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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


• Participate on Advisory Board with:

Roche, Merck Serono, Amgen, Bayer, Servier, Sanofi, BTG, Lilly

• Speaker and Chairman for educational events with:

Boston Scientific, BTG, Roche, Merck Serono, Bayer, Lilly, Servier, Sanofi

• Investigator and researcher in data generating activities supported and sponsored by

Roche, Mologen, AstraZeneca, Bayer

Disclosures Dirk Arnold, 2014-2019

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)

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)

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 2017

Maintenance or observation after induction?

PFS

OS

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)

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)

Reinacher-Schick, Arnold et al., Ann Oncol 2018

Figure 1A) PFS left vs. right sided mCRCs in randomized

patients.

B) PFS by maintenance arm in randomized

patients with right sided tumors.

C) PFS by mainenance arm in randomized

patients with left sided tumors.

FU=Fluoropyrimidine, Bev=Bevacizumab

A B

C

Does sidedness pedict benefit?

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)

TRIBE2: a phase III, randomized strategy study by GONO

in the 1st- and 2nd-line treatment of unresectable

metastatic colorectal cancer (mCRC) patients (pts)

C.Cremolini, C.Antoniotti, S. Lonardi, D. Rossini, F. Pietrantonio, S.S. Cordio, S. Murgioni, F.

Marmorino, E. Maiello, A. Passardi, G. Masi, E. Tamburini, D. Santini, R. Grande, A.

Zaniboni, C. Granetto, F. Loupakis, L. Delliponti, L. Boni, A. Falcone

on behalf of the GONO Investigators

2018 ESMO Congress

Munich, 19 – 23 October 2018

SAGLB.AFL.17.03.0196a (06/17)

R

1:1

FOLFOX +

bev*

FOLFOXIRI

+ bev*

PD15FU/bev

5FU/bev

Progression Free Survival 2

FOLFIRI +

bev* PD25FU/bev

PD1FOLFOXIRI

+ bev* 5FU/bevPD2

Arm A

Arm B

* Up to 8 cycles

Intensive or sequential treatment?Tribe-2 trial

SAGLB.AFL.17.03.0196a (06/17)

Median follow up =

22.8 mos

Arm A

N = 340

Arm B

N = 339

Events, N (%) 235 (69%) 188 (55%)

Median PFS2, mos 16.2 18.9

HR = 0.69 [95% CI: 0.57-0.83] p<0.001

Intensive or sequential treatment?Tribe-2 trial, PFS 2 (= sequence)

SAGLB.AFL.17.03.0196a (06/17)

Median follow up =

22.8 mos

FOLFOX + bev

N = 340

FOLFOXIRI + bev

N = 339

Events, N (%) 288 (85%) 261 (77%)

Median PFS, mos 9.9 12.0

HR = 0.73 [95% CI: 0.62-0.87] p<0.001

Intensive or sequential treatment?Tribe-2 trial, PFS1 (= „1st line“)

SAGLB.AFL.17.03.0196a (06/17)

R

1:1

FOLFOX +

bev*

FOLFOXIRI

+ bev*

PD15FU/bev

5FU/bev

Progression Free Survival 2

FOLFIRI +

bev* PD25FU/bev

PD1FOLFOXIRI

+ bev* 5FU/bevPD2

Arm A

Arm B

* Up to 8 cycles

Intensive or sequential treatment?Tribe-2 trial

SAGLB.AFL.17.03.0196a (06/17)

Aranda et al., Eur J Cancer 2018

Maintenance following FOLFOX/Cet´mab: The TTD MACRO2 trial

SAGLB.AFL.17.03.0196a (06/17)

Maintenance following FOLFOX/Cet´mab: The TTD MACRO2 trial

Aranda et al., Eur J Cancer 2018

SAGLB.AFL.17.03.0196a (06/17)

VALENTINO Trial: EGFR maintenance

Pietrantonio et al., ASCO 2018

SAGLB.AFL.17.03.0196a (06/17)

HR = 1.55; 95% CI: 1.09-2.20; P = 0.011

Median PFS 10.2 vs. 13.0 months



SAGLB.AFL.17.03.0196a (06/17)

HR = 1.55; 95% CI: 1.09-2.20; P = 0.011

Median PFS 10.2 vs. 13.0 months


Same

treat-

ment

here!


SAGLB.AFL.17.03.0196a (06/17)

German AIO: PanaMa Trial

SAGLB.AFL.17.03.0196a (06/17)

Marusyk et al., Science 2013

SAGLB.AFL.17.03.0196a (06/17)

Re-challenge of EGFR Inhibitors?

Goldberg et al ESMO Open 2018

→ Time interval?

→ Detection?

SAGLB.AFL.17.03.0196a (06/17)

0

100

200

300

400

500

600

700

800

900C

EA (

ng/

ml)

CEA

Response by RECIST (CT scan)

Tumor burden (CT-scan)

1 32 4 5 6 7

cycles of chemotherapy

Evaluation of response to treatment in mCRC

Montagut, Siravegna & Bardelli . Ann Oncol 2015

SAGLB.AFL.17.03.0196a (06/17)

0

10

20

30

40

50

60

0

100

200

300

400

500

600

700

800

900

Mu

tate

d a

llele

s (%

)

CEA

(n

g/m

l)

CEA

ctDNA mutation in plasma

Molecular response by liquid

biopsy

Blood draws (ctDNA)

Tumor burden

1 32 4 5 6 7

Response by RECIST (CT scan)

cycles of chemotherapy

Evaluation of response to treatment in mCRC

Montagut, Siravegna & Bardelli . Ann Oncol 2015

SAGLB.AFL.17.03.0196a (06/17)

Nachweis der „erneuten Wildtypsituation“

Rossini et al., ASCO 2018

→ ORR 22%

→ DCR 54%

ctDNA for RAS/BRAF

mutations

(ddPCR+NGS)

The „again or still wildtype“ situation

SAGLB.AFL.17.03.0196a (06/17)

Wirksamkeit in Abhängigkeit des ctDNA Mutationstatus

→ Mutations in ctDNA in 48% (12/25)

→ Confirmed response only in ctDNA RAS WT (before re-induction)

The „again or still wildtype“ situation

Rossini et al., ASCO 2018

SAGLB.AFL.17.03.0196a (06/17)

CRICKET trial: Phase 2 single-arm study of re-challenge with cetuximab + irinotecan as 3rd-line

therapy in RAS and BRAF WT pts with acquired resistance to 1st-line cetuximab- and irinotecan-

containing therapy

CRICKET trial: Re-challenge with anti-EGFRs

Cremolini C, et al. JAMA Oncol 2019; 5:343-350

ctDNA, circulating tumor DNA

SAGLB.AFL.17.03.0196a (06/17)

Induction

chemotherapy+ antibody

„best maintenance“

De-escalation ?

pause ?

other compound?

„best ablation“

resection

„ablation toolbox“

severalmanifeststions,

„palliative“

Oligometastastaticdisease

„ablative“

post induction

where ?response?

Contemporary mCRC algorithm

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

esmo.org

FLUOROPYRIMIDINE (FP) AND BEVACIZUMAB ±

ATEZOLIZUMAB AS FIRST-LINE TREATMENT FOR

BRAFWT METASTATIC COLORECTAL CANCER:

FINDINGS FROM THE MODUL TRIAL OF BIOMARKER-

DRIVEN MAINTENANCE

Grothey A,1 Tabernero J,2 Arnold D,3 de Gramont A,4 Ducreux M,5 O’Dwyer PJ,6

Van Cutsem E,7 Bosanac I,8 Srock S,8 Mancao C,8 Gilberg F,8 Winter J,8 Schmoll H-J9

1West Cancer Center, Germantown, TN, USA; 2Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology

(VHIO), Barcelona, Spain; 3Asklepios Clinic Altona, Hamburg, Germany; 4Franco-British Institute, Levallois-Perret,

France; 5Gustave Roussy, Villejuif, Université Paris Saclay, France; 6Abramson Cancer Center, University of

Pennsylvania, Philadelphia, PA, USA; 7University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium; 8F.

Hoffmann-La Roche Ltd, Basel, Switzerland; 9Martin-Luther-University, Halle, Germany

SAGLB.AFL.17.03.0196a (06/17)

MODUL: overall study design

Cohort 1BRAFmut

Cohort 2BRAFwt

R

R

5-FU/LV + cetuximab + vemurafenib

FP + bevacizumab + atezolizumab

FP + bevacizumab

FP + bevacizumab

Induction treatmenta,b Biomarker-driven maintenance treatment

Cohort 3HER2+

FP + bevacizumab

Capecitabine + trastuzumab + pertuzumab

R

Cobimetinib + atezolizumab

FP + bevacizumab

Cohort 4HER2– BRAFwt

R

TREATMENT

UNTIL

PD

Follow-up

Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort

Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR);

duration of response (DoR); change in ECOG performance status; safety

FOLFOX +

bevacizumab

8 cycles (16w)

or

FOLFOX +

bevacizumab

6 cycles (12w)

then

5-FU/LV +

bevacizumab

2 cycles (4w)

CR

PR

SD

Grothey et al., ESMO 2018

SAGLB.AFL.17.03.0196a (06/17)

Cohort 1BRAFmut

Cohort 2BRAFwt

R

R

5-FU/LV + cetuximab + vemurafenib

FP + bevacizumab + atezolizumab

FP + bevacizumab

FP + bevacizumab

Induction treatmenta,b Biomarker-driven maintenance treatment

Cohort 3HER2+

FP + bevacizumab

Capecitabine + trastuzumab + pertuzumab

R

Cobimetinib + atezolizumab

FP + bevacizumab

Cohort 4HER2– BRAFwt

R

TREATMENT

UNTIL

PD

Follow-up

Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort

Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR);

duration of response (DoR); change in ECOG performance status; safety

FOLFOX +

bevacizumab

8 cycles (16w)

or

FOLFOX +

bevacizumab

6 cycles (12w)

then

5-FU/LV +

bevacizumab

2 cycles (4w)

CR

PR

SD

MODUL: overall study design


SAGLB.AFL.17.03.0196a (06/17)

OSPFS

FP + bev + atezo FP + bev

Median PFS, months 7.20 7.39

Stratified HR (95% CI) 0.96 (0.77–1.20)

p=0.727

FP + bev + atezo FP + bev

Median OS, months 22.05 21.91

Stratified HR (95% CI) 0.86 (0.66–1.13)

p=0.283

No. at risk

FP+bev+atezo

FP+bev

Time (months)

0 3 6 9 12 15 18 21

1.00

0.75

0.50

0.25

0.00

297 224 147 103 70 49 29 15

148 109 74 55 29 21 17 6

24 27 30

6 1 0

3 1 0

FP + bev + atezo

FP + bev

Surv

ival pro

babili

ty

297 293 275 244 214 189 164 104

148 142 130 120 108 94 79 49

70 28 8

30 14 5

0

0

Time (months)

0 3 6 9 12 15 18 21

1.00

0.75

0.50

0.25

0.00

24 27 30 33

FP + bev + atezo

FP + bev

No. at risk

FP+bev+atezo

FP+bev

Surv

ival pro

babili

ty

Primary analysis of PFS: 1L BRAFwt

Median follow-up 18.7 months


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)

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)

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., Lancet Oncol 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)Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014

Treatment sequences: Strategies

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)

SAGLB.AFL.17.03.0196a (06/17)

11

Cet (Arm B, n=37)

Median PFS 5.7 months

(95 % CI : 4.1 – 7.1)

Bev (Arm A, n=36)

Median PFS 8.2 months

(95% CI: 6.6 - 8.6)

HR 0.665 (95% CI: 0.407 – 1.087)

p=0.1035

Cet (Arm B, n=37)

Median OS 12.6 months

(95 % CI : 6.8 – 22.5)

Bev (Arm A, n=36)

Median OS 21.1 months

(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)

SPRITT trial, KRAS wild-type; N=182

SPIRITT trial, Hecht et al., Clin Colorectal Cancer 2015

bev→ bev sequence bev→ bev sequence

PRODIGE trial, KRAS wild-type; N=130

Prodige trial, Hiret et al., ASCO 2016

bev→ egfr bev→ egfr

After 1st line bev combo:2nd line/bev versus 2nd line/egfr

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

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)

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)

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

Results according to VEGF-D levels

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

Tabernero J et al., Ann Oncol 2018

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)

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

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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)

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)

83

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)

85

SAGLB.AFL.17.03.0196a (06/17)

86

SAGLB.AFL.17.03.0196a (06/17)

87

SAGLB.AFL.17.03.0196a (06/17)

88

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)

Trifluridine/tipiracil efficacy in mCRC (RECOURSE)

Mayer RJ, et al. N Engl J Med 2015;372:1909–19

TFD/TPI

(N=534)

Placebo

(N=266)

Median

OS, mo*7.1 5.3

Stratified log-rank test:

p<0.001; HR 0.68

95% CI 0.58–0.81

Alive at

12 mo, %

27 18

Overall survival Progression-free survival

0 2 4 6 8 10 1612 14

47.3%

20.8%

No. at Risk:

Placebo

534TFD/TPI

Months from randomization

266 51 10 2 2 1 0

238 121 30 18 5 2

2

66

1

4

Pro

gre

ss

ion

-fre

e

dis

trib

uti

on

fu

nc

tio

n (

%)

0

50

100

CT scans were performed

every 8 weeks from month 2

TFD/TPI

(N=534)

Placebo

(N=266)

Median

PFS, mo*2.0 1.7

Stratified log-rank test:

p<0.001; HR 0.48

95% CI 0.41–0.57

Ove

rall

su

rviv

al

dis

trib

uti

on

fu

nc

tio

n (

%)

Time from randomization (months)

0 3 6 9 12 15 18

266 198 107 47 24

534 459 294 137 64 23 7

9 3

TFD/TPI

No. at risk:

Placebo

0

50

100

SAGLB.AFL.17.03.0196a (06/17)

Trifluridine/tipiracil effectively prolongs time to deterioration (ECOG PS ≥2) (RECOURSE)

Trifluridine/tipiracil

No. at risk:

Placebo

EC

OG

perf

orm

an

ce s

tatu

s <

2 (

%)

Months from randomization0 3 6 9 12 15 18

266 134 57 21 11

534 352 188 84 28 7 03 1

100

0

50

5.7

4.0

Longer median time to

worsening ECOG PS

from 0–1 to ≥2

(5.7 vs. 4.0)

84% of patients

maintain ECOG PS2


SAGLB.AFL.17.03.0196a (06/17)

Trifluridine/tipiracil – haematological AEs (RECOURSE)

Most common AEs*

Trifluridine/tipiracil

(N=533)

Placebo

(N=265)

Grade ≥3 Grade ≥3

Haematological

Neutropenia, % 38 0

Leukopenia, % 21 0

Anaemia, % 18 3

Thrombocytopenia, % 5 <1

Non-haematological

Nausea,% 2 1

Vomiting,% 2 <1

Decreased appetite,% 4 5

Fatigue,% 4 6

Diarrhoea,% 3 <1

Abdominal pain,% 2 4

Fever,% 1 <1

Asthenia,% 3 3


SAGLB.AFL.17.03.0196a (06/17)

PRECONNECT (phase 3b EAP): Progression-free survival

Falcone A, et al. ESMO WCGC 2018

Efficacy based on investigator

assessment

• Median PFS: 2.8 months (95% CI

2.7–3.3), range (0.1–11.1);

• ORR: 2.4% (95% CI 1.2–4.2).

• DCR: 36.8% (95% CI 32.4–41.4).

• At cut-off, 40 deaths were

reported in this population

100

80

60

40

20

0

Eve

nt-

fre

e (

%)

Time from start of treatment (months)

0 2 4 6 8 10 12

462 295 130 62 23 5 0N

Patients at risk

SAGLB.AFL.17.03.0196a (06/17)

84% of patients are ECOG PS 0–1 at the end of FTD/TPI treatment

Eve

nt-

free

(%

)

Time from start of treatment (months)

0 2 4 6 8 10 120

50

100

60

70

80

90

40

30

20

10

Time to first ECOG PS deterioration to PS ≥2

Median Range: 8.7 (0.2–11.0) months

Falcone A, et al. ESMO WCGC 2018

PRECONNECT (phase 3b EAP): Time to deterioration of PS

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)

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

What to do after 1st line discontinuation?

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)

Arnold et al., Ann Oncol 2018

SAGLB.AFL.17.03.0196a (06/17)

Möhler et al., Eur J Cancer 2016

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.

SAGLB.AFL.17.03.0196a (06/17)

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

What to do after 1st line discontinuation?

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