Nuovi dati Colon

Roma, 7 Ottobre 2017

Alain Gelibter

Policlinico Umberto I

UOC Oncologia B

1

NEOADJUVANT FOLFOX 4 VERSUS FOLFOX 4 PLUS CETUXIMAB VERSUS IMMEDIATE SURGERY FOR HIGH-

RISK STAGE II AND III COLON CANCERS: A PHASE II MULTICENTRE RANDOMISED CONTROLLED TRIAL

(PRODIGE 22) KAROUI Mehdi, RULLIER Anne, MARIETTE Christophe, MAILLARD Emilie, BARDIER Armelle, POIZAT Flora, LUCIANI

Alain, SARRAN Anthony, LEGOUX Jean-Louis, DE CHAISEMARTIN Ccile, LECAILLE Cdric, BOUCHE Olivier, MAUVAIS Franois, BRUNETTI Francesco, PRUDHOMME Michel, SEITZ Jean-Franois, LEPAGE Cme, TAIEB Julien

esmo.org

However recurrence rates at 3 years (95%CI)

IDEA (2017) PETACC8 (2014)

pT1-T3, N1 Capox 3m 15% (13.1-16.9) -

pT4/ or N2 Folfox 6m 35.3% (32.7-37.8) Folfox + Cetuximab 6m 43.1% (32.5-55.4)

Qian Shi et al., ASCO 2017; Taieb J et al., Lancet Oncol 2014

BACKGROUND AND RATIONALE (2)

Reasons for this relative failure

- Delayed start of chemotherapy

- Growth factors stimulation / immunosuppression induced by surgery

Van der Bij G et al., Ann Surg 2009;249

PRODIGE 22 STUDY DESIGN

Multicenter randomized phase II trial

FOLFOX (4 cycles)

High risk T3

T4

N2

SURGERY

SURGERY

FOLFOX (12 cycles)

Stage III ou II (investig)

FOLFOX (8 cycles)

FOLFOX + Cetuximab

(4 cycles) SURGERY

FOLFOX + Cetuximab

(8 cycles)

R

RAS WT

esmo.org Challenge: to make decisions on small numbers, dropping of cetuximab arm based upon lack

of TRG from 13 pts. Morbidity the same as in the surgery only arm: IDMC decision

esmo.org

120 patients

Surgery (52) ITT population

Folfox-Cetuximab (3) : TRG 1 = 0

Folfox preop (52)

Interim analysis Folfox

(n = 13)

Folfox-Cetuximab

(n = 13)

Surgery

(n = 13)

TRG 1 3 0 0

Severe morbidity (Dindo > 3) 1 (7.7%) 2 (15.3%) 2 (15.3%)

Colectomy (51)

Protocol deviation (1) Metastatic disease (1)

PT related complication (1)

Disease progression under CT (1) Surgery (49)

Unresectable PT (1)

Colectomy (48)

esmo.org

PRODIGE 22 ENDPOINTS (1)

Primary endpoint: Tumor response

(Ryan simplified Tumor Regression Grade)

double central

independent

and blinded review

esmo.org

PRODIGE 22 ENDPOINTS (2)

Secondary outcome measures

- Chemotherapy toxicity

- Primary tumor (PT) complications under chemotherapy

- Postoperative morbidity

- Quality of surgery

- Radiological staging

- 3 years DFS

- Quality of life

BASELINE CHARACTERISTICS

FOLFOX

(n = 52)

Surgery

(n = 52)

Total

(n = 104)

Age (years, median) 64.6 62.2 62.6

Males (n, %) 30 (58%) 33 (63%) 63 (60.5%)

BMI (kg/m, median) 24.3 26.4 25.3

Tumor location (n, %)

Right / transverse

Left / sigmoid

27 (52%)

25 (48%)

21 (40%)

31 (60%)

48 (46%)

56 (54%)

CEA level > 2.5N (n, %) 10 (19%) 10 (19%) 20 (19%)

Small numbers and lack of stratification potentially can have Large consequences.

FOLFOX PREOP: ADVERSE EVENTS

FOLFOX

(n = 50)

Pts who completed 4 cycles 48 (96%)

Pts with grade > 3 AE (n, %) 19 (38%)

Pts who discontinued study drug for AE

Primary tumor complication

2 (4%)

0

Time to surgery (median, days) 31 (20 - 62)

Grade > 3 AE, n (%)

Anemia 1 (2%)

Thrombocytopenia 1 (2%)

Neutropenia 5 (10%)

Diarrhea 2 (4%)

Nausea 4 (8%)

Fatigue 2 (4%)

Fever 2 (4%)

Deep venous thrombosis 1 (2%)

Acute coronary

syndrome

1 (2%)

esmo.org

POST-OPERATIVE RESULTS

FOLFOX

(n = 49)

Surgery

(n = 51)

Total

(n = 100 )

PT resection 48 51 99%

Mortality 0 1 (2%) 1%

Overall morbidity 17 (34.5%) 18 (35%) 35%

Severe morbidity (> Dindo III) 4 (8%) 4 (8%) 8%

Surgical complications

Anastomotic leak

11

1

14

1

25%

2%

R0 resection 46 (94%) 48 (98%) 94%

Complete mesocolic excision 95% 91% 93%

PATHOLOGICAL RESULTS

Surgery

(n = 51)

FOLFOX

(n = 48) p

Stage

I

II

III

0.019

0

20 (39%)

31 (61%)

4 (8%)

25 (52%)

19 (40%)

pT4 and/ or N2 30 (59%) 18 (37.5%) 0.033

Vascular emboli, lymphatic and/

or perineural invasion 25 (49%) 9 (19%) 0.001

Number of harvested LN (mean) 25.2 +/- 11.2 26.6 +/- 11.3 0.529

Number of positive LN (mean) 2.5 +/- 3.9 1.65 +/- 2.9 0.215

Radiological

concordance

awaited.

Up to 40% of

patients

receiving

Oxaliplatin

unnecessarily.

How many would

not have

required chemo

at all

esmo.org

PRIMARY ENDPOINT: TUMOR RESPONSE

FOLFOX

(n = 52)

Surgery

(n = 52) p

TRG 1 4 (8%) 0 0.118

TRG 2 19 (36%) 4 (8%)

TRG 3 25 (48%) 45 (86%)

Non available 4 (8%) 3 (6%)

Significant tumor

regression (TRG 1 + 2) 23 (44%) 4 (8%)

esmo.org

PRODIGE 22 : CONCLUSION

Neoadjuvant FOLFOX chemotherapy (4 cycles) in a perioperative

setting in patients with locally advanced colon cancer :

- is well tolerated

- does not increase surgical morbidity

- is not associated with major histological response (TRG1)

- is associated with significant tumor regression as compared

to upfront surgery (TRG 1+2 : 44% vs. 8% p

VOLFI:

mFOLFOXIRI + PANITUMUMAB VERSUS FOLFOXIRI

esmo.org

Abstract 475O

AS FIRST-LINE TREATMENT IN PATIENTS WITH RAS WILD-TYPE

METASTATIC COLORECTAL CANCER (mCRC):

A RANDOMIZED PHASE II TRIAL OF THE AIO (AIO-KRK-0109)

M. Geissler (Esslingen, Germany), U. M. Martens (Heilbronn, Germany),

J. R. Knorrenschield (Marburg, Germany), J. Greeve (Paderborn, Germany),

A. Florschuetz (Dessau, Germany), A. Tannapfel (Bochum, Germany),

S. Wessendorf (Esslingen, Germany), P. Bchner-Steudel (Halle, Germany), T. J. Ettrich (Ulm, Germany), S. Kanzler (Schweinfurt, Germany), V. Heinemann (Munich, Germany),

S. Held (Leverkusen, Germany), A. Reinacher-Schick (Bochum, Germany)

Presented by Michael Geissler at the ESMO congress 2017.

Slides are property of the author. Permission required for reuse.

The study was sponsored by AIO-Studien-gGmbH (Berlin, Germany)

The study was financially supported by an unrestricted grant from Amgen. NCT01328171

EudraCT 2009-017731-17

RATIONALE

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FOLFOXIRI is an active and intensive chemotherapeutic regimen in mCRC

(Falcone et al. 2007)

FOLFOXIRI+bevacizumab (TRIBE, STEAM, OLIVIA) and FOLFOXIRI + anti-

EGFR mAb (TRIP, MACBETH) resulted in high RR and long OS

However, there is no randomized trial demonstrating superiority of FOLFOXIRI

plus an anti-EGFR or anti-VEGF mAb compared to FOLFOXIRI alone

Therefore, the VOLFI trial compared the FOLFOXIRI Falcone protocol with

modified FOLFOXIRI + panitumumab

PHASE II TRIAL DESIGN

mCRC

Unresectable

1st-line

WT RAS**

Age 18yrs

ECOG PS 0-1

(n=96)

Randomization:

6/2011 - 1/2017

R

Treatment until PD, resectability,

or to maximum 12 cycles

mFOLFOXIRI +

panitumumab 6 mg/kg

Q2W

N=63 Irinotecan 150 mg/m2***, oxaliplatin 85 mg/m2,

LV 200 mg/m2, 5-FU 3000 mg/m2 CIV;

Planned safety analysis after 10 patients

treated in panitumumab arm

FOLFOXIRI Q2W

N=33

2:1

If resectable:

Surgery, then

protocol treatment to

maximum 12 cycles

If CR/PR/SD after 12 cycles:

re-induction

(same combination)

recommended on PD

Strata:

Cohort 1: histologically confirmed and definitively inoperable or unresectable

Cohort 2: chance of secondary resection with curative intent (*pretreatment liver/tumor biopsy)

*

*

21 active centers in Germany **amendment in 11/2013 to include all RAS wild-type only

***Trial started with irinotecan 165 mg/m2 (n=2), first amendment to 130 mg/m2

(n=9) and final amendment to 150 mg/m2 (n=52)

1 cycle FOLFOXIRI

prior R was allowed

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HYPOTHESIS AND ENDPOINTS

Secondary endpoints Secondary tumor resection rate

Time to relapse

Progression free survival (PFS)

Overall survival (OS)

Pathological response and liver toxicity in resected tumor

specimens

Toxicity

QoL (QLQ-C30)

Statistical hypothesis ORR Arm A >75% vs. Arm B 60%

N=62 patients arm A RAS wt; 2-sided Fisher exact test, type I

RAS mutations