jy douillard, md, phd, cmo esmo preceptorship programme the role of maintenance treatment...

ESMO Preceptorship Programme

The role of Maintenance treatmentAppropriate endpoints according to ESMO consensus

JY Douillard, MD, PhD, CMO ESMO

Colorectal Cancer– Singapore-October 20-22 2016

MAINTENANCE THERAPY

• Most patients with mCRC have no hope for cure and will receive several lines of chemo +/-targeted therapies with a median Overall Survival of 30 months

• For patients fit for intensive induction chemotherapy, the optimal sequence and duration are unknown, reduction of treatment intensity is often required for toxicity or patient request

• Quantity of life has improved and Quality of life should be considered

• Maintenance treatment apply after induction to maintain benefit as long as possible

• With lower toxicity regimen

• Improvement of disease control (PFS)

• Not at the detriment of QoL

• Several strategies are available

Available strategies in clinical practice

Induction phase 4-6 months with

controlled disease

Continuous with dose reduction according to toxicity

Intermittent with treatment breaks

Maintenance with less toxic drugs

Disease Progression

Re-induction

2nd – Line

2nd – Line

CONTINUED VS: INTERMITTENT CHEMO

Maughan TS et al. The Lancet 2003 361, 457-464

Induction phase 12 w5FU-based (GM, Lockich)Or Raltitrexed

ORSTB

Continue until PD

STOP and restart PD

Primary endpoint: Overall Survival (OS)

n=354

Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial

TS Maughan, MD, RD James, MRCP, DJ Kerr, FRCP, JA Ledermann, MD, MT Seymour, MD, C Topham, MD, C McArdle, FRCS, D Cain, PhD, Mr RJ Stephens

The LancetVolume 361, Issue 9356, Pages 457-464 (February 2003)

DOI: 10.1016/S0140-6736(03)12461-0

CR06

The Lancet 2003 361, 457-464DOI: (10.1016/S0140-6736(03)12461-0) Copyright © 2003 Elsevier Ltd Terms and Conditions

Intermittent Continued

OS median* 10.8 11.3 m ns1y OS % 46 452y OS % 19 13PFS 3.7 4.9 m ns*since randomization

http://www.elsevier.com/termsandconditions

Folfiri Continuous vs Intermittent2 months on/2months off -Stop and Go-

337 patients randomized

• 147 in the final analysis

continuous Folfiri

• 146 in the final analysis

Intermittent Folfiri

ORR : 34 vs.42% (int/cont) (NS)

DCR: 67 Vs. 76% (NS)

Labianca R et al, Annals Oncol 22: 1236-1242, 2011

In this study, discontinuing chemotherapy resulted in: Similar PFS and OS Slightly better QoL Reduced toxicity 10 week less chemotherapy Same incidence of exposure to second line

“Interpretation: Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression. They showed that it is safe to stop chemotherapy after 12 weeks and re-start the same treatment on progression in patients with chemosensitive advanced colorectal cancer.”

Lancet 2003; 361: 457–64

CONTINUED VS: INTERMITTENT CHEMO

H. Y. Luo et al. Ann Oncol 2016;27:1074-1081

R274 mCRC

L1 = 18-24 weeksXelox or Folfox

Response or stable disease observation

Capecitabine2000mg/m2/d1-14

Primary endpoint: PFS from randomization

PD

PFS

PFS 2

Capecitabine maintenance

H. Y. Luo et al. Ann Oncol 2016;27:1074-1081

PFS from randomization

PFS from induction treatment (PFS2)

overall survival

Maintenance chemotherapy after induction vs. Continuous chemo until PD

Christophe Tournigand et al. JCO 2006;24:394-400

Chemotherapy regimens: (A) FOLFOX4; (B) FOLFOX7; and (C) simplified LV5FU2.


A (Folfox 4) until PD

B (Folfox 7) (6 cycles)C (LV5FU2 x12)B (Folfox 7)

OPTIMOX 1

B C B

A

Primary End-Point. Duration of Disease Control


Duration of disease control

Progression-free survival

Overall survival

ConclusionOxaliplatin can be safely stopped after six cycles in a FOLFOX regimen.No difference in PFS and OS, less grade 3-4 toxicity in arm B

Primary End-Point

Comparison of the proportion of patients who developed a grade 3 or 4 toxicity at each cycle.


©2006 by American Society of Clinical Oncology

Drug exposure: n patients receiving each cycle

N patients with G3-4 toxicity

Neurotoxicity G3-4

mFOLFOX7 x 6, sLV5FU2 maintenance, mFOLFOX7

mFOLFOX7 x 6, chemo-free interval, mFOLFOX7

n = 99

n = 103

R

OPTIMOX 2

Benoist Chibaudel et al. JCO 2009;27:5727-5733

DDC

PFS

OS

mFOLFOX 7 reintroduced at progression

Primary End-Point: DCC

Optimox 2: conclusion• DCC and PFS are improved• OS is not• Similar toxicity in both arms

mFolfox 7: Oxali 100mg/m2

Treatment discontinuation STOP and GO:

Similar PFS and OS Slightly better QoL Reduced toxicity

Maintenance Capecitabine vs Observation: Improved PFS and PFS 2 No benefit on OS

Maintenance with reduced toxicity regimen OPTIMOX Strategy

No alteration or improved DCC and PFS Less toxicity with maintenance due to Oxaliplatin reduction No survival benefit

MAINTENANCE CHEMOTHERAPYCONCLUSION

CONTRIBUTION OF TARGETED AGENT IN MAINTENANCEBevacizumabCetuximab

D. Koeberle et al. Ann Oncol 2015;26:709-714

RmCRC

L1 = 4-6 monthsCT + bev

Response or stable disease pause

bevacizumab 7.5 mg/kg/3 weeks

Primary endpoint: TTP non inferiority

SAKK 41/06Kaplan–Meier curves for time to progression from randomization.

D. Koeberle et al. Ann Oncol 2015;26:709-714

TTP 4.1 vs. 2.9 mHR 0.74 (0.58-0.96)Non-inferiority not demonstrated

OS 25.4 vs. 23.8mP=0.19

R

Maintenance with bevacizumab and capecitabine: CAIRO3

Primary endpoint PFS2 = Delay up to 2nd progression after rechallenge with CAPOX-bevacizumab

Secondary endpoints : PFS1, TTP2, OS TTP2 : time to progression or death after first progression, whatever the treatment used

SD or OR(n = 558)

mCRC Non resectable 1st line OMS 0-1

Observation(n = 279)

PFS2

PFS1

Prog

ress

ion

RechallengeCAPOX-bevacizumab

(n = 212 [76 %])

RechallengeCAPOX-bevacizumab

(n = 131 [47 %])

Prog

ress

ion

CAPOX-bevacizumab

(6 cycles)

Capecitabine + bevacizumab *

(n = 279)

* Capecitabine 625 mg/m2 2 x/j en continu + bevacizumab 7,5 mg/kg i.v. every 3 weeks

Phase III trial DCCG (Dutch Colorectal Cancer Group

Figure 2

The Lancet 2015 385, 1843-1852DOI: (10.1016/S0140-6736(14)62004-3)

CAIRO 3: OUTCOMES

Simkens L et al. The Lancet 2015; 385: 1843-52

PFS 1 PFS 2

Time to 2nd PD OS

Figure 1

The Lancet Oncology 2015 16, 1355-1369DOI: (10.1016/S1470-2045(15)00042-X)

Figure 3

The Lancet Oncology 2015 16, 1355-1369DOI: (10.1016/S1470-2045(15)00042-X)

Failure of strategy

PFS

OS

Figure 8

The Lancet Oncology 2015 16, 1355-1369DOI: (10.1016/S1470-2045(15)00042-X) Copyright © 2015 Elsevier Ltd Terms and Conditions

AIO 0207: Quality of Life


MAINTENANCE TRIALS: COMBINED ANALYSIS, VS. NO THERAPY PFS

PFS

OS

Koopman M, et al. J Clin Oncol. 2014;32(Suppl3): Abstract LBA388. Koeberle D, et al. J Clin Oncol 31;2013(Suppl); Abstract 3503.Presented by Dirk Arnold, et al. ASCO 2014. Abstract 3503. On behalf of the AIO CRC Study Group, Presented at 2014 ASCO AnnualMeeting. Courtesy of Prof Arnold.

CONTRIBUTION OF TARGETED AGENT IN MAINTENANCEBevacizumabCetuximab

Phase II trial, Kras wt exon 2 (later retested for Kras, Nras, Braf)

n=78*

n=91*

• *14/78 and 25/91 did not complete the 12w induction, • result will be expressed on per protocol population, not intent to treat• Imbalanced population for Braf in defavor of the continued arm• 13 patients received Xelox rather than Folfox (5 and 8 in the Contimued arm)

Wasan H et al The Lancet Oncology 2014; 15: 631-39

Primary Endpoint: Failure-Free Survival at 10 months

COIN BFailure Free Survival (Primary Endpoint)

The Lancet Oncology 2014 15, 631-639DOI: (10.1016/S1470-2045(14)70106-8) Copyright © 2014 Wasan et al. Open Access article distributed under the terms of CC BY Terms and Conditions

All Wild-type population:Median FFS (months):Intermittent: 12.3 mContinued: 14.5 m


The Lancet Oncology 2014 15, 631-639DOI: (10.1016/S1470-2045(14)70106-8) Copyright © 2014 Wasan et al. Open Access article distributed under the terms of CC BY Terms and Conditions

COIN BOverall Survival

All Wild-type population:Median OS (months):Intermittent: 18.8 mContinued: 21.7 m


COIN B

Intermittent Folfox-Cetuximab with Cetuximab maintenance: conclusion

• In COIN-B, planned maintenance with cetuximab was associated with• a greater failure-free survival, • a greater progression-free survival, • a greater overall survival, • an improved disease control at 24 weeks, • and a longer chemotherapy-free interval

than was intermittent cetuximab.

• These benefits occurred despite an imbalance of prognostic factors at baseline

• COIN-B was designed as an exploratory, hypothesis generating study to complement COIN.

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-

label, phase 3 trial

Prof Christophe Tournigand, MD, Benoist Chibaudel, MD, Benoit Samson, MD, Prof Werner Scheithauer, MD, Dewi Vernerey, PhD, Paul Mésange, PhD, Gérard Lledo, MD, Frédéric Viret, MD, Jean-François Ramée, MD, Prof Nicole Tubiana-Mathieu, MD, Jérôme Dauba,

MD, Olivier Dupuis, MD, Yves Rinaldi, MD, May Mabro, MD, Nathalie Aucoin, MD, Jean Latreille, MD, Prof Franck Bonnetain, PhD, Prof Christophe Louvet, MD, Annette K Larsen, PhD, Prof Thierry André, MD, Prof Aimery de Gramont, MD

The Lancet OncologyVolume 16, Issue 15, Pages 1493-1505 (November 2015)

DOI: 10.1016/S1470-2045(15)00216-8

Copyright © 2015 Elsevier Ltd Terms and Conditions

Switch maintenance with another EGFR targeting agent


Maintenance: Bev + erlotinib DREAM

Induction, N=700

33

Bevacizumab(7.5 mg/kg /21d)

+ erlotinib(150 mg/d)

until progression

NoProgression

Maintenance, N=446

N=222

Bevacizumab(7.5 mg/kg /21d)

until progression

N=2244.1.07 – 13.10.11

REGISTRATION

mFOLFOX7bevacizumab(59%)

XELOX2bevacizumab(30%)

FOLFIRIbevacizumab(10%)

6 MONTHS

R

Primary Endpoint: PFS after maintenance randomisation (4.5 6.5m)

Berry SR et al, Annals Oncol 26: 477–485, 2015

If maintenance is prefrerred:

ESMO Highlights Copenhagen J.Taïeb

Abst 462

PFS HR 0.63 (0.37-1.08)

41Van Cutsem E et al.

42Van Cutsem E et al.

MAINTENANCE THERAPYIndividualisation and discussion with the patient is essential:

For patients receiving FOLFOX or CAPOX plus bevacizumab-based therapy, consider maintenance therapy after 6–8 cycles with a combination of a fluoropyrimidine plus bevacizumab

Patients receiving FOLFIRI can continue on induction therapy for as long as tumourshrinkage continues and the treatment is tolerable

Bevacizumab as monotherapy is not recommended as maintenance therapy

As overall survival has not been improved by maintenance strategies, treatment holidays are a valid option and should be discussed with the patientPause remains useful in patients with:

Normalisation of CEA Slow-growing tumours Good response to initial therapy…

For patients receiving initial therapy with a single agent fluoropyrimidine (plus bevacizumab) induction therapy should be maintained

jy douillard, md, phd, cmo esmo preceptorship programme the role of maintenance treatment...

Documents