“Enfermedad limitada al hígado en cáncer colorrectal metastásico RAS WT: ¿qué aporta...

“Enfermedad limitada al hígado en

cáncer colorrectal metastásico RAS WT:

¿qué aporta Panitumumab?”.

Dr. Carles Pericay PijaumeOncología Médica,

Hospital Universitari de Sabadell, Corporació Sanitària Parc Taulí (Sabadell)

Madrid, 12 de Febrero de 2015

CRC liver metastases are common and predict a poor prognosis if untreated

1. Ferlay J et al. Eur J Cancer. 2013;49(6):1374–403; 2. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99. CRC, colorectal cancer.

• In 2012, CRC was the 2nd most common cancer in Europe:1

– 447,000 new cases

– 215,000 deaths

• ~ 50% of CRC patients develop liver metastases2

– Liver metastases responsible for 2/3 of CRC patient deaths2

• 0-6% 5 year survival for untreated CRC liver metastases3

Resection of liver metastases improves survival

Simmonds PC et al. Br J Cancer. 2006;94(7):982–99 Error bars indicate range.

70

60

50

40

30

20

10

0

R0 resected(16 studies)

Med

ian

5-ye

ar s

urvi

val,

%

Resected,R0/R1 unclear

(19 studies)

Non-radicalresection(11 studies)

Not resected(6 studies)

30% 32%

7%

0%

Surgical series published after 1980

Current definition of liver metastases resectability

1. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 2. Spolverato G et al. World J Gastrointest Oncol. 2013;5(12):207–21; 3. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 4. Adams RB et al. HPB. 2013;15(2):91–103; 5. Adam R et al. Oncologist. 2012;17(10):1225–39; 6. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer [v.3.2014]. www.nccn.org (accessed 20/02/2014).

FLR, functional liver remnant; R0, resection with microscopically

negative margins

• NCCN Guidelines criteria for resection suitability6

“... the likelihood of achieving complete resection of all evident disease with negative surgical margins and maintaining adequate liver reserve”

• The criteria for liver metastasis resectability have not been standardized1-3

Medical fitness for surgery

Resectability1-5

Oncological considerations

Technical considerations

e.g.• Resectable extrahepatic

disease• Number of lesions ≥ 5• Tumour progression

e.g.• R0 with ≥ 25%–30% FLR• Complex procedure

Yes Yes

ESMO 2012 Clinical GuidelinesStratification of mCRC patients for 1st-line treatment

Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516 CT, chemotherapy; R0, resection with microscopically negative margins.

Initially R0 resectable

Potentially R0 resectable with CT& patient can tolerate CT and surgery

Yes

Group 0

Group 0

Group 1

Group 1

No

Symptomatic or aggressive disease

No

Far advanced/bulky disease

Group 2

Group 2

Group 2

Metastatic colorectal cancer

Patient can tolerate CT

Group 3

Group 3

No

No No

Yes

Yes

mCRC patient distribution between ESMO guideline first-line treatment stratification groups

Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037–45.

*Some patients may become resectable following exceptional response to treatment. CT, chemotherapy;

R0, resection with microscopically negative margins.

Group 2*Group 1 Group 3Group 0

Initially R0 resectable

Metastatic colorectal cancer

Non-resectable at clinical presentation

~15%1,2 ~85%1,2

Potentially resectable

10-30%2 70-90%2

Never resectable

What is conversion chemotherapy?

1. Adam R, et al. Oncologist 2012;17:1225–39; 2. Nordlinger B, Benoist S. J Clin Oncol 2006;24:4954–5; 3. Nordlinger B, et al. Clin Colorectal Cancer 2010;9:212–8; 4. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516.

*Chemotherapy to convert unresectable liver metastases to resectable.

Conversion chemotherapy*

Resection

mCRC with initially non-resectable liver metastases

Tumour shrinkage

Conversion CT + surgery for treatment of mCRC with unresectable liver metastases

Adam R, et al. J Clin Oncol 2009; 27:1829-35.*Last preoperative regimen, FL (18%), FOLFOX (62%),

FOLFIRI (6%), FOLFOXIRI (9%), Other (5%)

Minimum follow-up 5 years

Response evaluated every 2 months

mCRC withunresectable

liver metastases(n = 184)

Conversionchemotherapy*

Surgery

• Study objectives: evaluation of possibility of cure, determination of predictive factors of disease cure

FOLLOW

-

UP

Single centre study of consecutive patients

An oncosurgical approach offers the chance of cure to a subgroup of initially non-resectable patients

Adam R, et al. J Clin Oncol 2009; 27:1829-35.Cure = disease-free ≥ 5 years after last hepatectomy / last resection of extrahepatic metastases;

CRC, colorectal cancer; DFS, disease-free survival; OS, overall survival.

0 2 3 4 5 8 10Time (years)

7 96

Sur

viva

l pr

obab

ility

1.0

0.6

0.8

0.4

0.2

0

33%

19%

27%

15%

OS (n = 184)

DFS (n = 184)

1

10-year survival5-year survival

• Cure was achieved in 16% of CRC patients with liver metastases who became eligible for surgery after response to conversion chemotherapy

Response to CT correlates with liver resectability

Folprecht G, et al. Ann Oncol 2005;16:1311–9. CT, chemotherapy

Rate of liver resection following CT

Selected patients, r = 0.96 P = 0.002

Non-selected patients, r = 0.74 P < 0.0001

Phase III trial data, r = 0.67 P = 0.024

• Patient selection and efficacy of pre-operative CT were strong predictors for resectability of liver metastases

Res

ectio

n r

ate

0.9

Response rate

0.3 0.4 0.60.5 0.7 0.80.0

0.2

0.1

0.4

0.3

0.5

0.6

NO16966: BEV + CT significantly improves PFS but not RR or OS in combination with XELOX/FOLFOX4 (ITT)

Re

sp

on

se

ra

te (

%)

0

10

20

30

40

50

60

70

Placebo + FOLFOX4/XELOX

BEV +

FOLFOX4/XELOX

3838

p=0.99

Months Months

RR

Re

sp

on

se

ra

te (

%)

0

10

20

30

40

50

60

70

Placebo + IFL BEV + IFL

4535

p=0.004

RR

AVF2107g: Bevacizumab significantly improves RR, PFS and OS in combination with IFL (ITT)

CRYSTAL: Cetuximab + FOLFIRI significantly improves RR, PFS and OS vs FOLFIRI (KRAS wt)

Re

sp

on

se

ra

te (

%)

0

10

20

30

40

50

60

70

FOLFIRI Cetuximab + FOLFIRI

57

40

p<0.001RR

OPUS: Cetuximab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt)

Re

sp

on

se

ra

te (

%)

0

10

20

30

40

50

60

70

FOLFOX4 Cetuximab +FOLFOX4

57

34

p=0.0027RR

PRIME: Panitumumab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt)

Re

sp

on

se

ra

te (

%)

0

10

20

30

40

50

60

70

FOLFOX Pani + FOLFOX

5748

p=0.018RR

CRYSTAL y OPUS (KRAS WT)

n RR (%) R0 resections (%)

CRYSTALFOLFIRI + ERBITUXFOLFIRI

316350

5740

p<0.001

5.12.0

p=0.03

OPUSFOLFOX + ERBITUXFOLFOX

8297

5734

p<0.003

7.33.1

p=0.22

FOLFIRI + ERBITUXFOLFIRI

6872

7144

p=0.002

13.25.6

p=0.15

FOLFOX + ERBITUXFOLFOX

2523

7639

p=0.018

16.04.3

p=0.35

All

pa

tien

tsL

ive

r lim

ited

Van Cutsem ASCO-GI 2011

0%

5%

10%

15%

20%

25%

30%

17.5%

27.8%

0%

5%

10%

15%

20%

25%

30%

7.0%8.3%

PRIME: Increased R0 resection rate in LLDP

atie

nts

(%

)

KRAS wt KRAS wt: LLD

Pat

ien

ts (

%)

Douillard J-Y, et al. J Clin Oncol 2010;28:4697–4705;

Petrelli F, et al. Int J Colorectal Dis 2012;27:997–1004

Conceptualizing the relevance of DpR for survival

Lethaltumor load

Baselinetumor load

Time under treatment

Tumor shrinkage

No tumor shrinkage

PFS

PFS

PFS

OS

Mansmann UR, et al. ASCO GI 2013 (Abstract no. 427)

CRYSTAL and OPUS: More patients demonstrate ETS when treated with cetuximab

38% 62%

31% 69%≥20%* (n=54)

<20%* (n=24)

<20%* (n=115)≥20%* (n=184)

Cetuximab + FOLFOX4

Cetuximab + FOLFIRI CRYSTAL

OPUS

Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)*Radiologic evaluation reported by the

investigator and reviewed by an IRC

n=299

n=78

mOS 30.0 mo

mOS 18.6 mo

mOS 26.0 mo

mOS 15.7 mo

HR 0.53 p<0.001

HR 0.43

p=0.006

Pro

bab

ility

of

OS

Pro

bab

ility

of

OS

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

Cetuximab + FOLFIRI

Cetuximab + FOLFOX4

≥20%* (n=54)<20%* (n=24)

<20%* (n=115)≥20%* (n=184)

(months)6050403020100

(months)403020100

PRIME: More patients had RECIST response or ETS at week 8 with panitumumab + CT than with CT alone

Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P)

39

51

0

10

20

30

40

50

60

70

80

3839

69

0

10

20

30

40

50

60

70

80

56

Patients with RECIST response

Patients with ETS

Pat

ien

ts (

%)

Pat

ien

ts (

%)

FOLFOX

(n = 298)

Pani + FOLFOX

(n=286)

FOLFOX

(n = 298)

Pani + FOLFOX

(n=284)

OS was significantly longer in patients achieving RECIST response or ETS in both arms

● Patients demonstrating ETS who received pantitumumab plus FOLFOX showed a greater OS benefit compared with those receiving FOLFOX alone (30.0 vs 25.1 months)

FOLFOX FOLFOX + pani

ETS <20%(n=130)

≥20%(n=158)

<20%(n=87)

≥20%(n=197)

Median OS, months (95% CI)

16.6(12.4–18.8)

25.1(22.1–32.8)

10.7(9.4–16.1)

30.0(27.2–33.1)

HR, p-value HR=0.52, p<0.0001 HR=0.43, p<0.0001

Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P)

FOLFOX FOLFOX + pani

RECIST response <30% (n=130)

≥30% (n=112)

<30%(n=141)

≥30%(n=145)

Median OS, months (95% CI)

17.6(15.4–20.2)

29.5(22.5–34.5)

18.0(14.0–21.7)

30.3(26.6–36.8)

HR, p-value HR=0.54, p<0.0001 HR=0.53, p<0.0001

Downsizing initially unresectable metastases offers similar 5-year survival as initially resectable patients

1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Kanas GP, et al. Clin Epidemiol 2012;4:283–301; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99. *median; CRC, colorectal cancer; CT, chemotherapy.

Initially non-resectable

Resection

37% (8-79%)2

0% (0-6%)3

Initially resectable

Resection

38% (30-68%)2

Conversion CT

Untreated

CRC liver metastases

5-year survival*(range)

A meta analysis of resectability and outcomes with anti-EGFR mAb therapy (KRAS exon 2 WT, LLD)

Petrelli F, Barni S. Int J Colorectal Dis 2012;27:997-1004.

CT, chemotherapy; mCRC, metastatic colorectal cancer; LLD, liver limited disease; mAb, monoclonal antibody; ORR, overall response

rate; OS, overall survival; PFS, progression-free survival.

• Comparison of first-line CT + / - cetuximab or panitumumab– KRAS WT initially unresectable liver-limited mCRC

• Meta analysis of RCTs: – Primary outcome: rate of R0 resection

– Secondary outcomes: PFS, OS and ORR

• Four RCTs involving 484 KRAS WT patients were included:– PRIME, Douillard 2010

– COIN, Maughan 2011

– CRYSTAL, Van Cutsem 2011

– OPUS, Van Cutsem 2011

Impact of anti-EGFR mAb therapy on outcomes(KRAS exon 2 WT, LLD)

Petrelli F, Barni S. Int J Colorectal Dis 2012;27:997-1004.CT, chemotherapy; mAb, monoclonal antibody;

R0, resection with microscopically negative margins.

• Meta-analysis indicates EGFR inhibitors increase R0 resection rate by 60% in mCRC patients with unresectable liver-limited disease

0

20

40

60

80

43

72

Pro

port

ion,

%

Response rate

CT alone

P = 0.001

CT+ EGFR mAb0

5

10

15

20

11

18

Pro

port

ion,

%

R0 resection rate

CT alone

P = 0.04

CT + EGFR mAb

20060314 TrialFOLFIRI + panitumumab in 1st-line mCRC

www.amgentrials.com; protocol ID: 20060314; ClinicalTrials.gov ID: NCT00508404. Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138:65-72.

DoR, duration of response; PFS, progression-free survival; TTP, time to progression; DoSD, duration of stable disease; TTF, time to treatment failure; ORR, overall response rate.

mCRC (n = 150)

FOLFIRI (Q2W) +panitumumab 6 mg/kg (Q2W on day 1 of each cycle)

END

OF

TREATMENT

STUDY

END

OFF

OLLOW-UP

SAFETY

8 weeks after end of treatment

Disease assessment every 8 weeks until week 48, then every 3 months

until disease progression

• Study endpoints: ORR (1°), PFS, disease control rate, DoR, TTP, DoSD, TTF, safety- The incidence of R0 resection was also reported

KRAS WT tumours were more likely to respond to treatment with panitumumab plus FOLFIRI

Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138:65-72. CT, chemotherapy; R0, resection with microscopically negative margins.

• A higher proportion of patients with KRAS WT than with KRAS MT had an objective response and R0 resection

0

20

40

60

38

56

Pro

port

ion,

%

Objective response rate

KRAS MT KRAS WT0

5

10

15

20

6

19

Pro

port

ion,

%

R0 resection rate, patients with LLD

KRAS MT KRAS WT

PRIME study FOLFOX4 ± panitumumab in 1st-line treatment of metastatic CRC

www.amgentrials.com: ID: 20050203; ClinicalTrials.gov ID: NCT00364013;1. Douillard JY, et al. J Clin Oncol 2010; 28:4697-705; 2. Douillard JY, et al. N Engl J Med 2013; 369:1023-34.

*KRAS status was prospectively analysed; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin;

DoR, duration of response; ORR, objective response rate; OS, overall survival; TTR, time to response; Q2W, every 2 weeks.

mCRC KRAS* WT(n = 1183)

Disease assessment every 8 weeks

FOLFOX4 (Q2W) +panitumumab 6 mg/kg

(Q2W)

FOLFOX4 (Q2W)

R

1:1

END

OF

TREATMENT

FOLLOW-UP

LONG

TERM

• Study endpoints: PFS (1°), OS, ORR, TTR, DoR, safety and tolerability- Primary Analysis: pre-specified; after >50% of KRAS exon 2 WT patients had died1,2

- Updated OS Analysis: exploratory; after >80% of KRAS exon 2 WT & MT patients died2

PRIME study RAS analysis Post-hoc analysis objective

Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).RAS WT, KRAS & NRAS exons 2/3/4;

LLD, liver-limited disease

Post-hoc analysis to evaluate tumour shrinkage, resection rates and PFS and OS outcomes for

patients with RAS WT and LLD treated inthe 1st-line PRIME study

PRIME study RAS analysis Patient population and objective(RAS WT LLD patients, updated analysis)

Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).CLM, colorectal liver metastases; LLD, liver-limited disease;

RAS, KRAS & NRAS exons 2/3/4.

LLD(n = 41)

LLD(n = 48)

Other only mets(n = 39)

Other only mets(n = 36)

Liver plus other mets(n = 172)

FOLFOX4(n = 252)

First-line mCRC RAS WT(n = 505)

FOLFOX4 + Panitumumab(n = 253)

Liver plus other mets(n = 169)

PRIME study RAS analysis Objective response and tumour shrinkage (RAS WT LLD patients, updated analysis)

Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).

#Patients assessed at baseline and week 8; §Patients assessed at baseline and at least one other time point; LLD, liver-limited disease;

RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive.

0

20

40

60

80

100

6679

Pro

po

rtio

n,

%

Objective response Tumour shrinkage ≥ 30% at wk 8#

0

20

40

60

80

100

65 73

Me

dia

n s

hri

nka

ge

, %

Maximum tumour shrinkage§

0

20

40

60

80

100

51

79

Pro

po

rtio

n,

%

FOLFOX4

Panitumumab + FOLFOX4

P = 0.231 P = 0.015 P = 0.270

n = 41 n = 48 n = 35 n = 43 n = 39 n = 46

PRIME study RAS analysis Metastasectomy and complete resection rates (RAS WT, LLD patients, updated analysis)

Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).*Subgroup of patients with metastasectomy; LLD, liver-limited disease;


0

5

10

15

9

15

Pat

ient

s, n

0

5

10

15

7

14

Pat

ient

s, n

Metastasectomy (all resections) Complete resection*

P = 0.349 P = 0.216

FOLFOX4(n= 41)


(n= 48)

FOLFOX4(n= 41)


(n= 48)

PRIME study RAS analysis PFS, OS (RAS WT, LLD patients, updated analysis)

Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).LLD, liver-limited disease; PFS progression-free survival; OS, overall survival;


PFS

Eventsn (%)

Median OS months

Panitumumab + FOLFOX4 (n = 48) 38 (79) 11.3

FOLFOX4 (n = 41) 37 (90) 9.9

OS

Months

0

20

40

60

80

100

90

70

50

30

10

Kap

lan-

Mei

er e

stim

ate

0 364 8 12 16 28 3220 24 40 44 48 52

HR (95% CI) = 0.75 (0.48, 1.19) P = 0.2223

0

20

40

60

80

100

90

70

50

30

10

Kap

lan-

Mei

er e

stim

ate

Months0 644 8 12 16 20 24 28 32 60565248444036

HR (95% CI) = 0.71 (0.43, 1.16) P = 0.1737

Eventsn (%)

Median OS months

Panitumumab + FOLFOX4 (n = 48) 32 (67) 40.7

FOLFOX4 (n = 41) 31 (76) 33.4

1- Hurwitz 2004, 2- Saltz 2008, 3- Okines 2009, 4- Masi 2010, 5- Falcone 2012, 6- Wong 2011, 7- Gruenberger 2008, 8- Gruenberger 2013

Study Treatment Selected patients n TR (%) R0 (%)

AVF 21071 B-IFLIFL

No 402 45 < 2

NO 169662 B-FOLFOXB-XELOX

No 700701

3838

6.34.9

First-BEAT3 B-CT (oxali/CPT) No 1914 - 9 (12/7)

GONO4 B-FOLFOXIRI No (LLD) 57 (30)

77 (80) (26)

TRIBE5 b-FOLFOXIRIFOLFIRI

No (LLD) 252256

6553

15 (32)12 (28)

LLD CRC patients

Gruenberger7 B-XELOX Resectable 56 73 92

BOXER6 B- XELOX non-resectable and borderline

46 78 10-40

OLIVIA8 B-FOLFOXIRIB-FOLFOX6

non- resectable disease

4139

8061

49%23%

NEOADJUVANT BEVACIZUMAB IN LIVER METASTASES

CELIM: Tasas de Respuesta y Resección R0

All patients

Cetuximab + FOLFOX6

Cetuximab + FOLFIRI KRAS wt KRAS mt

n=106 n=53 n=53 n=67 n=27

CR/PR 62% 68% 57% 70% 41%

95% CI 52–72% 54–80% 42–70% 58–81% 22–61%

R0 resections 34% 38% 30% 33% 30%

95% CI 25–44% 25–52% 18–44% 22–45% 14–50%

Folprecht G, et al. Lancet Oncol 2010; 11: 38–47Folprecht G, et al. EMCC 2011 (Abstract-Poster No. 6009)

POCHER: Alta tasa de respuestas y resecciones

Response rate R0 resection rate

0

10

20

30

40

50

60

70

80

Pat

ient

s (%

)

79%

60%

Pat

ient

s (%

)

2-year OS rate

0

10

20

30

40

50

60

70

80

68%

Pat

ient

s (%

)

0

10

20

30

40

50

60

70

80

Garufi C, Br J Cancer, 2010

Phase II trial of panitumumab plus FOLFOX4 or FOLFIRI in subjects with KRAS wild-type colorectal cancer and liver-limited disease: The PLANET studyA. Abad1*, B. Massuti2, C. Grávalos3, P. Escudero4, C. Guillén-Ponce5, J.L. Manzano1, A. Gomez6, Mª J. Safont7, J. Gallego8, J. Sastre9, C. Pericay10, R. Dueñas11, C. López-López12, F. Losa13, M. Valladares14, E. González15, A. Yuste2, A. Carrato5, Enrique Aranda6 On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)

1.Germans Trias i Pujol Hospital –ICO, Badalona, Spain; 2. General Hospital, Alicante, Spain; 3. Doce de Octubre Hospital, Madrid, Spain; 4. Clínico Lozano Blesa Hospital, Zaragoza, Spain; 5. Universitario Ramón y Cajal Hospital, Madrid, Spain; 6. Maimonides Institute of Biomedical Research, IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba. Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Spain; 7. General Hospital, Valencia, Spain; 8. General Universitario de Elche Hospital, Alicante, Spain; 9. Hospital Clínico San Carlos, Madrid; Center affiliated to the Red Temática de Investigación Cooperativa, RD06/0020/0021, Spain, Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid; 10. Sabadell Hospital, Corporación Sanitaria Parc Taulí, Barcelona, Spain; 11. Complejo Hospitalario de Jaén Hospital, Jaén, Spain; 12. Marqués de Valdecilla Hospital, Santander, Spain; 13. General de L´Hospitalet Hospital, Barcelona, Spain; 14. Complejo Hospitalario Universitario Hospital, La Coruña, Spain; 15. Virgen de las Nieves Hospital, Granada, Spain; *actual address: Oncology Unit, Campus CIMA, Barcelona, Spain

▼Panitumumab in 1st-line mCRC

▼ This medicinal product is subject to additional monitoring. All suspected adverse reactions should be reported

PLANET study Objectives

To evaluate the efficacy and safety of the addition of Pmab to standard CT regimens, either FOLFIRI or FOLFOX4, as first-line treatment in WT KRAS

CCR patients with liver-only metastases.

To explore possible differences in outcomes according to other RAS mutations.

• ClinicalTrials.gov identifier: NCT00885885

R

1:1

• Sponsor: Spanish Cooperative Group for Digestive Tumour Therapy (TTD)• Principal investigators: Dr. Albert Abad & Dr. Alfredo Carrato

FOLFOX4 (Q2W) +panitumumab 6 mg/kg

(Q2W)

FOLFIRI (Q2W) +panitumumab 6 mg/kg

(Q2W))

Response Rate, Resectability Rate,

Safety, PFS,OS

WT KRAS liver-only mCRC

not suitable for initial surgery

N=80

PLANET study Study design

PLANET study Endpoints

• Primary Endpoint:

• Objective response rate (ORR) over the entire Pmab+CT treatment period

• Secondary Endpoints:

• Resection rate (R0+R1) of liver metastases

• Time to resection

• Progression-free survival (PFS)

• Overall survival (OS)

• Adverse Events (AEs) and peri-operative safety

• Exploratory Endpoints:

• Response according to molecular biomarkers (RAS status)

PLANET study Key eligibility criteria

Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster). EGFR, epidermal growth factor receptor

• >18 years of age

• WT KRAS CRC

• Synchronous or metachronous liver-only metastases deemed resectable or unresectable, meeting one of the following criteria– ≥4 liver metastases

– ≥1 metastasis >10 cm in diameter

– Liver metastases not resectable

• No prior anti-EGFR therapy

• Karnofsky performance status ≥70%

• Adequate haematologic, renal and metabolic function

PLANET study Patient disposition and characteristics

Pmab-FOLFOX4(N = 38)

Pmab-FOLFIRI (N = 39)

TOTAL(N = 77)

Male, n (%) 31 (81.6) 28 (71.8) 59 (76.6)

Median age, years (min, max) 65 (32, 79) 63 (37, 83) 64 (32, 83)

Mean body mass index, kg/m2 (SD) 27.4 (4.4) 25.9 (3.6) 26.7 (4.0)

Median time since CCR diagnosis, months (Q1, Q3)

3.4 (1.3, 22.7)

1.6 (0.6, 11,5)

1.9 (0.6, 22.2)

Technically resectable liver metastases, n (%) 12 (31.6) 12 (30.8) 24 (31.2)

Prior surgery for primary tumor, n (%) 26 (68.4) 22 (56.4) 48 (62.3)

Prior adjuvant/neoadjuvant CT and/or radiotherapy, n (%) 6 (15.8) 4 (10.3) 10 (13.0)

Prior FOLFOX, n (%) 3 (7.9) 3 (7.7) 6 (7.8)

• 77 patients were analyzed

– 38 received Pmab-FOLFOX4

– 39 received Pmab-FOLFIRI

Abad et al. Presented at the 16th World Congress on Gastrointestinal Cancer, June 25-28, 2014, Barcelona (Spain); Abstract nº PD-0006

PLANET study Response rate and resectability – presented a ESMO

Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).WT RAS, WT KRAS & NRAS exons 2/3/4;

NA, not achieved

PLANET study OS

P log rank = 0.848P Wilcoxon = 0.915

P log-rank = 0.935P Wilcoxon = 0.634

Pro

port

ion

even

t-fr

ee (

%)

Pro

port

ion

even

t-fr

ee (

%)

0

20

40

60

80

100

90

70

50

30

10

0 6010 20 30 0 5040302010

Median, months(95% CI)

Panitumumab + FOLFOX4 32.5 (20.6–NA)

Panitumumab + FOLFIRI 42.4 (17.8–51.5)

WT KRAS exon 2

0

20

40

60

80

100

90

70

50

30

10

Months Months

WT RAS

Median, months(95% CI)

Panitumumab + FOLFOX4 39.0 (26.4–NA)

Panitumumab + FOLFIRI 45.8 (32.8–51.5)

40 50

• Metastases are:– Limited to liver and / or lung

– Clearly R0-resectable, even without preoperative chemotherapy

• Treatment aim is curative and to decrease risk of relapse

ESMO Clinical Groups for 1st-line treatment Definition of Group 0 (initially resectable) patients

Schmoll HJ, et al. Ann Oncol 2012; 23:2479-516. R0, resection with microscopically negative margins.

Group 2Group 1 Group 3Group 0

Non-resectable at clinical presentationInitially R0 resectable

EORTC intergroup study 40983 [EPOC] Surgery ± FOLFOX4 for resectable liver metastases from colorectal cancer

ClinicalTrials.gov identifier: NCT00006479Nordlinger B, et al. Lancet 2008; 371:1007-16; Nordlinger B, et al. Lancet 2013; 14:1208-14.

mCRC metastatic colorectal cancer; LLD, liver limited disease; OS, overall survival; PFS, progression free survival.

R

1:1

mCRC with initially

resectable LLD

(n = 364)

FOLFOX46 cycles

None

FOLFOX46 cycles

None

• Study endpoints: PFS (1°), OS, resectability, tumour response, safety

Open label, phase 3 study

SURGERY

EORTC intergroup study 40983 [EPOC] Progression free survival

Nordlinger B, et al. Lancet 2008; 371:1007-16. PFS, progression free survival.

Pro

por

tion

even

t-fr

ee (

%)

Pro

por

tion

even

t-fr

ee (

%)

0

20

40

60

80

100

0 61 2 3 4 5 0 654321 0

20

40

60

80

100

Years Years

All eligible patients All resected patients

HR (96% CI) = 0.77 (0.60, 1.00) P = 0.041

HR (96% CI) = 0.73 (0.55, 0.97) P = 0.025

3-year PFS, %

Surgery + FOLFOX4 (n = 171)

36.2

Surgery (n = 171) 28.1

3-year PFS, %

Surgery + FOLFOX4 (n = 151)

42.4

Surgery (n = 152) 33.2

• Perioperative FOLFOX4 reduced the risk of PFS events by ~25%

20100086 EORTC BOS-2 studyPatients with resectable liver metastases

ClinicalTrials.gov identifier: NCT01508000. BOS, biologics, oxaliplatin and surgery, OS, overall survival.

R

KRAS WT mCRC with

resectable LLD

(n = 360)

6 cycles

mFOLFOX6

mFOLFOX6 +bevacizumab

mFOLFOX6 +panitumumab

6 cycles

mFOLFOX6

mFOLFOX6 +bevacizumab

mFOLFOX6 +panitumumab

Open label, phase 2 study

• Study endpoints: PFS (1°), pathological response rate, resection rate, OS, safety

SURGERY

FOLLOW

-

UP

Conclusiones

• El CCRm tiene mal pronóstico si no se trata.

• La cirugía hepática ofrece posibilidad de curación (15%)

• Hasta un 30% de los tumnores inicialmente irresecables se

convierten en resecables tras QT de conversión

• Las combinaciones de quimioterapia con tratamientos biológicos

ofrecen tasas de respuestas superiores a 50% en pacientes no

seleccionados, y superiores a 70% en pacientes con enfermedad

limitada al hígado.

• Los datos de los estudios fase III (PRIME), y los estudios de los

estudios fase II con pacientes seleccionados (PLANET), permiten

emular los resultados de otras combinaciones

Conclusiones

• Cuando hablemos del tratamiento de conversión

en pacientes afectos de CCRm potencialmente

resecables, las combinaciones con panitumumab

han demostrado ser igualmente eficaces que

otras combinaciones de tratamiento estudiadas

con anterioridad.

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