Optimal Treatment Strategy

in mCRC

Prof. V. Heinemann CCCLMU, Klinikum Grosshadern

Ludwig-Maximilian-University of Munich, Germany

Group Clinical presentation Treatment goal Treatment

intensity

GROUP 0 Clearly R0-resectable liver and/or

lung metastases

Cure, decrease

risk of relapse

Nothing or

moderate

(FOLFOX)

GROUP 1

Not R0-resectable liver and/or

lung metastases only, may become

resectable after induction CT

Maximum

tumor shrinkage

Upfront most

active

combination

GROUP 2 Multiple metastases/sites, with rapid progression and/or tumor-related symptoms

Clinically relevant

tumor shrinkage

as soon as possible,

control PD

Upfront active

combination: at

least doublet

GROUP 3

- Multiple metastases/sites,

- no option for resection

- initially asymptomatic,

- less aggressive disease

- unfit

Prevent further

progression, low

toxicity

Watchful waiting

or sequential

approach (triplet

regimens only in

selected patients)

Clinical ESMO Groups 0 - 3

Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516

How to procede in

resectable mCRC

(Group 0)

Goals: cure, prolongation of DFS and OS

Perioperative Chemotherapy in resectable liver metastasis

Perioperative

Chemo

Primary

Surgery Significance

3-year-PFS

resected patients 42.4% 33.2%

HR=0.73

P=0.025

3-year-PFS

eligible patients 36.2% 28.1%

HR=0.77

P=0.041

5-year OS rate eligible patients

52.4% 48.3% n.s.

Median OS HR = 0.88 (95% CI 0.68-1.14) n.s.

Nordlinger et al. Lancet 2008

Nordlinger, ASCO 2012, #3508

Surgery 6 x FOLFOX4 6 x FOLFOX4

Surgery

R primary endpoint = PFS ( ≤HR 0.71)

n = 364

Median Follow-up = 8.5 years

Neoadjuvant chemotherapy in resectable metastases has only been

investigated as a perioperative treatment

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

125 171 83 57 37 22 8

115 171 115 74 43 21 5

Surgery

Pre&Postop CT

Progression-free survival in eligible patients Nordlinger et al. Lancet 2008

HR= 0.77; CI: 0.60-1.00, p=0.041

LV5FU + Oxaliplatin Periop CT

28.1%

36.2%

+8.1% at 3 years

Surgery only

New EPOC Study: Trial Design in resectable and borderline resectable patients

Chemotherapy 12 weeks

Liver resection

Chemotherapy 12 weeks

Operable (including borderline operable)

colorectal liver metastases

Chemotherapy + Cetuximab 12 weeks

Liver resection

Chemotherapy + Cetuximab 12 weeks

R

Arm A (control)

Arm B (experimental)

Primrose J, et al. Lancet Oncology

Chemo

• FOLFOX (68% vs 67%)

• CAPOX (27% vs 24%)

KRAS wild-type

672 pts screened

272 pts randomised

New EPOC: Resectable liver metastasis

Primrose J, et al. Lancet Oncology 2014

Chemo

(n = 134)

Chemo +

Cetuximab

(n = 137)

Complete response 5.2% 5.1%

Partial response 48.5% 53.3%

ORR 54% 58%

Stable disease 19.4% 17.5%

Progressive disease 8.2% 7.3%

Not assessable 2.2% 1.5%

Message:

No advantage from the addition

of cetuximab in resectable

liver metastasis

Van Loon K, Venook AP JCO 2014

• 38 year old female patient

• KRAS wt, BRAF wt, MSS

• 13-cm lesion in the right liver lobe

with increased FDG-uptake

(SUVmax 11.8)

• Tumor in the hepatic flexure of

the colon with markedly

increased FDG uptake

Synchronous Liver Metastasis

Van Loon K, Venook AP JCO 2014

Plausible Treatment Paradigm for synchronous liver mets

Simultaneous Hepatopulmonary CRC Mets

Dave RV, et al. Br J Surgery 2014

How to procede in

initially non-resectable mCRC

(Group 1)

Goal: maximal tumor shrinkage = conversion to resectability

R0-resection;

prolongation of DFS and OS

total of 12 cycles

Chemotherapy +/- cetuximab in

unresectable liver metastasis

Chemo + Cet OP Chemo + Cet

Chemo OP Chemo

R N = 138

prim. endpoint = conversion to resection

total of 12 cycles

Le-Chi Ye, et al. JCO 2013

Chemotherapy +/- cetuximab in

unresectable liver metastasis

Chemotherapy: FOLFIRI or FOLFOX6

Chemo + Cet OP Chemo + Cet

Chemo OP Chemo

R N = 138

prim. endpoint = conversion to resection

total of 12 cycles

Chemo + Cet

n=70

Chemo

n=68 p

ORR 57.1% 29.4% <0.01

R0-Resection Rate 25.7% 7.4% <0.01

Overall Survival 30.9 mo 21.0 mo 0.013

3-yr-OS 41% 18% 0.013

OS pts with surgery 46.4 mo 36.0 mo 0.94

OS pts no surgery 25.7 mo 19.6 mo 0.05

Ye, Le-Chi JCO 2013

Chemo: FOLFOX6 49%, FOLFIRI 31%, both 20%

Chemotherapy +/- cetuximab in

unresectable liver metastasis

An optimal strategy is

to determine the RAS- and BRAF-

status of the tumor upfront

Ras Mutations Affect Pattern of Metastasis

Yaeger R, et al. Cancer 2014

All patients

Bone mets

Lung mets

Brain mets

Ras mutation associated with higher cumulative incidence of subsequent site specific metastasis

Lung: 32.5% vs 19%

Bone: 8.8% vs 4.4%

Brain: 1.4% vs 0.2%

Liver: 13.0% vs 14.3%

CRYSTAL: RAS wt selection extended the

ORR benefit with cetuximab + FOLFIRI

1. Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019

2. Ciardiello F et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 3506)

3. Van Cutsem E, et al. Ann Oncol 2014;25(suppl 2):ii113

4. Erbitux SmPC June/2014

Resp

on

se r

ate

(%

)

0

10

20

30

40

50

60

70

FOLFIRI

(n=350)

Cetuximab +

FOLFIRI (n=316)

57

40

OR 2.069

p<0.001

Resp

on

se r

ate

(%

)

0

10

20

30

40

50

60

70

FOLFIRI

(n=189)

Cetuximab +

FOLFIRI (n=178)

66

39

OR 3.11

p<0.0001

*RAS evaluable in 430/666 (65%) patients with KRAS exon 2 wt

mCRC; RAS wt: 367/430 (85%), 5% sensitivity cut-off; cetuximab is

not indicated for the treatment of patients with mCRC whose tumors

have RAS mutations or for whom RAS tumor status is unknown4

KRAS exon 2 wt1 RAS wt* (subgroup)2,3

CRYSTAL: Cetuximab improves RR and R0 liver resection rate

in patients with both LLD and non-LLD (RAS wt)

LLD: liver-limited disease

0

10

20

30

40

50

60

70

80

90

100

Re

sp

on

se

(%

)

37

84

39

61

LLD Non-LLD

Odds ratio: 8.99

p<0.0001 Odds ratio: 2.44

p=0.0003

0

5

10

15

20

R0

re

se

cti

on

(%

)

7

16

Cet + CT

(n=43)

CT alone

(n=46)

Cet + CT

(n=135)

CT alone

(n=143)

Odds ratio: 2.68

p=0.179

Odds ratio: 5.94

p=0.04

4 1

Kohne CH, et al. Ann Oncol (2014) 25 (suppl 4): iv184 (541P)

CALGB 80405: FOLFOX vs FOLFIRI

N = 733

FOLFOX

+ BEV

N = 271

FOLFOX +

CETUX

N = 259

FOLFIRI +

BEV

N = 98

FOLFIRI +

CETUX

N = 105

ORR

56%

67%

61%

62%

NR

44%

33%

39%

38%

* KRAS-wild-type

INVESTIGATOR ASSESSMENT; DOCUMENTED, NOT AUDITED

Comparable response rates with FOLFOX and FOLFIRI as

chemotherapy backbone

Effect of Targeted Therapy on Incremental

Response Rates

Cetuximab (RAS WT) Incremental

response rate

CRYSTAL (FOLFIRI) 27%

OPUS (FOLFOX) 29%

FIRE-3 (FOLFIRI)* 16%

CALGB (FOLFOX or FOLFIRI)* 15%

Panitumumab (RAS WT)

PRIME (FOLFOX) ?

*compared to chemotherapy + bevacizumab

Bevacizumab Incremental

response rate

AVF2107g (IFL) +10%

NO16966 (FOLFOX/XELOX) 0%

MAX2010 +8%

AVEX (Cape) +9%

Comparators Incremental

response rate

Falcone FOLFOXIRI 60%

FOLFIRI 34% 26%

Souglakos FOLFOXIRI 43%

FOLFIRI 34% 9%

TRIBE FOLFOXIRI + Bev 65%

FOLFIRI + Bev 53% 12%

OLIVIA FOLFOXIRI +Bev 81%

FOLFOX + Bev 65% 16%

Efficacy of Triplet Therapy

FOLFIRI

Cetuximab

FOLFOXIRI FOLFOXIRI

+ Bev

Study FIRE-3 Falcone TRIBE

Diarrhea 12 20 18

Neutropenia 24 50 49

Febrile Neutropenia 2 5 8

60-day mortality 0 2 4

Grade 3-4 Toxicity

Conversion therapy with FOLFOXIRI is feasible and effective, but is

associated with greater toxicity than FOLFIRI + cetuximab

Optimal Treatment of BRAF mutant mCRC

FOLFOXIRI + bevacizumab

Pooled analysis of 25 patients

Salvatore L, et al. ASCO 2012, #3585

PFS = 11.8 mo

OS = 23.8 mo

FIRE-3: FOLFIRI + cetuximab vs

FOLFIRI + bevacizumab in 48 patients

Stintzing S et al. ASCO-GI 2014

Optimal depth of response is an

important treatment goal in non-

resectable metastasis

Maximal depth of response is an important

treatment goal in initially unresectable metastasis

Lethal

tumor

load

Baseline

tumor

load

Time under treatment

OS

Early tumor shrinkage

Depth of response (smallest tumor size)

• DpR is the maximal tumor

shrinkage in 1st-line

• DpR correlates with overall

survival

FIRE-3: Head-to-head trial of cetuximab + FOLFIRI

vs bevacizumab + FOLFIRI in 1st line mCRC

Open-label, randomized, multicenter, Phase III investigator sponsored trial (IST)

Patients with untreated

KRAS exon 2 wt mCRC

N=592

R

Cetuximab + FOLFIRI

(n=297)

Bevacizumab + FOLFIRI

(n=295)

● Primary endpoint: ORR

● Secondary endpoints: PFS, OS, time to failure of strategy, depth of response, secondary resection rate, safety

● Amended October 2008 to include only patients with KRAS exon 2 wt mCRC

113 patients with KRAS exon 2 mt mCRC were enrolled before the amendment

● Retrospective RAS subgroup analysis (RAS-evaluable population, including both RAS wt and new RAS mt: n=407)

Heinemann V, et al. Lancet Oncol. 2014 Sep;15(10):1065-75

p = Fisher´s exact test (two-sided)

CT evaluable

population

FOLFIRI +

Cetuximab

FOLFIRI +

Bevacizumab

ORR % 95%-CI % 95%-CI Odds

ratio p

KRAS exon 2 wt

n= 493 66.5 60.1 – 72.5 55.6 49.3 – 61.8

1.58

(1.10-2.28) 0.016

Final RAS wt

n= 330 72.0 64.3 – 78.8 56.1 48.3 – 63.6

2.01

(1.27-3.19) 0.003

Independent evaluation

of response

FIRE-3: Evaluation of depth of

response (DpR) in RAS wt tumors

Stintzing S, et al. Ann Oncol 25 (Suppl 5): v1–v41, 2014

Cetuximab + FOLFIRI Bevacizumab + FOLFIRI

Median DpR, % -48.9 -32.3

p value <0.0001

Depth of response correlated significantly with OS and PFS (two-sided Bravais Pearson test)

Cetuximab + FOLFIRI

Bevacizumab + FOLFIRI

+20%

-30%

+100%

-100%

Median time to tumor nadir:

FOLFIRI + Cet: 15.0 weeks

FOLFIRI + Bev: 15.7 weeks

Therapeutic Strategy at the CCCM for resectable metastases

Resectable metastases

1 organ + limited

additional metastases

Surgery MTD decision

Resectable metastases

1 organ Surgery MTD decision

Resectable metastases

in liver and lung

2-stage

Surgery MTD decision

Based on the DpR concept, we believe that also surgical reduction of tumor

load is a valuable strategy to prolong OS

RAS

Mutant WT

good PS

Multidisciplinary

tumorboard

NO YES

Triplet plus

bevacizumab

Alberto Sobrero Amsterdam 2014

Therapeutic Strategy for primarily unresectable metastases based on RAS status

Doublet plus

bevacizumab

Multidisciplinary

tumorboard

FOLFOX/FOLFIRI + Cet

FOLFOX + Pani