

100%

60%

40%

20%

0%

April 18. 2017 data cutoff

Response Rate

Cetuxim

ab +

Irinotec

an

(n=45)a

Vemurafe

nib

+

Cetuxima

b +

Irinotecan

(n=43)a

P-valuec

Partial

response 4% 16%

P=0.001 Stable

disease 18% 48%

Progressionb 56% 12%

Disease

Control 22% 67%

Rate

a93 patients had measurable disease; b Including symptomatic

deterioration; c Chi-squared


Cetuximab + Irinotecan

Vemurafenib + Cetuximab + Irinotecan

April 18. 2017 data cutoff

100%

20%

-100%

0%

-30%

100%

20%

-100%

0%

-30%

BEACON CRC Phase 3 Study Design1

Safety Lead-in Completed Phase 3 Currently Enrolling

ENCO 300 mg QD

+

BINI 45 mg BID

+

CETUX 400 mg/m2 (initial),

then 250 mg/m2 QW

Triplet therapy

ENCO + BINI + CETUX

n=205

Doublet Therapy

ENCO + CETUX

n=205

Control Arm

FOLFIRI + CETUX, or

IRI + CETUX

n=205

Disease

progression

Disease

progression

Disease

progression

Continued

follow-up

for

evaluation

of OS

R

1:1:1

1. Clinicaltrials.gov/ct2/show/NCT02928224; https://clinicaltrials.gov/ct2/show/NCT02928224 (February 2018).

N=30

Van Cutsem et al., ESMO GI 2018

2 6 1 1 7 2 1 6 9 1 4 7 8 1 3 2 8 2 5 2 4 2 3 2 7 1 5 1 2 4 * 2 2 2 1 1 9 2 0 1 8 1 1 6 * 1 0 3 5 *

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

1 0 0

P a rt ia l R e s p o n s e (n = 1 1 )

C o m p le te R e s p o n s e (n = 3 )

Best Percentage Change in Tumor Measurements from Baseline

*Patients with lymph node disease with decreases in short axis dimensions consistent with RECIST 1.1 defined Complete Response. †One patient had no baseline sum of longest diameters and is not presented.

1. Kopetz S, et al. J Clin Oncol. 2017;35:Abstr 3505, with permission.

Be

st

% C

ha

ng

e f

rom

Ba

se

lin

e

Patients†

1 Cetuximab + Irinotecan from SWOG S1406


BEACON SLI: Overall Survival 100

0

10

20

30

40

50

60

70

80

90

0 3 6 9 12 15 18 Time (mo)

Ove

rall

su

rviv

al (%

)

Patients with BRAFV600 mutation (N=29)

Censored patients

1-year OS rate: 62%

29 28 25 22 18 6 0

Survival Rate 1 Prior

Regimen

2 Prior

Regimens

6 mo 88% 85%

12 mo 63% 62%

Patients at risk


Median OS: Not reached Data fully mature through 12.6 months

Ras and effector dependencies

• KRAS subtype lines:

– depend on the canonical RAS-RAF MAPK pathway

– upregulate genes involved in the maintenance of the epithelial phenotype

• RSK subtype lines:

– depend on the RSK-MTOR/PI3K axis to drive aerobic metabolism to supplement glycolysis

– express mesenchymal markers ZEB1, TGFB, TWIST

Tina Yuan, Rachel Bagni, Cyril Benes, Arnaud

Amzallag, Bob Stephens, Ming Yi, FNLCR

Cell Feb 2018

RS

K

KR

AS

KRAS suptype: RAF/MEK/ERK dependencies

1. Inhibition of this signaling with MEK inhibitors

such as trametinib, selumetinib alone or in

combination

2. Inhibition of ERK with inhibitors such as MK-

8353, BVD-523

3.Combination of MEK and ERK inhibition to

overcome resistance

4.Pan raf inhibitors LY3009120

5.RAF/MEK inhibitor RO5126766

6.Combination of AKT/MEK PI3K/MEK inhibitors

7.Cdk4/6 and MEK inhibitors

MLH1 rs1799977 Outcome Data from KRAS mut mCRC patients in TRIBE FOLFIRI/bevacizumab arm

HR 3.14 (95%CI 1.37-7.18) Median OS 25.8 vs 18.4 months

CCL2 rs4586 Outcome Data from KRAS mut mCRC patients in TRIBE FOLFIRI/bev Arm

HR 0.51 (95%CI 0.28-0.92) Median PFS 25.8 vs 18.4 months

RAS mutated

BRAF mutated, MSS

MSI-High

RAS/BRAF wild type

• “Left Sided”

• “Right Sided”

Current View of mCRC Treatment

FOLFOXIRI + Bev

Vemurafenib/

Cetuximab/Irinotecan

or Clinical Trial

FOLFOX + Bev PD-1 inhibition

FOLFOX + Bev FOLFIRI + Bev

Salvage

Oral

agents:

Rego

TAS-102 FOLFOX + Cet/Pan

(or Bev)

FOLFOX + Bev FOLFIRI + Bev Irinotecan +

Cetuximab/Pantimumab

FOLFIRI + Bev (or

Cet/Pan)

FOLFOX + cetux

The one who knows more, may decide better

Documents

Colon Cancer: State of the Art...2018/09/12 · 0.006 *Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary,