what comes after 1 st line? - european society for medical ......disclosures advisory role bayer,...

ESMO Preceptorship Programme

What comes after 1st line?

Dirk Arnold

Instituto CUF de Oncologia, Lisbon, Portugal

Colorectal Cancer– Valencia – 12-13 May 2017

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

Factors that impact on treatment decisions

1st line 2nd and further line

Treatment goal Pretreatment

Disease-related factorsInformation from pretreatment

(including reported toxicity)

Patient-related factors Disease-related factors

Biomarkers Patient-related factors

Anticipated toxicity Treatment goal

Biomarkers

Factors that impact on treatment decisions

1st line 2nd and further line

Treatment goal Pretreatment

Disease-related factorsInformation from pretreatment

(efficacy, duration, toxicity)

Patient-related factors Disease-related factors

Biomarkers Patient-related factors

Anticipated toxicity Treatment goal

Biomarkers

Closer follow-up after resection of the primary tumor, earlier detection of metastatic disease

Improvements in the efficacy of systemic therapies and better selection

More patients have access to surgical resection of mets. - or other local ablative interventions

Implementation of ‘continuum of care’ treatment strategies,

plus early integration of optimal supportive care measures

ESMO Consensus Guidelines: Care is improving

ESMO Consensus Guidelines. Van Cutsem E, et al. Ann Oncol. 2016;27:1386–422

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 in oncology practices subscribing to a US-wide chemotherapy order entry system2

Despite advances, the prognosis of mCRC patients pretreated with all available

agents is poor and there is a high unmet need for newer treatments

1L

2L

3L

Chibaudel B et al. Ther Adv Med Oncol 2012;4:75-89

Abrams TA et al. J Natl Cancer Inst 2014; 106(2): djt371

Salvatore L et al. ExpertRev Anticancer Ther 2015;15:1283-92

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

OS

and

QoL

Schmoll et al., Ann Oncol 2012

ESMO Consensus 2012: Sequences

FOLFOX �� FOLFIRI vs. FOLFIRI �� FOLFOX

Tournigand et al., J Clin Oncol 2004:

Median OS 20.6 months

FOLFOX �� FOLFIRI vs. FOLFIRI �� FOLFOX

Tournigand et al., J Clin Oncol 2004:

Median OS 20.6 months

ESMO Consensus 2012: Sequences

Schmoll et al., Ann Oncol 2012

Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014

ESMO CP Guideline 2014: Sequences

VEGF Resistance occurs – but when ?

Chemo (B)

other (anti-EGFR)

Chemo (A)

Anti-VEGF

R

R

Chemo (A)

Anti-VEGF

Chemo (B)R

R

BEV + standard first-line CT

(either oxaliplatin or

irinotecan-based)

(n=820)

Randomize 1:1

Standard second-line CT (oxaliplatin

or irinotecan-based) until PD

BEV (2.5 mg/kg/wk) +

standard second-line CT (oxaliplatin

or irinotecan-based) until PD

PD

TML Study: Design (phase III)

CT switch:

Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

CT switch:

Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

Primary endpoint • Overall survival (OS) from randomisation

Secondary endpoints included • Progression-free survival (PFS)

• Best overall response rate

• Safety

Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)

• First-line PFS (≤9 months, >9 months)

• Time from last BEV dose (≤42 days, >42 days)

• ECOG PS at baseline (0/1, 2)

Arnold et al., ASCO 2012

Benounna et al., Lancet Oncol 2013

2L chemo alone or plus continued Bevacizumab after progression with

chemotherapy plus Bevacizumab

Benounna, Sastre, Arnold et al., Lancet Oncol 2013

TML study: Results

BEBYP Phase II Study

I"line'CT'*'+'BV'

! Center'

! PS'0/1"2'

! CT"free'interval'

''''(>'vs'≤'3'mos)'

! II"line'CT'

• FOLFIRI'

• FOLFOX'

• FOLFOXIRI'

• Fluoropyrimidine'mono!tx'

• FOLFIRI'

• mFOLFOX!6'

•

•

BEBYP Study: Results

PFS OS

Masi et al., Ann Oncol 2015

TML trial: Subgroup analyses

Vieitez de Prado, Borg, Arnold et al., ESMO 2012

Benounna, Sastre, Arnold et al., Lancet Oncol 2013

Antiangiogenic treatment in mCRC

Arnold & Tabernero, J Oncopathol 2013

cc

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

Van Cutsem et al., J Clin Oncol 2012

PFS: HR 0.76, p<0.001

med. 4.7 vs. 6.9 mos.

OS: HR 0.82, p<0.0032

med. 12.06 vs. 13.5 mos.

Overall survival

Progression free survival

VELOUR trial: Stratified Subgroups

Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611

All Grades Grade 3-4 All Grades Grade 3-4

Diarrhea 56.5 7.8 69.2 19.3

Neutropenia

Complicated neutropenia

56.3 29.5

2.8

67.8 36.7

5.7

Asthenic conditions (HLT) 50.2 10.6 60.4 16.9

Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7

Thrombocytopenia 33.8 1.7 47.4 3.3

Infections (SOC) 32.7 6.9 46.2 12.3

** From lab

Van Cutsem et al., J Clin Oncol 2012

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

RAISE: Study Design

Treatment until disease progression

or unacceptable

toxicity

Primary endpoint: Overall survival

Ramucirumab (8 mg/kg) and FOLFIRI* every 2 weeks per cycle

N=525

Placebo and FOLFIRI* every 2 weeks per cycle

N=525

R A

N

D

O

M I

Z

E

(1:1) Stratification factors:

• Geographic regions • KRAS mutation status • Time to disease progression after

beginning first-line therapy

Progression during

or after bevacizumab, oxaliplatin, and a

fluoropyrimidine

Sample size assumptions • Hazard ratio of 0.8 • Median overall survival of 10 months in the control arm vs 12.5 months with

ramucirumab with a 2-sided α level of 0.05 • Enrollment of 1050 patients with 756 events for 85% power

• Gatekeeping from OS to PFS to ORR

Abbreviations: IG=immunogenicity; PFS=progression-free survival; PK=pharmacokinetics; OS=overall survival; ORR=objective response rate. *Irinotecan: 180 mg/m2; Folinic acid: 400 mg/m2 ; 5-Fluorouracil: 400 mg/m2 bolus, followed by 2400 mg/m2 administered intravenously over 46 to 48 hours (continuously).

Secondary endpoints: PFS, ORR, PRO, Safety, PK, IG

Tabernero et al., GI Cancer Symposium 2015

Tabernero et al., Lancet Oncology 2015

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

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=0.75

p=0.0011

HR=0.81

p=0.0062

HR=0.82

p=0.0032

HR=0.84

p=0.022

mPFS, months 7.3 4.7 5.7 4.1 6.9 4.7 5.7 4.4

HR=0.61

p<0.0001

HR=0.68

p<0.0001

HR=0.76

p=0.00007

HR=0.79

p=0.0005

ORR, %22.7 8.6 5.4 3.9 19.8 11.1 13.4 12.5

p<0.0001 ns p=0.0001 ns

2nd line with anti-VEGF combinations

1. Langer, et al. ESMO 2008; 2 . Peeters, et al. JCO 2010; 3. Van Cutsem, et al. WCGC 2011

4. 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 2012;

Van Cutsem, et al. J Clin Oncol 2012 ; Tabernero et al., Lancet Oncol 2015


Chemo (B)

other (anti-EGFR)

Chemo (A)

Anti-VEGF

R

R

Chemo (A)

Anti-VEGF

Chemo (B)R

R

?


Chemo (B)

other (anti-EGFR)

Chemo (A)

Anti-VEGF

R

R

Chemo (A)

Anti-VEGF

Chemo (B)R

R

Anti-VEGF

Chemo (A) Chemo (B)R otherR

Regorafenib

TAS 102 combo?

CIT plus anti-VEGF?

Sobrero et al., J Clin Oncol 2008

OS, high crossover-rate PFS

Peeters et al., Clin Cancer Res 2015

181 trial: 2nd line FOLFIRI +/- Panitumumab

FOLFIRI/p´mab FOLFIRI/p´mab

ORR (Ras cohort):

FOLFIRI/p´mab41%

FOLFIRI 10%

Peeters et al., Clin Cancer Res 2015

181 trial: 2nd line FOLFIRI +/- Panitumumab

Hecht et al., Clin Colorectal Cancer 2015

2nd line, after FOLFOX/bev:

FOLFIRI/bev - or FOLFIRI/p´́́́mab? SPIRITT trial

KRAS wild-type; N=182

Hecht et al., Clin Colorectal Cancer 2015

2nd line, after FOLFOX/bev:

FOLFIRI/bev - or FOLFIRI/p´́́́mab? SPIRITT trial

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

Primary Endpoint:

Progression-free rate at 4

months

Hiret et al., ASCO 2016

2nd line, after FP combo/bev:FP-combo/bev - or FP-combo/p´́́́mab? PRODIGE-18 trial

Hiret et al., ASCO 2016

2nd line, after FP combo/bev:FP-combo/bev - or FP-combo/p´́́́mab? PRODIGE-18 trial

N=130

„TML-like“

„TML-like“

Are there optimal sequences? STRATEGIC-1

Phase III, GERCOR

PI: Benoist Chibaudel

Closer follow-up after resection of the primary tumor, earlier detection of metastatic disease

Improvements in the efficacy of systemic therapies and better selection

More patients have access to surgical resection of mets. - or other local ablative interventions

Implementation of ‘continuum of care’ treatment strategies,

plus early integration of optimal supportive care measures

ESMO Consensus Guidelines: Care is improving

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 in oncology practices subscribing to a US-wide chemotherapy order entry system2

1L

2L

3L

Chibaudel B et al. Ther Adv Med Oncol 2012;4:75-89

Abrams TA et al. J Natl Cancer Inst 2014; 106(2): djt371

Salvatore L et al. ExpertRev Anticancer Ther 2015;15:1283-92

Regorafenib (BAY 73-4506):

an oral multikinase inhibitor 1,2,3

Inhibition ofroliferation

Inhibition ofangiogenesis

Inhibition pf signallingIn tumor –

microenvironment

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.

Grothey et al., WCGC 2015 (oral presentation)

CORRECT&

CONCUR&

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

Randomized trials with Regorafenib

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.

Treatment-emergent hepatic and hematologic laboratory

values, regardless of relation to study drug

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Proportion of patients (%)CORRECT CONCUR

Regorafenib Placebo Regorafenib Placebo

ALT increased

Grade 3

Grade 4

5

<1

3

<1

9

0

1

0

AST increased

Grade 3

Grade 4

5

<1

4

<1

10

<1

3

0

Blood bilirubin increased

Grade 3

Grade 4

10

3

5

3

7

4

4

0

Anemia

Grade 3

Grade 4

5

<1

3

0

8

0

1

0

Neutropenia

Grade 3

Grade 4

<1

0

0

0

3

1

0

0

Thrombocytopenia

Grade 3

Grade 4

2

<1

<1

0

3

<1

0

0

Japan May 2014 FDA September 2015 EMA April 2016

New option for pre-treated mCRC

Trifluridine/tipiracil is indicated for the treatment of adult patients with

metastatic colorectal cancer (mCRC) who have been previously treated

with, or are not considered candidates for, available therapies including

fluoropyrimidine-, oxaliplatin- and irinotecan based chemotherapies, anti-VEGF

agents, and anti-EGFR agents.

Trifluridine/tipiracil Summary of Product Characteristics

Trifluridine/tipiracil approved

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

Cytotoxicity of trifluridine/tipiracil in 5-FU-resistant tumorsR

ate

of

tum

ou

r g

row

th

inh

ibit

ion

(%

)

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

5-week old nude rats were subcutaneously transplanted in the dorsal region with human colorectal DLD-1 cells; response was measured after 14 days

of treatment.

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

RECOURSE Refractory colorectal cancer study

� Multicentre, randomized, double-blind, placebo-controlled, Phase 3 study

‒ Stratification: KRAS status, time from diagnosis of metastatic disease,

geographical region

� Treatment continuation until progression, intolerant toxicity or patient refusal

� Sites: 13 countries, 101 sites

mCRC

• Patients previously received 2 or more prior

regimens

– Refractory / intolerable to

– Fluoropyrimidine

– Irinotecan

– Oxaliplatin

– Bevacizumab

– Anti-EGFR if wild-type KRAS

• Known KRAS status

• ECOG PS 0-1

• Adequate bone marrow and organ function

2:1

RA

ND

OM

IZ

AT

IO

N

Trifluridine/tipiracil + BSC

(N=534)35 mg/m2 BID POd1–5, 8–12 q4w

Placebo + BSC

(N=266)BID PO

d1–5, 8–12 q4w

Endpoints

• Primary: OS

• Secondary: PFS, Safety, Tolerability, Time to ECOG PS≥2, ORR, DCR, DoR, Subgroup by KRAS (OS and PFS)

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919

RECOURSE Overall Survival

Su

rviv

al

dis

trib

uti

on

fu

nc

tio

n

Months from randomization

0 3 6 9 12 15 180

0.5

1.0

266 198 107 47 24

534 459 294 137 64Trifluridine/tipiracil

No. at Risk:

Placebo

Trifluridine/tipiracil

(N=534)

Placebo

(N=266)

Median OS (months)* 7.1 5.3

Stratified log-rank test: p<0.0001

HR: 0.68, 95% CI [0.58, 0.81]

Alive at 12 months, % 27 18

23 79 3


RECOURSE OS subgroup analyses

Subgroup Favours trifluridine/tipiracil Favours placebo Events / N HR (95% CI)

All patients 574 / 800 0.68 (0.58-0.81)

KRAS statusWild typeMutant

280 / 393294 / 407

0.580.80

(0.45-0.74)(0.63-1.02)

Time since diagnosis of first metastasis<18 months≥18 months

131 / 166443 / 634

0.840.64

(0.58-1.21)(0.53-0.78)

Geographic regionJapanUS, Europe & Australia

227 / 266347 / 534

0.750.64

(0.57-1.00)(0.52-0.80)

Age<65 years≥65 years

316 / 448258 / 352

0.740.62

(0.59-0.94)(0.48-0.80)

GenderMaleFemale

348 / 491226 / 309

0.690.68

(0.56-0.87)(0.51-0.90)

ECOG performance status01

298 / 448276 / 352

0.730.61

(0.58-0.93)(0.48-0.79)

Primary tumor siteColonRectum

361 / 499213 / 301

0.680.64

(0.55-0.85)(0.48-0.85)

Number of prior regimens23≥4

106 / 140137 / 173331 / 487

1.050.740.59

(0.68-1.63)(0.51-1.08)(0.47-0.73)

Prior use of regorafenibYesNo

94 / 144480 / 656

0.690.69

(0.45-1.05)(0.57-0.83)

Refractory to fluoropyrimidinepart of last prior regimen 329 / 455 0.75 (0.59-0.94)

0.3 0.5 1 2.0Hazard ratio: Trifluridine/tipiracil vs. placebo (95% CI)


RECOURSE Overall Response rate and Disease control rate

0%

10%

20%

30%

40%

50%

60%

p<0.001

Response rateDisease control rate

44%

16%

PlaceboTrifluridine/tipiracil


(N=112) %

Placebo

(N=57) %

CR 0 0

PR 1.6 0

SD 42.4 15.9

ORR (%) 1.6 0.4

Mayer RJ et al. N Engl J Med. 2015;372:1909-1919

RECOURSE Time to ECOG Performance Status ≥2


(N=534)

Placebo

(N=266)

Median PFS (months) 5.7 4.0

Stratified log-rank test: p<0.001

HR: 0.66, 95% CI [0.56, 0.78]

% w

ith

EC

OG

pe

rfo

rma

nc

e s

tatu

s <

2

Months from randomization

0 3 6 9 12 15 180

50

100

266 134 57 21 11

534 352 188 84 28Trifluridine/tipiracil

No. at Risk:

Placebo

7 03 1

Van Cutsem E, et al. ESMO 2016. Abstract 515P

RECOURSE Frequency of adverse events

Event, %


(N=533)

Placebo

(N=265)

Any Grade Grade ≥3 Any Grade Grade ≥3

Any event, % 98 69 93 52

Any serious event, % 30 34

Most common eventsa, %

Nausea 48 2 24 1

Vomiting 28 2 14 <1

Decreased appetite 39 4 29 5

Fatigue 35 4 23 6

Diarrhea 32 3 12 <1

Abdominal pain 21 2 18 4

Fever 19 1 14 <1

Asthenia 18 3 11 3Per NCI CTCAE version 4.03aAdverse events of any grade that occurred in ≥10% of patients in the trifluridine/tipiracil group and in a greater percentage in that group than in the placebo group


RECOURSE Adverse events of special interest*

Event, %


(N=533)

Placebo

(N=265)

Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4

Febrile neutropenia 3.8 2.8 0.9 0 0 0

Stomatitis 7.9 0.4 0 6.0 0 0

Hand-foot syndrome 2.3 0 0 2.3 0 0

Alopecia 6.8 0 0 1.1 0 0

Proteinuria 4.1 0 0 1.9 0 0

Cardiac ischemia events 0.4 0.2 0 0.4 0 0.4

Thromboembolic events 3.9 1.7 0.2 2.3 1.1 0.4

Pulmonary embolism 1.7 1.3 0.2 0 0 0


RECOURSE Frequency of laboratory abnormalities

Laboratory abnormalities, %


(N=533)

Placebo

(N=265)

Any Grade Grade ≥3 Any Grade Grade ≥3

Neutropenia 67 38 <1 0

Leukopenia 77 21 5 0

Anemia 77 18 33 3

Thrombocytopenia 42 5 8 <1

Increases in alanine

aminotransferase24 2 27 4

Increase in aspartate

aminotransferase30 4 35 6

Increase in total bilirubin 36 9 26 12

Increase in alkaline phosphatase 39 8 45 11

Increase in creatinine 13 <1 12 <1


Guidelines ESMO 2016

Guidelines NCCN 2017

NCCN Guidelines v1.2017

NICE recommendation

NICE 2016

Retreatment May Refer to Reintroduction or

Rechallenge with 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

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 series

of on-label therapy in

22 institutions in

Canada

Patients with KRAS WT mCRC who

had received a CETUX-based

regimen and, after progression,

monotherapy with panitumumab

Prior response to CETUX-based

regimen correlated with better

response to panitumumab (n=48;

ORR=31%; SD=16%) vs no prior

response (n=28; ORR=7%; SD=7%)

Panitumumab

monotherapy has limited

benefit for mCRC that did

not respond to prior

CETUX-based regimen

Liu X, et

al. 3104 Retrospective analysis

of patients re-treated

with an anti-EGFR

agent in phase I/II

studies

KRAS wild type mCRC; prior

cetuximab 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 between

skin tox during first

CETUX + IRI-based

therapy 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

al1285 Retrospective pooled

analysis 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 may

benefit from Oxaliplatin

reintroduction: defined by the

efficacy of induction therapy

followed by an OFI of at least

6 mo between 2 periods of

FOLFOX therapy

Bhadkamkar,

et al2126 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 Oxaliplatin

regimen

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 KRAS

WT 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 al420 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)

Level IV Evidence

Level IV Evidence

Level III Evidence

Level IV Evidence

G.SM.ON.09.2014.1007

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.

Thank you for your attention!

Dirk Arnold

Instituto CUF de Oncologia

Lisboa, Portugal

[email protected]

what comes after 1 st line? - european society for medical ......disclosures advisory role bayer,...

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