Later lines of treatment and concept of continuum

of care

Claus-Henning Köhne

Universitätsklinik Onkologie / Hämatologie

Nordwestdeutsches Tumorzentrum

▪ Regorafenib is recommended in patients pretreated with

fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and in

RAS wild-type patients with anti-EGFR antibodies

▪ Regorafenib is superior to placebo in terms of overall survival, although

there are safety / toxicity concerns in frail patients.

▪ TAS 102 is a new option for patients pretreated with

fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and in

RAS wild-type patients with anti-EGFR antibodies

Third and further line therapy

Treatment of metastatic disease

ESMO PRECEPTORSHIP PROGRAM

Regorafenib (BAY 73-4506):

an oral multikinase inhibitor 1,2,3

1. Wilhelm SM, et al. Int J Cancer. 2011;1219(1):245-255. 2. 2. Mross K, et al. Clin Cancer Research 2012;18(9):2658-2667.3. 3Strumberg D, et al. Expert Opin Investig Drugs. 2012;21(6):879-889.

Inhibition of

roliferation

Inhibition of

angiogenesis

Inhibition pf signalling

In tumor –

microenvironment

CORRECT Trial: Regorafenib or Placebo

after failure of standard therapy

Pat. With

pretreated

mCRC

(n=760)*

R 2:1

Placebo + BSC

(n=255)

Regorafenib + BSC

(n=505)

Preceding treatment MUST have been contained Fluoropyrimidine, Oxaliplatin, Irinotecan, Bevacizumab,

and (in KRAS wt) Cetuximab or Panitumumab

Van Cutsem, E, et al. J Clin Oncol. 2012;30(15S): Abstract 3502

CORRECT CONCUR

Regorafenib(n=505)

Placebo(n=255)

Regorafenib(n=136)

Placebo(n=68)

Median age, years (IQR) 61 (54–67) 61 (54–68) 58 (50–66) 56 (49–62)

Male, % 62 60 63 49

Race, %Asian 15 14 100 100

Median body mass index, kg/m2 25 26 23 23

ECOG PS 0/1, % 52/48 57/43 26/74 22/78

KRAS wild-type/mutant/unknown, % 41/54/5 37/62/2 37/34/29 43/26/31

>3 prior treatment lines for metastatic disease, % 49 47 38 40

Previous targeted biological treatment, %NoneAny (anti-VEGF, anti-EGFR, or both)Anti-VEGF, but not anti-EGFRAnti-EGFR, but not anti-VEGFAnti-VEGF and anti-EGFR

0100480

52

0100520

48

4159241818

3862192518

Baseline characteristics

ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IQR, interquartile range;VEGF, vascular endothelial growth factor.Grothey A, Van Cutsem E, et al. Lancet 2013;381:303–312; Li J, et al. Lancet Oncol 2015;16:619–629.

Overall'survival'(OS)'

CORRECT&

CONCUR&

Grothey&A,&Van&Cutsem&E,&et#al.#Lancet#2013;381:303–312;&Li&J,&et#al.#Lancet#Oncol#2015;16:619–629.#

Regorafenib trials outcome

Proportion of patients (%)

CORRECT CONCUR

Regorafenib(n=500)†

Placebo(n=253)†

Regorafenib(n=136)

Placebo(n=68)

Hand–foot skin reaction 17 <1 16 0

Fatigue 10 5 3 1

Hypertension 7 1 11 3

Diarrhea 7 1 1 1

Hypophosphatemia 4 <1 7 0

Lipase increase 3 <1 4 1

Rash 6 0 4 0

Selected drug-related grade ≥3 adverse events*

Grothey A, Van Cutsem E, et al. Lancet 2013;381:303–312; Li J, et al. Lancet Oncol 2015;16:619–629.

*Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0 (CONCUR).†Safety analyses are based on 753 patients who initiated treatment.

Difference between 5-FU and TAS-102

FdUMP

Inhibit

T

T

5-FU

dTTP

dTMP

TS

dUMP

Inhibit DNA

duplication

TAS-102

FTD

Thymidine (T)

Phosphorylation

DNA duplication

Incorporation

into DNA

F3dTMP

F3dTDP

FTD

F3dTTP

DNA damage

trifluridine (FTD)

tipiracil hydrochloride (TPI),

a thymidine phosphorylase inhibitor improves bioavailability of FTD

F3dTMP: trifluoromethyl deoxyuridine 5′- monophosphate

RECOURSE Trial: TAS-102 vs. placebo

Mayer R J et al N Engl J Med 2015;372:1909-19.

TAS 102 Tolerance

Mayer R J et al N Engl J Med 2015;372:1909-19.

Limited Evidence for Retreatment with Anti-EGFR in mCRC

Author n Study Design Population Outcome Comments

Saif M, et al.1

15 Retrospective case review of cases at 2 institutions (Yale and St Francis)

Patients who had tolerated panitumumab with clinical benefit after failure on cetuximab therapy

MR in 3/11; SD in 3/11. Median duration of SD: 4 mo

Grade 3/4 skin rash in 5 (33%) patients and asthenia in 1 patient

Metges J, et al. PANERB2

106 Prospective case seriesof on-label therapy in 22 institutions in Canada

Patients with KRAS WT mCRC whohad received a CETUX-based regimen and, after progression, monotherapy with panitumumab

Prior response to CETUX-basedregimen correlated with better response to panitumumab (n=48; ORR=31%; SD=16%) vs no prior response (n=28; ORR=7%; SD=7%)

Panitumumabmonotherapy has limited benefit for mCRC that did not respond to prior CETUX-based regimen

Liu X, et al. 3

104 Retrospective analysisof patients re-treated with an anti-EGFR agent in phase I/II studies

KRAS wild type mCRC; priorcetuximab or panitumumab therapy; retreatment anti-EGFR agents were cetuxumab + oxaloplatin or iritonecan based regimen (n= 77) or cetuxumab + erlotinib (n=15) or cetuxumab + sirolimus (n=12). Median interval between prior anti-EGFR and retreatment was 4.55 mo

CR/PR/SD rate was 56% for anti-EGFR retreatment, and had been 38% for initial anti-EGFR therapy. Prior CR/PR/SD with anti-EGFR correlated with ~3.5× higher ORR; longer interval between initial and retreatment correlated with ~2× higher ORR.

Prior responders to cetuximab-based treatment with longer interval length between initial and retreatment were more likely to respond to anti-EGFR therapy when re-treated (P <.001)

Santini D, et al.4

39 Phase II multicenter single-arm trial in patients retreated with CETUX-IRI after prior clinical benefit with the same regimen

Patients with clinical benefit after a line of CETUX + IRI-based therapy and then PD (“IRI-refractory”) who had received a new line of therapy after PD, and then progressed after treatment with this new line of therapy.

ORR was 53.8%; 19 (49%) PRs and 2 (5%) CRs; SD in 36% pts median PFS: 6.6 mo(must have had at least SD with prior CETUX + IRI-based therapy)

Correlation betweenskin tox during first CETUX + IRI-basedtherapy and rechallenge (P = 0.01)

1. Saif M, et al. Clin CRC. 2010;9:315-318; 2. Metges J, et al. ESMO. 2012: Ab 572P; 3. Liu X, et al. ASCO 2014. Ab 3607; 4. Santini D, et al. Ann Oncol. 2012;23: 2313-2318; Levels per Howick J, et al. Oxford Centre for Evidence-Based Medicine. 2011;

http://www.cebm.net/index.aspx?o=5653.

Level IV Evidence

Level IV Evidence

Level IV Evidence

Level III Evidence

G.SM.ON.09.2014.1007

Limited Evidence for Retreatment with Oxaliplatin in mCRC

Author n Study Design Population Outcome Comments

Chibaudel, et al1

285 Retrospective pooledanalysis of OPTIMOX-1 (n=165) and -2 (n=120), looking at Oxaloplatin-Free Interval (OFI)

Patients who received FOLFOX reintroduction which was scheduled or recommended at progression during maintenance or chemotherapy free interval for patients initially sensitive to oxaloplatin and in the absence of residual sensory neuropathy

PFS and OS higher if prior response to Oxaliplatin. OFI of >6 mo identifies a subgroup of patients in which FOLFOX has efficacy comparable to that in oxaliplatin-naive patients (ORR: 14%; SD: 31%)

A sensitive subset of patients maybenefit from Oxaliplatinreintroduction: defined by the efficacy of induction therapy followed by an OFI of at least 6 mo between 2 periods of FOLFOX therapy

Bhadkamkar, et al2

126 Retrospective database analysis (Prior oxaliplatin for Adjuvant, n=29; Unresectable mCRC, n=75; perioperative for metastasectomy, n=22)

Patients with mCRC who were retreated with an Oxaliplatinregimen

Median time to progression or discontinuation of Oxali was 3.1-3.3 mo

Cumulative neurotoxicity and hypersensitivity

Yau, et al3 28 Prospective, open-label, single arm phase II ; Efficacy and safety of capecitabine, oxaloplatin and irinotecan(CapeOxIri) in patients with treatment-refractory mCRC.

Patients with PD during or within 2 mo after prior last standard therapy. Patients had PD with prior 5FU, irinotecan or oxaloplatin. All KRASWT patients had progressed with prior cetuxumab-based therapies.

Overall, 6 (21%) PR, and 12 (43%) SD; 64% with clinical benefit (PR or SD). Median PFS was 6.2 months and median OS was 10.3 months

AEs included neuropathy (41%), diarrhea (41%), malaise (30%). Most common Gr 3-4 AEs :neutropenia (37%), thrombocytopenia (15%), anemia (15%)

Townsend,et al4

20 Retrospective analysis of Australian database for rechallenge with FOX

Patients with mCRC previously treated with Oxaliplatin, 5-FU, and irinotecan, chemotherapy (±bevacizumab) and anti-EGFR (if KRAS WT) or patients who had progressed within 12 mo of adjuvant Oxaliplatin-based therapy who were rechallenged with FOX

ORR was 18%, and 47% had SD. The median PFS was 3.7 mo median OS was 7.8 mo and 1-year survival was 37%

12% with worsening neuropathy;allergic reaction to Oxaliplatin in 1 patient (treatment continued with premedication)

FOX, fluoropyrimidine+oxaliplatin; OFI, oxaliplatin-free interval; ORR, objective response rate; OS, overall survival; PD, progressive disease; SD, stable disease.1. Chibaudel B, et al. Eur J Cancer. 2013;49:3813-3820; 2. Bhadkamkar N, et al. J Clin Oncol. 2013;31(4 suppl): Abstract 500;

3. Yau TC, et al. J Clin Oncol. 2014;32(suppl): Abstract e14511; 4. Townsend A, et al. Am J Clin Oncol. 2013:36:49-52.

Level IV Evidence

Level IV Evidence

Level III Evidence

Level IV Evidence

G.SM.ON.09.2014.1007

Special molecular subgroups

• Her2/neu

• BRAFmut

Mechanism of Resistance to EGFR antibodies

HER2 or HER3

overexpresseion

Stintzing & Heinemann Cancer Discov 2015

Arena et al. Science Translational Medicine 2016

MM-151 a third-generation EGFR inhibitor consisting of three fully human

immunoglobulin G1 antibodies that simultaneously engage distinct, non-

overlapping epitopes on EGFR

Resistant Cmab & Pmab

Resistant Cmab only

Montagut Nat Med 2012

S492R mutation

KRAS, NRAS, BRAF WT

HER2+

% T

um

or

shrinkage

aft

er

cetu

xim

ab tre

atm

ent

*

In mCRC patient-derived xenografts (PDX) resistant to anti-EGFR

monoclonal antibodies HER2 was found to be amplified

Patient

HER2 FISH

Xenopatient

CEP 17

HER2

Bertotti A. et al, Cancer Discovery 2011

Jeong et al. Clin Colorectal Can 2017

EGFR antibody resistance due to HER2 receptor

overexpression

lapatinib and

trastuzumab

lapatinib

trastuzumab

vehicle

Bertotti A. et al, Cancer Discovery 2011; Trusolino L. data on file

HER2-amplified mCRC PDX are sensitive to dual HER2-blockade

with lapatinib and trastuzumab but not to single agent

849 mCRC KRAS exon 2 WT

803 HER2-negative

21 not eligible (PS ≥2 or comorbidities)

Trastuzumab iv 4mg/kg load and then 2mg/kg/qw

Lapatinib po 1000 mg/qdPD

24 Enrolled

CE-CT scan: baseline, q8 weeks, at progression

HER2 ctDNA (plasma): baseline, q2 weeks, at progression

HER2 ECD (serum): baseline, q8 weeks, at progression

NGS Custom Panel (plasma, tissue): baseline, at progression

Tumor assessment re-biopsy

If possible

23 Evaluable for response

1 too early for safety &

efficacy assessment

46 HER2+ (5.4%)

HERACLES Diagnostic Criteria

HER2 IHC 2+ or 3+ in > 50% cells

and

FISH+ (HER2:CEP17 > 2) in > 50% cells

HERACLES Consort and Flow Chart

Sartore-Bianchi et al. Lancet Oncol 2016

Ch

ange

in t

arge

t le

sio

nfr

om

bas

elin

e (%

)

HER2 3+ HER2 2+ Patients on treatment PD NEW LESION

Waterfall plot

(best % tumor shrinkage)

Spaghetti plot

(tumor shrinkage trend)

Ch

ange

in t

arge

t le

sio

nfr

om

bas

elin

e (%

)

Trastuzumab/Lapatinib

Responses by HER2 IHC Score (46/849 5.4%)

RR 34%

Trastuzumab iv 4mg/kg load and then 2mg/kg/qwLapatinib po 1000 mg/qd

*3 patients are not shown: 122026 (IHC 2+,not yet

assessed);

121011 (IHC 3+) and 121013 (IHC 3+) early clinical PDs.

Sartore-Bianchi et al. Lancet Oncol 2016

Safety

Well tolerated

• Main toxicities: skin, GI, fatigue

• No grade 4 toxicities

• No withdrawal due to patient’s request

• No cardiac toxicity

Good compliance

• 96.4% of dosage received over planned

• 0% off treatment due to toxicities

• Median 6 months on treatment for responders

(range 5.3-16)

Sartore-Bianchi et al. Lancet Oncol 2016

Numbers of estimated pts. with indicated target

Colorectum | HER2 4 694 1 443

Lung | ALK 7 577 929

Lung | EGFR 20 477 3 098

Melanoma | BRAF 36 108 6 001

fraction of patients with genetic marker

Incidence data, EU Globocan 2012

total cases

Estimated quantitative impact as incidence in 2012

of actionable genetic markers in selected tumor types

Sartore-Bianchi et al. Lancet Oncol 2016

Special molecular subgroups

• Her2/neu

• BRAFmut

Vemurafenib in BRAF V600E Mutation

RAS

BRAFBRAF

InhibitorRelease of EGFR from

feedback inhibition with BRAF

inhibition and suppression

of ERK signaling

Proliferation

Angiogenesis

Survival

Invasion and metastasis

Ligand

MEK

ERK

PIP3PIP2PI3K-α

AKT

mTOR

Mechanisms of Resistance to BRAF Inhibition in Colorectal Cancer

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

BRAFmut disease

Efficacy: Encorafenib (E), Alpelisib (A), Cetuximab (C)

Median Overall Survival in BRAFm CRC With the Triplet and Doublet Regimens Compared With Historical Controls

28

6.0 5.8 5.74.7 4.3 4.1

13.1 12.4

02468

101214

21

3

3 4 5

Me

dia

n O

ve

rall S

urv

iva

l (M

on

ths

)

BRAFm CRC=BRAF-mutant colorectal cancer; CETUX=cetuximab; chemo=chemotherapy; FOLFIRI=folinic acid, fluorouracil, and irinotecan

1. De Roock W, et al. Lancet Oncol. 2010;11(8):753-762 2. Ulivi P, et al. J Transl Med. 2012;10:87 3. Peeters M, et al. J Clin Oncol. 2014;32:5s

4. Saridaki Z, et al. PLoS One. 2011;6(1):e15980 5. Loupakis F, et al. Br J Cancer. 2009;101(4):715-721

2nd line+

n=24

2nd line+

n=12

2nd line

n=23

2nd line

n=22

2nd line+

n=8

2nd line+

n=13

2nd line+

n=52

2nd line+

n=50

Introduction

Treatment of BRAF V600E mutations

Study Design

SWOG 1406

Response Rate

SWOG 1406 randomised Phase II Trial

Cetuximab / Irinotecan +/- Vemurafenib

Kopetz et al. ASCO 2017

Secondary Endpoint: Overall Survival

Summery BRAF mCRC

▪ Patients with BRAF mut disease have a poor prognosis

▪ Consider Intensive chemotherapy (FOLFOXIRI)

▪ EGFR inhibitors have a role

▪ VEGF inhibitors may have a role

▪ Combinations with EGFR, BRAF & MEK inhibitors are emerging

▪ Randomised trials are ongoing

Thank you for your attention

BRAF(V600E) + MSI-H/dMMR

28

Weeks

100 Percent Change from Baseline (%)

06121

824303

642485

460667

27884

75 50 25 0 -25 -50 -75 -100

Overma

n MJ, e

t al. J C

linOnco

l. 2016;3

4(suppl)

: Abstra

ct 3501

.

Nivolum

ab (MSI

-H)

1 Year

1 Year

Cobi/ate

zo(MSS

)

Bendell

J, et al.

J ClinO

ncol. 20

16;34(su

ppl): Ab

stract 3

502.

Efficac

y

COTEZO: Ongoing Phase III Study

•Chemo-refractory

advanced or mCRC*

•Stratification factors:

− MSI status

− Liver metastasis

Cobimetinib +

atezolizumab

Regorafenib

Atezolizumab2:1:1

N = 360

OS1OS2

National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT02788279. Accessed: July 5, 2017.

• Primary endpoint: Overall survival

• Secondary endpoints: Progression-free survival, investigator-assessed objective response,

duration of response (DOR), Quality of Life (EORTC QLQ-C30)

*After the approximate 5% cap for MSI-high patients is reached, only MSS patients will be eligible

Once the 50% cap for wild-type RAS has been reached, only extended RAS-mutant patients will be eligible

To Tur

n Cold

Tumo

r to Ho

t: Lear

ning F

rom CR

C

Tabern

ero J,

et al. J

Clin O

ncol. 2

017;35

(Suppl

4): Ab

stract 3

002.

CEA-T

CB (C

EA-CD

3) plus

atezol

izuma

b for C

RC

MEK in

hibitor

induce

s CD8

T-cell

accum

ulation

and MH

C I Exp

ressio

n

Cobime

tinib +

atezol

izuma

b

(CRC 2

3 patie

nts, KR

AS mu

tant 20

patien

ts)

3 of 4

respon

ders w

ere

misma

tch-rep

air pro

ficient

Bendel

l JC, et

al. J C

lin On

col. 20

16;34(

suppl):

Abstra

ct 3502

.

CT26 (K

RAS m

utant)

T-cell

prolife

ration,

engage

ment a

nd

activa

tion wit

hout M

HC-pe

ptide c

omple

x

Non-MS

I-H

Summery

• About 5% of mCRC have a MSI-H tumor phenotype

• Checkpoint inhibitors show promising activity in pretreated

patients with MSI-H mCRC

• “Modulation” by MEK inhibitor may convert MSS tumors to

become snesitive to checkpoint inhibitors

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 2dStage 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

Presented by: Dr Michael J. Overman

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.

Efficacy Checkmate 142 : >= 1 prior therapy

46

100

75

50

25

0

-25

-50

-75

-100

Be

st

Re

du

cti

on

fro

m B

as

eli

ne

in

Ta

rge

tL

es

ion

(%)

Confirmed CR or PR per investigator

***

**************

**************************

**

*

Andre….Overmann et al. ASCO 2017

OS rate (95% CI), %

6 months 89 (80.2, 94.2)

9 months 88 (78.1, 93.1)

Median OS (95% CI), months NR (NE, NE)

RR 55%

MR/PR 80%

OS rate (95% CI), %

6 months 89 (80.2, 94.2)

9 months 88 (78.1, 93.1)

Median OS (95% CI),

months

NR (NE, NE)

PFS

OS