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SAGLB.AFL.17.03.0196a (06/17)SAGLB.AFL.17.03.0196a (06/17)

SAGLB.AFL.17.03.0196a (06/17)

The role of maintenance treatment– and what to do after 1st line ?

Instituto CUF de Oncologia

Lisboa, Portugal

Asklepios Tumorzentrum Hamburg

AK Altona , Abt. Onkologie, Hämatologie und Palliativmedizin

ATZ: Organisationsfelder

„Disease

Track /

Programs“

per Tumorentität

Klinische

„Core

Facilities“

unabhängig von

Tumorentität

QM /

Zertifizierung /

Register

Fortbildung /

Veranstaltung

Studien /

Wissenschaft

Marketing / PR

Klinischer Bereichadministrativer

Bereich

Ergänzende

klinische

Angebote

unabhängig von

Tumorentität

SAGLB.AFL.17.03.0196a (06/17)

Disclosures

Advisory role

• Bayer, Boehringer, BTG, Lilly, Merck Serono, Roche, Sanofi, Servier

Honoraria for speeches

• Bayer, BTG, Lilly, Roche, Sanofi, Servier

Trial and research support

• Roche, Sanofi

SAGLB.AFL.17.03.0196a (06/17)

• Diagnostic work-up and biomarkers

• Choice of treatment in 1st line

• Integration of local and ablative treatments

• The principle of „continuum of care“ in mCRC

Ways to improve OS in metastatic CRC

Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016

SAGLB.AFL.17.03.0196a (06/17)

33

EVALUATION OF RESPONSE

SIDEDNESS + GENOTYPE

mFOLFOXIRI +

panitumumab

mFOLFOXIRI +

panitumumab

FOLFOXIRIFOLFOXIRI

left right

ORR (%)

10

20

30

40

50

60

70

80

90

100

90,6

68,0

60,0

37,5

OR 4.518

(1.29-15.71)

P=0.0210

OR 2.500

(0.37-16.88)

P=0.6372

mFOLFOXIRI +

panitumumab

mFOLFOXIRI +

panitumumab

FOLFOXIRIFOLFOXIRI

super wild-type

ORR (%)

BRAF mutation

10

20

30

40

50

60

70

80

90

100

86,0

64,7

71,4

22,2

OR 3.364

(0.90-12.54)

P=0.0806

OR 8.750

(0.9-84.80)P=0.1262

N=60 N=16N=78 N=18

Phase II VOLFI trial: FOLFOXIRI +/- Panitumumab

Geissler et al., ESMO 2017

SAGLB.AFL.17.03.0196a (06/17)

Induction

Best systemictreatment

Best maintenance

De-escalation ?

pause ?

other compound?

Best ablation

resection

„ablation toolbox“

severalmanifeststions,

„palliative“

Oligometastastaticdisease

„ablative“

post induction

where ?response?

Metastatic CRC: Main principles in 1st line

Arnold et al, Clin Colorect Cancer 2017

SAGLB.AFL.17.03.0196a (06/17)

OPTIMOX'Studies'

OPTIMOX/1'N=620'

FOLFOX'4'un: l'TF'

FOLFOX'7' FOLFOX'7'

sLV5FU2'

OPTIMOX/2'N=202'

mFOLFOX'7' mFOLFOX'7'

sLV5FU2'

mFOLFOX'7' mFOLFOX'7'

Chemo'free'interval'

Chibaudel'et'al.,'J'Clin'Oncol'2009'

Tournigand'et'al,'J'Clin'Oncol'2006'

„First generation maintenance trials“


SAGLB.AFL.17.03.0196a (06/17)Chibaudel et al., J Clin Oncol 2009

HR 0.88; p=0.42

Median 19.5 vs. 23.8 mos

(=4.3 mos. shorter OS)

„First generation maintenance trials“: OPTIMOX-2

No treatment („CFI“) vs. FP after 3 mos. combination CT

SAGLB.AFL.17.03.0196a (06/17)

“Deescalation maintenance”: Trials

1. Koopman, et al. ; 2. Arnold, et al. ASCO 2014 ; 3. Koeberle, et al. ASCO 2013

SAKK 41/063

Previously

untreated mCRC

(n=852*/452)

FP +

oxaliplatin +

Bev

(24 weeks)

With CR/PR/SD

BevN=156

FP + BevN=158

No therapyN=158

R PD

AIO 02072

Previously

untreated mCRC

n=558

XELOX + Bev

(18 weeks, x6)

With CR/PR/SD

Cape + BevN=278

No therapyN=279

R PD

CAIRO31

Primary endpoint: superiority in PFS2 (maintenance and reinduction treatment)

Primary endpoint: non-inferiority in TFS (maintenance and reinduction treatment)

Bev + CT

(16-24 weeks)

Previously

untreated mCRC

(n=262

R

BevN=131

No therapyN=131

PD

PD

Primary endpoint: non-inferiority in TTP (from randomisation)

XELOX + Bev

XELOX + Bev

SAGLB.AFL.17.03.0196a (06/17)

Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016

SAGLB.AFL.17.03.0196a (06/17)

No tx. Bev FP/Bev

Median TFS

Median PFS1

Re-induction

No re-induction

45% 43% 21%

Re-induction rates and PFS1/TFS

2

4

6

months

Presented by: Dirk Arnold, M.D., on behalf of the AIO CRC study group

SAGLB.AFL.17.03.0196a (06/17)

De-escalation maintenance: „Time to failure of strategy“ (TFS)

AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol 2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015

HR nihil vs. FP/Bev: 0.76; p<0.04 HR nihil vs. FP/Bev: 0.67;

p<0.0001

SAGLB.AFL.17.03.0196a (06/17)

HR nihil vs. FP/Bev: 0.49; p<0.0001 HR nihil vs. FP/Bev: 0.43;

p<0.0001


De-escalation maintenance: „Time to first progression (PFS)

SAGLB.AFL.17.03.0196a (06/17)

HR nihil vs. FP/Bev: exploratory, n.s. HR nihil vs. FP/Bev: 0.83; p=0.06

Median OS: 18.1 vs. 21.6 mos

(+3.5 mos.)


De-escalation maintenance: Overall survival (OS)

SAGLB.AFL.17.03.0196a (06/17)

Arnold et al., ASCO 2016 (oral presentation)Stein and Arnold, Clin Colorectal Cancer 2016

Maintenance or observation after induction?

PFS

OS

SAGLB.AFL.17.03.0196a (06/17)

Apricio et al., J Clin Oncol 2018

SAGLB.AFL.17.03.0196a (06/17)

Goey et al., ESMO 2016; poster discussion session

Clinical factors influencing outcome in

metastatic colorectal cancer patients treated with fluoropyrimidine and

bevacizumab (FP+Bev) maintenance treatment vs observation:

a pooled analysis of the phase 3 CAIRO3 and AIO 0207 trials

Kaitlyn Goey ● Sjoerd Elias ● Axel Hinke ● Martijn van Oijen ● Kees Punt ● Susanna Hegewisch-Becker ● Dirk Arnold ● Miriam Koopman

April 29, 2016

SAGLB.AFL.17.03.0196a (06/17)Goey, Arnold et al., Br J Cancer 2017

SAGLB.AFL.17.03.0196a (06/17)

RAS & BRAF wild-type RAS or BRAF mutant

Hegewisch-Becker et al., Lancet Oncol 2015

Who benefits from active maintenance?

SAGLB.AFL.17.03.0196a (06/17)

Following FOLFOX/C´mab Continuation vs. C´mab only

Garcia Alfonso et al., ESMO 2014

SAGLB.AFL.17.03.0196a (06/17)

MEDIZINISCHE KLINIK UND POLIKLINIK III

DIREKTOR PROF. DR. W. HIDDEMANN

KLINIKUM DER UNIVERSITÄT MÜNCHEN®

FIRE-4 (AIO KRK-0114) DESIGN

19.05.181

R1

anti-

EGFR-free

therapyFOLFIRICetuximab

mCRCRAS-wild-

type

(FOLF)-IRICetuximab

R2

N= 450 N= 230

FOLFIRICetuximab

5-FU/CapeBevacizumab

1st

progression

2nd

progression

switch after

8-12 cycles

Induction 2nd-lineMaintenance Re-induction

physician‘schoice

(no anti EGFRsubstances)

Entry 1 Entry 2

Primary Endpoint: OS3 after randomisation R2Secondary Endpoint: PFS in 1st-line

SAGLB.AFL.17.03.0196a (06/17)

ESMO Guideline: Maintenance treatment

• Patients receiving FOLFOX or CAPOX as induction therapy should be allocated to maintenance therapy after 6–8 cycles.

• Patients receiving FOLFIRI as induction should continue for (at least) as long as tumour shrinkage continues.

• Optimal maintenance treatment after a bevacizumab-containing induction is a combination of a fluoropyrimidine plus bevacizumab. Bevacizumab monotherapy as maintenance is not recommended.

• Individualisation and discussion with the patient is essential.


SAGLB.AFL.17.03.0196a (06/17)

The price to pay? Toxicity

Hegewisch-Becker et al., Lancet Oncol 2015; Simkens et al., Lancet 2015

SAGLB.AFL.17.03.0196a (06/17)

Erhaltungstherapie.

40,0.

50,0.

60,0.

70,0.

80,0.

Woche.0. Woche.06. Woche.12. Woche.18. Woche.24.

FP/Bev. 57,2. 58,5. 54,1. 56,6. 56,3.

Bev. 54,3. 58,3. 58,3. 58. 55,4.

Ø.Tx. 55,1. 58,3. 58,5. 58,7. 57.

GH

S/Q

oL(s

core

( FP/Bev vs Bev: p= 0,439 FP/Bev vs Ø Tx: p= 0,486

Bev vs Ø Tx: p= 0,927

T-Test 2-sided

Koopman et al, GI Caancer Symposium 2014; Quidde et al., DGHO 2014 (presentation)

[TITLE]

Presented By Miriam Koopman, MD, PhD at 2014 Gastrointestinal Cancers Symposium

AIO 0207

CAIRO-3

100% 98% 97% 97% 95%N=427

N=491

Quality of life whilst maintenance

SAGLB.AFL.17.03.0196a (06/17)

Erhaltungstherapie.

0.

10.

20.

30.

40.

Abnahme der QHS/QoL Zunahme der QHS/QoL

0.

10.

20.

30.

40.

FP/Bev.

Bev.

Ø.Tx.

Patientenanzahl in %

(Mittelwert1) Patientenanzahl in %

(Mittelwert1)

1 Mittelwert über die einzelnen Messzeiträume

(Woche 6-12. 6-18, 6-24)

@ wk 24:

% of patients

with at least 10 IP

„overall HRQoL“

improvement

@ wk 24:

% of patients

with at least 10 IP

„overall HRQoL“

deterioration

AIO 0207: Quality of life analyses

Quidde et al., Ann Oncol 2016

SAGLB.AFL.17.03.0196a (06/17)

Mannsmann UR ASCO GI 2013, abstract no. 427

∆ OS

No tumor shrinkage

PFS

PFS

∆ PFS

Tumor shrinkage

Lethal tumor load

Baseline tumor load

Time under treatment

SAGLB.AFL.17.03.0196a (06/17)

Time

Cel

lco

un

t

Goldie-Coldman Hypothesis:

less therapy-resistant clones with a smaller number of cells

- Goldie JH et al., Cancer Res. 1984

- Withers HR et al., Sem Radiat Oncol 2006

Norton-Simon Hypothesis: kinetic resistance - poorer response to chemotherapy in small residualsNorton L et al., Cancer Treat Rep 1986, Oncologist 2005

Chemotherapy

Metastasis 1

Metastasis 2Primary

Subclone

Gerlinger et al., New Engl J Med 2012

SAGLB.AFL.17.03.0196a (06/17)

Marusyk et al., Science 2013

SAGLB.AFL.17.03.0196a (06/17)

New compounds in maintenanceBev vs. Bev/Erlotinib following combination CT/Bev induction

PFS maintenance: HR 0.81; p=0.059

Median: 4.9 vs. 5.4 mos.

OS from maintenance: HR 0.79;

p=0.036

Median: 22.1 vs. 24.9 mos.

Tournigand et al., Lancet Oncol 2015

SAGLB.AFL.17.03.0196a (06/17)

UK FOCUS-4 trial

Lawler et al., The Oncologist 2015

SAGLB.AFL.17.03.0196a (06/17)

Cobimetinib + Atezolizumab + Bevacizumab

5-FU/LV + Cetuximab + Vemurafenib

Induction Treatment

Phase

Investigator’s

choice:

FOLFOX

+ bevacizumab

for 8 cycles

(16 weeks)

or

FOLFOX

+ bevacizumab

for 6 cycles

(12 weeks)

followed by

2 cycles

(4 weeks)

5-FU/LV

+ bevacizumab

Early

PD a

CR PR

SD

PD, evaluation of resectability, pt

refusal or ineligible for any cohort

Biomarker-driven Maintenance Treatment Phase Post-treatment

Follow-up Phase

BRAFmut

FP = fluoropyrimidine (5-FU or capecitabine)

a. Patients who progress early and who are not BRAFmut will enter the Post-treatment Follow-up Phase with initiation of 2nd-line treatment per Investigator discretion

T R E

A T

ME N

T U

N T I

L P D

Bev+ Atezo + Chemo of

choice

Cohort 1 BRAFmut R

5-FU/LV + Cetuximab + Vemurafenib

FP + Bevacizumab

«MSI Stable»

«MSI High» FP + Bevacizymab + Atezolizumab Testing Hierarchy:

a) Her2 -> BRAF -> MSI

b) Her2 ->MSI -> BRAF

Cohort 2

“No

Biomarker”

BRAFWT”

R

FP + Bevacizumab + Atezolizumab

FP + Bevacizumab

«Stratified for MSI »

Bev+ Atezo + Chemo of

choice

Cohort 3 Her2-pos

R

(FP) + Transtuzumab + Pertuzumab

FP + Bevacizumab «Stratified for IHC? »

Cohort 4 “No

Biomarker”

2

Where we might be in 1year from now MODUL Trial: New arms under discussion

FU plus anti EGFR plus anti V600E

FP plus Bevacizumab plus antiPD1

FP plus „double“ antiHER2

Beva plus antiPD1 plus antiMEK

modified from: Arnold et al., WCGC 2015

SAGLB.AFL.17.03.0196a (06/17)

Immunotherapy as „switch maintenance“

N= > 580; primary endpoint: OSPI: Dirk Arnold, DE & David Cunningham, UK

SAGLB.AFL.17.03.0196a (06/17)

Treatment goals change with “line” of therapy

adapted from Stintzing S. F1000 Prime Reports 2014;6:108

Line of systemic treatment Realistic treatment goal

Adjuvant‘Cure’

Reduce risk of recurrence

1st lineDeepest tumor response

Long duration of low/no tumor burden

2nd lineDurable disease control

Tumor response if needed

3rd lineDurable disease control

Maintenance of QoL and PS

Subsequent linesDisease control

and maintenance of QoL; palliation

OSandQoL

Arnold D . Clin Colorect Cancer 2016

SAGLB.AFL.17.03.0196a (06/17)

1st-line 2nd- and further-line

Treatment goal

Disease-related factors

Patient-related factors Disease-related factors

Biomarkers Patient-related factors

Anticipated toxicity Treatment goal

Biomarkers

Factors That Impact on Treatment Decisions

Arnold, WCGC 2016 (oral presentation)

SAGLB.AFL.17.03.0196a (06/17)

1st-line 2nd- and further-line

Treatment goal

Disease-related factors

Patient-related factors Disease-related factors

Biomarkers Patient-related factors

Anticipated toxicity Treatment goal

Biomarkers

Pretreatment

Information from pretreatment(including reported toxicity)

Factors That Impact on Treatment Decisions

Arnold, WCGC 2016 (oral presentation)

SAGLB.AFL.17.03.0196a (06/17)

Schmoll,(...,(Arnold,...,(Cervantes;(Ann(Oncol(2012(

(

Schmoll et al. Ann Oncol. 2012;23:2479-516.

ESMO Consensus 2012: Sequences

FOLFOX FOLFIRI vs. FOLFIRI FOLFOX

Tournigand et al. J Clin Oncol. 2004:

Median OS 20.6 months

SAGLB.AFL.17.03.0196a (06/17)Van Cutsem, Cervantes, Nordlinger & Arnold. Ann Oncol. 2014

ESMO 2014 Guidelines: Sequences

SAGLB.AFL.17.03.0196a (06/17)

Chemo (B)

Other (anti-EGFR)

Chemo (A)

Anti-VEGF

R

R

Chemo (A) Chemo (B)R

Anti-VEGF R

VEGF resistance occurs – but when?

Arnold et al., Clin Colorectal Cancer 2014

SAGLB.AFL.17.03.0196a (06/17)

2L chemo alone or plus continued Bevacizumab after progression with chemo plus Bevacizumab

TML study: Results

Arnold et al., J Clin Oncol Suppl. 2012Benounna, Arnold et al., Lancet Oncol 2013

SAGLB.AFL.17.03.0196a (06/17)Benounna, Sastre, Arnold et al. Lancet Oncol. 2013;14:29-37; Masi et al. Ann Oncol. 2015;26:724-30.

Bevacizumab Beyond Progression: 2 different trials, Overall Survival

TML, Int´l phase IIIBEBYP, Italian phase II

adjusted HR 0.77, p=0.043 (strat. log-rank)

Stratified HR 0.83; p=0.0211 (log-rank)

SAGLB.AFL.17.03.0196a (06/17)

TML trial: Subgroup analyses

Vieitez de Prado, Borg, Arnold et al., ESMO 2012Benounna, Arnold et al., Lancet Oncol 2013

SAGLB.AFL.17.03.0196a (06/17)

Antiangiogenic treatment in mCRC

Arnold & Tabernero, J Oncopathol 2013

SAGLB.AFL.17.03.0196a (06/17)

Antiangiogenic Treatment Options in mCRC

• When VEGF-A levels are reducedor activation of VEGFR-2 is reduced by an antagonist, there is evidence to suggest PlGF and VEGF-B ligands serve as an alternative angiogenic and/or metastatic pathway

• Targeting a broader set ofpro-angiogenic growth factors could help in overcoming antiangiogenic resistance (e.g., PlGF and VEGF-B)

‒ But, this hypothesis has yet to be confirmed in clinical studies

VEGFR-2

P

P

P

P

VEGF-BVEGF-APIGF

LymphangiogenicFactors

VEGF-DVEGF-C

RegorafenibSmall molecule MKI

Bevacizumab(Anti-VEGF-A

MAb)

Aflibercept(Fusion protein/

VEGF Trap)

Brave et al. Angiogenesis. 2010;13:337–347. Cao et al. Sci Signal. 2009

RamucirumabAnti-VEGFR-2 MAb

SAGLB.AFL.17.03.0196a (06/17)

Phase III VELOUR: 2nd line FOLFIRI +/- Aflibercept

Van Cutsem et al., J Clin Oncol 2012

PFS: HR 0.76, p<0.001med. 4.7 vs. 6.9 mos.

OS: HR 0.82, p<0.0032med. 12.06 vs. 13.5 mos.

SAGLB.AFL.17.03.0196a (06/17)

VELOUR trial: Stratified subgroups

Overall survival

Progression free survival

SAGLB.AFL.17.03.0196a (06/17)

Overall survival

Progression free survival

VELOUR trial: Stratified subgroups

SAGLB.AFL.17.03.0196a (06/17)

Phase III RAISE: 2nd line FOLFIRI +/- Ramucirumab

Tabernero et al., GI Cancer Symposium 2015

SAGLB.AFL.17.03.0196a (06/17)

E3200 TML VELOUR RAISE

Bev + FOLFOX4 (n=286)

FOLFOX

(n=291)Bev + CT(n=410)

CT

(n=409)

Aflib + FOLFIRI

(n=612)

Plac + FOLFIRI

(n=614)

Ramu + FOLFIRI

(n=536)

Plac + FOLFIRI

(n=536)

Bev before? none all 30% all

mOS, months 12.9 10.8 11.2 9.8 13.5 12.1 13.3 11.7

HR=0.75p=0.0011

HR=0.81

p=0.0062

HR=0.82p=0.0032

HR=0.84p=0.022

mPFS, months

7.3 4.7 5.7 4.1 6.9 4.7 5.7 4.4

HR=0.61p<0.0001

HR=0.68p<0.0001

HR=0.76p=0.00007

HR=0.79

p=0.0005ORR, %

22.7 8.6 5.4 3.9 19.8 11.1 13.4 12.5

p<0.0001 ns p=0.0001 ns

1. Langer, et al. ESMO 2008; 2 . Peeters, et al. JCO 2010; 3. Van Cutsem, et al. WCGC 20114. Giantonio, et al. J Clin Oncol 2007; 5. Roche data on file Plac = placebo

Giantonio, et al. J Clin Oncol 2007; Benounna, Arnold et al, Lancet Oncol 2013; Van Cutsem, et al. J Clin Oncol 2012 ; Tabernero et al., Lancet Oncol 2015

2nd line with anti-VEGF combinations

SAGLB.AFL.17.03.0196a (06/17)

Case #1: 57y/o lawyer, ECOG PS 0, motivated

• C. transversum cancer, diagnosed and resected (19 mos. ago)

• Synchronous liver mets and retroperitoneal mets

• intraoperatively localized peritoneal carcinomatosis

1st line FOLFOX/Bevacizumab for 5 months PR

FP/Bevacizumab maintenance for 8 more months

at progression 2 months re-induction of oxaliplatin neuropathy and increasing CEA

• RAS wild-type, BRAF wild-type

• What now?

SAGLB.AFL.17.03.0196a (06/17)

4

PRODIGE 18 STUDY DESIGN

Primary endpoint • PFS rate at 4 months (a CT-scan was performed every

6 weeks)

Secondary endpoints • Objective Response Rate (RECIST 1.1)

• Overall survival (OS)

• PFS

• OS from the start of first-line therapy

• Safety (adverse events using the NCIC-CTCAE)

• Quality of life

Stratification factors

• Type of first-line chemo. irinotecan vs oxaliplatin

• first-line PFS : ● 9 vs > 9 months

Patients with wtKRAS exon 2

mCRC progressing after Bev

plus chemotherapy doublet

(fluoropyrimidine + oxaliplatine

or irinotecan)

(n = 133)

R 1:1

Arm A

mFOLFOX6 or FOLFIRI

+ bevacizumab

Arm B

mFOLFOX6 or FOLFIRI

+ cetuximab

PD

with a chemotherapy

crossover from the

first-line to second-line

mFOLFOX6

Oxaliplatin: 85 mg/m², d1

Folinic acid: 400 mg/m², d1

5-FU bolus: 400 mg/m², d1

5-FU IV 46H: 2400 mg/m²

d1-d14

FOLFIRI

Irinotecan: 180 mg/m², d1

Folinic acid: 400 mg/m², d1

5-FU bolus: 400 mg/m², d1

5-FU IV 46 h: 2400 mg/m²

d1-d14

+ Bevacizumab: 5mg/kg, d1

or

+ Cetuximab: 500mg/m², d1

d1-d14

PD

SAGLB.AFL.17.03.0196a (06/17)

9

MEDIAN PFS AND MEDIAN OS (WTKRAS EXON 2)

Cet (Arm B, n=67)

Median PFS 5.6 months

(95 % CI : 4.2 – 6.5)

Bev (Arm A, n=65)


(95% CI: 5.7 - 8.2)

HR 0.710 (95% CI: 0.495–1.018)

p=0.0622

Cet (Arm B, n=67)


(95 % CI : 7.0 – 16.2)

Bev (Arm A, n=65)


(95% CI: 9.5 – 22.3)

HR 0.688 (95 CI: 0.456 – 1.038)

p=0.0750

Overall SurvivalProgression-Free Survival

Median follow-up was 37.4 months (95%CI: 25.1–39.6 months)

SAGLB.AFL.17.03.0196a (06/17)

11

Cet (Arm B, n=37)


(95 % CI : 4.1 – 7.1)

Bev (Arm A, n=36)


(95% CI: 6.6 - 8.6)

HR 0.665 (95% CI: 0.407 – 1.087)

p=0.1035

Cet (Arm B, n=37)


(95 % CI : 6.8 – 22.5)

Bev (Arm A, n=36)


(95% CI: 12.3 – 35.1)

HR 0.758 (95 CI: 0.416 – 1.383)

p=0.3669

MEDIAN PFS AND MEDIAN OS (WTKRAS, NRAS EXONS 2,3,4, WTBRAF)

Overall SurvivalProgression-Free Survival

Median follow-up was 29.2 months (CI95%: 19.7 – 41.4 months)

SAGLB.AFL.17.03.0196a (06/17)

KRAS wild-type; N=182

Hecht et al., Clin Colorectal Cancer 2015

2nd line, after FOLFOX/bev:FOLFIRI with bev or with p´mab? SPIRITT trial

ORR: 32% FOLFIRI/p´mab vs. 19% FOLFIRI/bev

bev egfr bev egfr

bev bev sequencebev bev sequence

SAGLB.AFL.17.03.0196a (06/17)

After 15 months 1st line: Now continued stabilisation with FOLFIRI + Aflibercept

07/2016 04/2017 09/2017


SAGLB.AFL.17.03.0196a (06/17)


• C. transversum cancer with synchronous liver mets and intraoperatively localized peritoneal carcinomatosis

• 16 mos. FP/(oxaliplatin)/bev strategy

• 14 mos. FOLFIRI/aflibercept strategy

• Now progressing

RAS wild-type, BRAF wild-type

• 4 mos. irinotecan/cetuximab PD

• 2 mos. TAS102 PD

• Re-introduction of oxaliplatin?

SAGLB.AFL.17.03.0196a (06/17)

Second-Line Treatment Options for wt KRAS/NRAS mCRC: Randomized Trials of Anti-EGFR Agents

Peeters et al. Clin Cancer Res. 2015;21:5469-79; Hecht et al. Clin Colorectal Cancer. 2015;14:72-80; Hiret S, et al. J Clin Oncol. 2016;34 (suppl; abstr 3514).

Trial TreatmentNo. Pts

ORR, %Median PFS,

moMedian OS,

mo

181 (RAS WT

subgp)1

FOLFIRIPanitumumab + FOLFIRI

294303

1041

6.7 (p=.023)

4.914.5 (p=.366)

12.5

SPIRITT (KRAS WT)2

Panitumumab + FOLFIRIBevacizumab + FOLFIRI

9191

3219

7.7 (p=0.97)

9.218.0 (p=0.75)

21.4

PRODIGE-18 (KRAS WT)3

Cetuximab + chemo* Bevacizumab + chemo*

6565

3225

5.7 (p=0.07)

7.511.4 (p=0.07)

19.3

*mFOLFOX6 or FOLFIRI

SAGLB.AFL.17.03.0196a (06/17)

Chemo (B)

Other (anti-EGFR)

Chemo (A)

Anti-VEGF

R

R


Anti-VEGF R

VEGF Resistance Occurs – But When?

?Arnold et al., Clin Colorectal Cancer 2014

SAGLB.AFL.17.03.0196a (06/17)

VEGF-A, VEGF-B, and PlGF are all involved in multiple pathways of angiogenic response

PlGF

VEGF-B

ENDOTHELIAL CELL

Survival, Migration, Proliferation

VEGF-A

MACROPHAGE

• Recruitment and activation

• Release of angiogenic factors

TUMOR CELL

• Proliferationand migration

• Chemoprotection

STROMAL CELLPERICYTE, SMC

• Migration

• Proliferation

DENDRITIC CELL

• Suppression of antigen recognition

VEGF-A

BM PROGENITORS LEUKEMIC CELL

Proliferation, Migration, Survival

sVEGFR-1

Fischer. Nat Rev Cancer. 2008;8:942–956.

SAGLB.AFL.17.03.0196a (06/17)

PlGF expression correlates with progression and survival status

S-C Wei et al. Gut. 2005;54:666-672; Escudero-Esparza A et al. Cancer Genomics & Proteomics. 2009;6:239-246.

UICC-TNM classification stage I, n=14; stage

II, n=27; stage III, n=22; stage IV, n=11 PlGF, placental growth factor; TNM, tumor node metastasis; VEGF, vascular endothelial growth factor

Distribution of Ratios Between

Pretreatment Expression Levels

of PlGF in Tumor and Non-tumor

Tissues (UICC-TNM)

Survival Curves of Patients in

Relation To Pretreatment PlGF

Expression Levels in Tumors

Pretreatment Levels of

PLGF-1 Transcript in CRC vs

Normal Tissue

SAGLB.AFL.17.03.0196a (06/17)

● Plasma and tumor tissue collection was mandatory.

● Analyses were performed to assess the correlations of the baseline individual marker levels with clinical outcomes.

● Plasma samples were collected from whole blood prior to cycle 1. VEGF-C, VEGF-D*, soluble VEGFR-1 (sVEGFR-1), sVEGFR-2, and sVEGFR-3 were assessed by exploratory, individual, proprietary Eli Lilly and Company-developed dual-monoclonal sandwich immunoassays (Version 1 for each).

● Archived tumor samples were submitted to the central laboratory for VEGFR-2 immunohistochemistry assay.

RAISE Study (2nd line, FOLFIRI +/- Ramucirumab)

Tabernero J et al., Proc. ESMO 2017

SAGLB.AFL.17.03.0196a (06/17)

High VEGF level (≥115 pg/mL, TR population)

Results according to VEGF-D levelsResults

Figure 1. Kaplan-Meier graph of overall survival by treatment arm with stratification

factors as covariates, high VEGF-D expression levels (≥115 pg/mL), TR population.

Results

Figure 2. Kaplan-Meier graph of overall survival by treatment arm with stratification

factors as covariates, low VEGF-D expression levels (<115 pg/mL), TR population.

Low VEGF level (<115 pg/mL, TR population)

Tabernero J et al., Proc. ESMO 2017

SAGLB.AFL.17.03.0196a (06/17)Tabernero et al. ASCO 2017 (poster 592)

SAGLB.AFL.17.03.0196a (06/17)

Potential biomarkers of Bevacizumab resistance and progression in mCRC

• Single arms trials showed an increase of PlGF at bevacizumab progression1,2

• An increase in serum VEGF-A level during or before disease progression has been documented2

• These increases may contribute to bevacizumab treatment resistance

1. Kopetz S et al. J Clin Oncol. 2010;28:453-9; 2. Hayashi H et al. Oncotarget. 2014;5:2588-94

0

10

20

30

40

PIG

F (

pg

/mL

)V

EG

F-A

(p

g/m

L) 200

150

100

50

00 1 2 3 4 5 6

Time (months)

VE

GF

-A (

pg

/mL

) 200

150

100

50

00 1 2 3 4 5 6

Time (months)

Responders(N=16)

Nonresponders(N=9)

P < .01*

P < .001*

P < .001*

0

10

20

30

40

50

0 1 2 4 6

PIGF† † † †

SAGLB.AFL.17.03.0196a (06/17)

Chemo

Biological

Assessment of CAF every 2 weeks and RECIST every 8 weeks

Bevacizumab Aflibercept

CHEMO A CHEMO B

PD

Conventional switch of

Chemo and Biological

at timepoint of PD

1st-line 2nd-line

PD

Chemo A/B = FP + Ox/IriN=60

PERMAD Trial: Determination of Markers for (Early) Angiogenic Switch

PI: Seufferlein, D and Arnold, PT; NCT02331927; https://clinicaltrials.gov/ct2/show/NCT02331927 accessed June 21, 2017.

https://clinicaltrials.gov/ct2/show/NCT02331927

SAGLB.AFL.17.03.0196a (06/17)

Chemo A/B = FP + Ox/Iri

PERMAD Trial: Randomized Part


CHEMO A CHEMO B


CHEMO A CHEMO B

R

Patients with marker change

and at least SD (RECIST)

Chemo

Chemo

Biological

Biological

Conventional switch

of chemo and

biological at timepoint

of PD

Marker-driven early

switch of biological

and conventional

switch of chemo at

timepoint of PD

1st-line 2nd-line

PD

n=120 n=60

PI: Seufferlein, D and Arnold, PT; NCT02331927; https://clinicaltrials.gov/ct2/show/NCT02331927 accessed June 21, 2017.

A

B

https://clinicaltrials.gov/ct2/show/NCT02331927

SAGLB.AFL.17.03.0196a (06/17)

RegorafenibTAS 102 combo?CIT plus anti-VEGF?

Anti-VEGF

Other

Chemo (B)

Other (anti-EGFR)

Chemo (A)

Anti-VEGF

R

R


VEGF Resistance Occurs – But When?

Arnold et al., Clin Colorectal Cancer 2014

SAGLB.AFL.17.03.0196a (06/17)

Treatment goals change with “line” of therapy

adapted from Stintzing S. F1000 Prime Reports 2014;6:108

Line of systemic treatment Realistic treatment goal

Adjuvant‘Cure’

Reduce risk of recurrence

1st lineDeepest tumor response

Long duration of low/no tumor burden

2nd lineDurable disease control

Tumor response if needed

3rd lineDurable disease control

Maintenance of QoL and PS

Subsequent linesDisease control

and maintenance of QoL; palliation

OSandQoL

Arnold D . Clin Colorect Cancer 2016

SAGLB.AFL.17.03.0196a (06/17)

Evidence-based treatment beyond 2nd line

Many patients are candidates for further treatment: After 2+ lines of treatment

a significant number of patients with mCRC are able and willing to receive more treatments

n=4877 patients with mCRC who received chemotherapy between Jan 2004 and March 2011 inoncology practices subscribing to a US-wide chemotherapy order entry system2

1L

2L

3L

Chibaudel et al. Ther Adv Med Oncol 2012; Abrams et al. J Natl Cancer Inst 2014; ; Salvatore L et al. Expert Rev Anticancer Ther 2015

SAGLB.AFL.17.03.0196a (06/17)

“Snapshot” of 3rd and 4th line treatment for mCRC

• A significant number of patients progressing beyond the 2nd line are still fit for further therapy.

• Italian study assessed oncologists’ clinical practice in the management of Italian mCRC patients,with a focus on the 3rd, 4th, and later lines of therapy.

3L treatment ECOG PS (%) patients 4L treatment ECOG PS (%) patients

ECOG 0

43%

ECOG 1

43%

ECOG 0

52%

ECOG 2

14%

ECOG 1

26%

ECOG 2

19%

ECOG 3

3%

Heiman F et al. Value in Health. 2015

SAGLB.AFL.17.03.0196a (06/17)

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

SAGLB.AFL.17.03.0196a (06/17)

CORRECT Trial: Regorafenib or Placebo after failure of standard therapy

Pat. mit

vorbehandeltem

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

SAGLB.AFL.17.03.0196a (06/17)

Grothey et al., WCGC 2015 (oral presentation)

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 vs. placebo: Two phase III trials

SAGLB.AFL.17.03.0196a (06/17)

74

SAGLB.AFL.17.03.0196a (06/17)

Tipiracil substantially increases bioavailability of trifluridine

Mean trifluridine plasma concentrations time profile after single dose of

trifluridine/tipiracil (35 mg/m2) or trifluridine alone

EMA Assessment Report for Lonsurf, http://www.ema.europa.eu/ema/(date last accessed 24 August, 2016)

Trifluridine/tipiracil dosing achieved:• 37-fold greater trifluridine AUC concentration• 22-fold greater trifluridine Cmax

SAGLB.AFL.17.03.0196a (06/17)

76

SAGLB.AFL.17.03.0196a (06/17)

77

SAGLB.AFL.17.03.0196a (06/17)

78

SAGLB.AFL.17.03.0196a (06/17)

79

SAGLB.AFL.17.03.0196a (06/17)

Cytotoxicity of trifluridine/tipiracil

1. Emura T, et al. Int J Oncol 2004;25:571–8

2. Emura T, et al. Int J Mol Med 2004;13:545–9

Rate

of

tum

ou

r g

row

th in

hib

itio

n

(%)

0

20

40

60

80

1005FU-sensitive xenograft 5FU-resistant xenograft

Dose

(mg/kg/day)

Control

Trifluridine/tipiracil 75



5-FU iv 15

5-FU continuous

infusion 20

UFT 17.5

SAGLB.AFL.17.03.0196a (06/17)

.Vogel et al. Cancer Treat Rev. 2017

Treatment arms nMedian OS,

monthsHR in OS

(95% CI), P valueMedian PFS,

monthsHR in PFS

(95% CI), P value

RECOURSEMayer, 2015

• Trifluridine/tipiracil• Placebo

800 7.1 vs 5.3*0.68 (0.58–0.81),

P <.0012.0 vs 1.7

0.48 (0.41–0.57),P <.001

CONCURLi, 2015

• Regorafenib• Placebo

204 8.8 vs 6.3*0.55 (0.40–0.77),

P = .000163.2 vs 1.7

0.31 (0.22–0.44),P <.0001

ASPECCTPrice, 2014

• Panitumumab• Cetuximab

1010 10.4 vs 10.0 0.97 (0.84–1.11) - 1.00 (0.88–1.14)

CORRECTGrothey, 2013

• Regorafenib• Placebo

760 6.4 vs 5.0*0.77 (0.64–0.94),

P = .00521.9 vs 1.7

0.49 (0.42–0.58),P <.0001

CO17Jonker, 2007

• Cetuximab + BSC• BSC

572 6.1 vs 4.6*0.77 (0.64–0.92),

P = .005-

0.68 (0.57–0.80),P <.001

Van Cutsem,2007

• Panitumumab + BSC• BSC

463 - 1.00 (0.82–1.22) 8.0 vs 7.3* 0.54 (0.44–0.66)

SAGLB.AFL.17.03.0196a (06/17)

Retreatment = Reintroduction or Rechallengewith a previously used regimen

Reintroduction1

No progression of CRC while on therapy

Treatment was either of a set duration (eg, adjuvant) or was stopped for a planned break (eg, to reduce or manage AEs)

Rechallenge2

Reintroduction, after an intervening treatment, of the same therapy to which tumor has already proved to be resistant

The disease is challenged with the same regimen/agent in later-line treatment

1. Maindrault G, et al. Ann Oncol. 2004;15:1210-1214; 2. Tonini G, et al. J Exp Clin Cancer Res. 2013;32:92.

=/

G.SM.ON.09.2014.1007

SAGLB.AFL.17.03.0196a (06/17)

Arnold et al., Ann Oncol 2018 (online ahead of print)

SAGLB.AFL.17.03.0196a (06/17)

Not all approaches are successful in refractory mCRC: Nintedanib Phase III LUME trial

Van Cutsem et al., ESMO 2016

PFS: 2.60 vs 1.41 mo

HR 0.57, P<0.0001

Investigator assessment

SAGLB.AFL.17.03.0196a (06/17)

Xu, et al., Chin J Cancer. 2017

PFS OS

Median PFS: 2.8 vs 1.5 months in famitinib vs placebo

(HR, 0.60, P = .004)

Median OS: 7.4 vs 7.2 months in famitinib vs placebo

(P = .657)

• Famitinib is a multikinase receptor inhibitor

• Famitinib vs placebo in patients with mCRC who have previously received at least 2 lines of standard chemotherapy

Not all approaches are successful in refractory mCRC: Famitinib rand. phase II trial

SAGLB.AFL.17.03.0196a (06/17)

Möhler et al., Eur J Cancer 2016

SAGLB.AFL.17.03.0196a (06/17)

Clinical activity and safety of cobimetinib and

atezolizumab in colorectal cancer

Johanna Bendell,1 Tae Won Kim,2 Boon Cher Goh,3 Jeffrey Wallin,4 Do-Youn Oh,5 Sae-Won Han,5 Carrie Lee,6 Matthew D. Hellmann,7 Jayesh Desai,8 Jeremy Lewin,9 Benjamin J. Solomon,10 Laura Q.

Chow,11 Wilson H. Miller Jr,12 Justin Gainor,13 Keith Flaherty,13 Jeffrey Infante,1 Meghna Das Thakur,4

Paul Foster,4 Edward Cha,4 Yung-Jue Bang5

1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 2Asan Medical Center, Seoul, South Korea; 3Cancer

Science Institute of Singapore, National University of Singapore, Singapore; 4Genentech, Inc., South San Francisco, CA; 5Seoul

National University Hospital, Seoul, South Korea; 6UNC Lineberger Comprehensive Cancer Center, University of North Carolina –

Chapel Hill, North Carolina; 7Memorial Sloan Kettering Cancer Center, New York, NY; 8Royal Melbourne Hospital, University of

Melbourne, Melbourne, VIC, Australia; 9Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; 10Peter

MacCallum Cancer Center, Melbourne, VIC, Australia; 11University of Washington, Seattle, WA; 12Segal Cancer Center and Jewish

General Hospital, McGill University, Montreal, QC, Canada; 13Massachusetts General Hospital, Boston, MA

Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016

SAGLB.AFL.17.03.0196a (06/17)

SAGLB.AFL.17.03.0196a (06/17)

MediaRelease

F. Hoffmann-La Roche Ltd 4070 Basel

Switzerland

Group Communications

Roche Group Media Relations

Tel. +41 61 688 88 88

www.roche.com

1/5

Basel,10thMay2018

ROCHEPROVIDESUPDATEONPHASEIIISTUDYOFTECENTRIQ®(ATEZOLIZUMAB)AND

COTELLIC®(COBIMETINIB)INPEOPLEWITHHEAVILYPRE-TREATEDLOCALLYADVANCED

ORMETASTATICCOLORECTALCANCER

Roche(SIX:RO,ROG;OTCQX:RHHBY)todayannouncedthatthePhaseIIIIMblaze370study

evaluatingthecombinationofTECENTRIQ®(atezolizumab)andCOTELLIC®(cobimetinib)didnot

meetitsprimaryendpointofoverallsurvival(OS)comparedtoregorafenib.Thestudyevaluatedthe

combinationinpeoplewithdifficult-to-treat,locallyadvancedormetastaticcolorectalcancer(CRC)

whosediseaseprogressedorwhowereintoleranttoatleasttwosystemicchemotherapyregimens.

Morethan95%ofpatientsinIMblaze370havemicrosatellitestable(MSS)tumoursandbasedonthe

availabledata,checkpointinhibitorsasmonotherapyhavenotdemonstratedclinicallymeaningful

efficacyinMSSmCRC.TheresultsfromIMblaze370wereconsistentwiththispriormonotherapy

experience,showingthattreatmentwithTECENTRIQalonedidnotprovideameaningfulclinical

benefitcomparedtoregorafenibinthispatientpopulation.

SafetyforthecombinationofTECENTRIQandCOTELLICappearedtobeconsistentwiththeknown

safetyprofilesoftheindividualmedicines,andnonewsafetysignalswereidentifiedwiththe

combination.TheresultsfromIMblaze370willbefurtherexaminedandpresentedatanupcoming

medicalmeeting.

“Whiletheseresultsarenotwhatwehopedfor,weremaincommittedtoapplyingourdeep

experiencetodevelopmedicinesthatwillimproveoutcomesforpeoplelivingwithgastrointestinal

cancers,”saidSandraHorning,M.D.,ChiefMedicalOfficerandHeadofGlobalProductDevelopment.

“Inparticular,wehaveanumberofstudiesevaluatingmedicinesincolorectalcancerthatcouldplay

animportantroleinthetreatmentofpeoplewiththisdiseaseinthefuture.”

RochehasanextensiveclinicaltrialdevelopmentprogramforTECENTRIQ,withmorethan50studies

ongoing,includingmultiplePhaseIIIstudiesacrosslung,kidney,skin,breast,colorectal,prostate,

MediaRelease

F. Hoffmann-La Roche Ltd 4070 Basel

Switzerland

Group Communications

Roche Group Media Relations

Tel. +41 61 688 88 88

www.roche.com

1/5

Basel,10thMay2018

ROCHEPROVIDESUPDATEONPHASEIIISTUDYOFTECENTRIQ®(ATEZOLIZUMAB)AND

COTELLIC®(COBIMETINIB)INPEOPLEWITHHEAVILYPRE-TREATEDLOCALLYADVANCED

ORMETASTATICCOLORECTALCANCER

Roche(SIX:RO,ROG;OTCQX:RHHBY)todayannouncedthatthePhaseIIIIMblaze370study

evaluatingthecombinationofTECENTRIQ®(atezolizumab)andCOTELLIC®(cobimetinib)didnot

meetitsprimaryendpointofoverallsurvival(OS)comparedtoregorafenib.Thestudyevaluatedthe

combinationinpeoplewithdifficult-to-treat,locallyadvancedormetastaticcolorectalcancer(CRC)

whosediseaseprogressedorwhowereintoleranttoatleasttwosystemicchemotherapyregimens.

Morethan95%ofpatientsinIMblaze370havemicrosatellitestable(MSS)tumoursandbasedonthe

availabledata,checkpointinhibitorsasmonotherapyhavenotdemonstratedclinicallymeaningful

efficacyinMSSmCRC.TheresultsfromIMblaze370wereconsistentwiththispriormonotherapy

experience,showingthattreatmentwithTECENTRIQalonedidnotprovideameaningfulclinical

benefitcomparedtoregorafenibinthispatientpopulation.

SafetyforthecombinationofTECENTRIQandCOTELLICappearedtobeconsistentwiththeknown

safetyprofilesoftheindividualmedicines,andnonewsafetysignalswereidentifiedwiththe

combination.TheresultsfromIMblaze370willbefurtherexaminedandpresentedatanupcoming

medicalmeeting.

“Whiletheseresultsarenotwhatwehopedfor,weremaincommittedtoapplyingourdeep

experiencetodevelopmedicinesthatwillimproveoutcomesforpeoplelivingwithgastrointestinal

cancers,”saidSandraHorning,M.D.,ChiefMedicalOfficerandHeadofGlobalProductDevelopment.

“Inparticular,wehaveanumberofstudiesevaluatingmedicinesincolorectalcancerthatcouldplay

animportantroleinthetreatmentofpeoplewiththisdiseaseinthefuture.”

RochehasanextensiveclinicaltrialdevelopmentprogramforTECENTRIQ,withmorethan50studies

ongoing,includingmultiplePhaseIIIstudiesacrosslung,kidney,skin,breast,colorectal,prostate,

SAGLB.AFL.17.03.0196a (06/17)

Sequences of „lines“ in 1L MCRC

Standard

ablative

ideal

0 10 20 30 40

Induction

post Induction

2nd line

post 2nd line

3rd line

Re-Induction

4th line2

bsctoday

Biologicmaintenance

or ablation

Biologicmaintenance

or ablation

SAGLB.AFL.17.03.0196a (06/17)

Dirk Arnold

Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, DE

Instituto CUF de Oncologia, Lisboa, PT

Statine

vor und während der Systemtherapie wirken protektiv!

Seicean et al., JACC 2012.

Statine

vor und während der Systemtherapie wirken protektiv!

Seicean et al., JACC 2012.

powerpoint presentation · instituto cuf de oncologia lisboa, portugal asklepios tumorzentrum...

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