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 Cécile, LECAILLE Cédric, BOUCHE Olivier, MAUVAIS François, BRUNETTI Francesco, PRUDHOMME Michel, SEITZ Jean-François, LEPAGE Côme, 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/m², 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%) <0.001

Ryan simplified Tumor Regression Grade

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<0.001)

- induces tumor downstaging

• Phase III studies testing this strategy to see if it significantly impacts 3y

DFS and 5y OS are now awaited

Failed to meet primary endpoint

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. Büchner-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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8

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 <0.05, type II <0.2

Primary endpoint • Objective response rate

RAS mutations

N = 4

CONSORT DIAGRAM

FOLFOXIRI Q2W

Follow up: mean 18.7 months

*Severe violation of inclusion criteria: 2

No valid ICF: 2

Randomized N = 34

Treated N = 34

RAS wt ITT:

N = 33

mFOLFOXIRI +

panitumumab 6 mg/kg

Q2W

Randomized N = 71

Treated N = 67

RAS wt ITT:

N = 63

N = 105

RAS mutations

N = 1

N = 4*

20

cohort mFOLFOXIRI +

Panitumumab

FOLFOXIRI

N % N %

I =definitive

non-resectable

43 68.3 22 66.7

II=potentially

resectable

20 31.7 11 33.3

PATIENT CHARACTERISTICS

21

mFOLFOXIRI

+ panitumumab

N=63

FOLFOXIRI

N=33

Gender Female, n(%)

Male, n (%)

22 (35)

41 (65)

9 (27)

24 (73)

Age (years)

mean

56.5 (31-76)

58.2 (32-77)

Prior adj. CTx, n (%)

6 (9.5)

3 (9.1)

ECOG-PS, n (%) 0 36 (57.1) 20 (60.6)

1 25 (39.7) 11 (33.3)

2 1 (1.6) 1 (3.0)

unknown 1 (1.6) 1 (3.0)

Previous cycle of FOLFOXIRI (%) 23.8 21.2

Surgery primary cancer, n(%) 28 (44.4) 17 (51.1)

Liver limited, n (%) 7 (11.1) 3 (9.1) Total 10.4%

PATIENT CHARACTERISTICS

TUMOR LOCATION

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mFOLFOXIRI

+ panitumumab

FOLFOXIRI

Total

% ITT

Left sided, n (%)

• Rectal cancer, n (%)

53 (84.1)

24 (38.1)

25 (75.8)

9 (27.3)

81.3%

34.4%

Right sided, n (%) 10 (15.9) 8 (24.2) 18.7%

TUMOR CHARACTERISTICS

GENOTYPE

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Central pathology review using NGS: N=76 (79.2%: technical reasons, no informed consent)

Genotype analysis n = 76

(79.2% of ITT) mFOLFOXIRI

+ panitumumab

N=50 genotype analysis

FOLFOXIRI

N=26 genotype analysis

Super wild-type (RAS + all BRAF), n (%) 43 (86.0) 17 (65.4)

BRAF mutation, n (%) 7 (14.0) 9 (34.6)

MSI, n (%) 1 (2.0) 1 (3.8)

PRIMARY ENDPOINT:

OBJECTIVE RESPONSE RATE

mFOLFOXIRI + panitumumab

N=63

FOLFOXIRI

N=33

Odds ratio

p % 95%-CI % 95%-CI

85.7

74.6 – 93.3

60.6

42.1 – 77.1

3.900

(1.44-10.52)

0.0096

85.7

24

60.6

ORR: Primary endpoint, clearly met

EVALUATION OF RESPONSE

SUBGROUP ANALYSES

OR Triplet+P (n) Triplet (n)

BRAF mut 7 9 8.750

BRAF wt 43 17 3.364

Right-sided 10 8 2.500

Left-sided 53 25 4.518

Adj. Chemo – Yes 6 3 2.500

Adj. Cx – No 47 25 4.500

ECOG 1-2 26 12 2.750

ECOG 0 36 20 5.073

Age ≤65 55 25 3.305

Age >65 8 8 7.000

Male 41 24 4.320

Favors FOLFOXIRI Favors mFOLFOXIRI + Panitumumab

EVALUATION OF RESPONSE

SIDEDNESS + GENOTYPE

OR 4.518

(1.29-15.71)

P=0.0210

OR 2.500

(0.37-16.88)

P=0.6372

OR 8.750

(0.9-84.80)

P=0.1262

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N=60

OR 3.364

(0.90-12.54)

P=0.0806

N=16 N=78 N=18

90.6

68.0

60.0

37.5

86.0

64.7

71.4

22.2

TRIBE

n=252

STEAM

n=93

MOMA

n=232*

CHARTA

n=125

VOLFI

=99 RAS WT

FOLFOXIRI/Bev vs FOLFIRI/Bev

FOLFOXIRI/Bev (seq’l vs conc’t) vs FOLFOX/Bev

FOLFOXIRI/Bev →

Bev ± metroCT

FOLFOX/Bev

± IRI

FOLFOXIRI +/- pan

RAS WT Regimen

Response rate 65% 60% 63% 70% 86%

Disease control rate 90% 91% 91% 91% 98%

Median PFS, months 12.3 11.7 9.5 12.0 10.8

Median OS, months 29.8 Too early Too early Too early Too early

RANDOMIZED TRIALS WITH TRIPLE CHEMOTHERAPY

Cremolini et al. Lancet Oncol 2015; Bendell et al. ASCO GI 2016 Falcone et al. ESMO 2016; Schmoll et al. ESMO 2016

TRIBE

n=252

STEAM

n=93

MOMA

n=232*

CHARTA

n=125

VOLFI

n=99 RAS WT

FOLFOXIRI/Bev vs FOLFIRI/Bev

FOLFOXIRI/Bev (seq’l vs conc’t) vs FOLFOX/Bev

FOLFOXIRI/Bev →

Bev ± metroCT

FOLFOX/Bev

± IRI

FOLFOXIRI +/- pan

RAS WT Regimen

Response rate 65% 60% 63% 70% 86%

Disease control rate 90% 91% 91% 91% 98%

Median PFS, months 12.3 11.7 9.5 12.0 10.8

Median OS, months 29.8 Too early Too early Too early Too early

RANDOMIZED TRIALS WITH TRIPLE CHEMOTHERAPY

Cremolini et al. Lancet Oncol 2015; Bendell et al. ASCO GI 2016 Falcone et al. ESMO 2016; Schmoll et al. ESMO 2016

SECONDARY RESECTIONS

OF METASTASES

mFOLFOXIRI

+ panitumumab,

(%)

FOLFOXIRI

(%)

P value

ITT (n=96) 15 (23.8) 4 (12.1) 0.2802

R0 10 (15.9) 3 (9.1)

R1 4 (6.3) 1 (3.0)

Cohort 2 (n=31)

Secondary

resection

14/20 (70%)* 4/11 (36.4%) 0.1277

R0 10/20 (50.0%) 3/11 (27.3%)

R1 4 (20.0%) 1/11 (9.1%)

*1 patient in Panitumumab arm and belonging to cohort 1 was resected

23.8

12.1

70.0

36.4

PFS – ITT POPULATION

INVESTIGATOR DETERMINED

mFOLFOXIRI+

panitumumab

+ + FOLFOXIRI

Censored

Results do not include previous FOLFOXIRI cycles before randomization

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P=0.6634

HR 1.107 (0.69-1.75)

Arm N

(events)

PFS (m)

median

95% CI

FOLFOXIRI 33 (30) 10.5 8.7-12.5

mFOLFOXIRI+

panitumumab 63 (50) 10.8 8.7-11.5

TOXICITY - SAEs

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Category mFOLFOXIRI

+ panitumumab

FOLFOXIRI P

N % N %

At least one SAE related to treatment 26 40.6 6 18.2 0.0393

At least one SAE with max. grade 3-5 and related to treatment 21 32.8 4 12.1 0.0297

Hematological toxicitiy grade 3-5 1 1.6 2 6.1 0.2662

Gastrointestinal toxicity (colitis, diarrhoea, ileus) grade 3-5 16 25 1 3 0.0093

Infections grade 3-5 10 15.6 4 12.1 0.7663

G-CSF support 21 33.3 5 15.2 0.0893

***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)

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• Primary endpoint was positive: first line treatment with mFOLFOXIRI +

panitumumab resulted in significantly higher ORR compared to FOLFOXIRI.

• The addition of panitumumab to FOLFOXIRI resulted in high response rates in left

and right sided as well as BRAF mutated mCRC.

• PFS was in the expected range, however, there was no difference in PFS

between both arms. OS data are still immature.

Conclusions

• DpR, ETS analyses

• EORTC QLQ-C30

• PFS/OS/TTR in secondary resected patients

• OS ITT, RAS/BRAF, sidedness

• Toxicity / AEs

• Dose reductions, relative dosage, numbers of delivered cycles

• Pathological response and liver toxicity in resected tumor specimens

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VOLFI (AIO-KRK-0109)

DATA PENDING

• EGFR moAb´s (here: panitumumab) add to improvement of ORR, even with triple chemotherapy

– and even in „unexpected“ subgroups (right-sided, BRAF mutant)

• The regimen seems to be tolerable – however, more toxicity and quality of life data needed

• Clinical role a bit unclear

R1 rates higher

PFS not improved

OS pending

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Personal conclusions:

Damien Hirst: Drugs

SUMMARY (II)

36

• mFOLFOXIRI + panitumumab has relevant, but manageable hematological

and gastrointestinal toxicity and should be used in ECOG 0-1 patients only.

Compared to the GONO FOLFOXIRI protocol, the irinotecan dose should be

reduced to 150 mg/m2.

• The high response rates are of particular interest for symptomatic patients and

those with a chance of secondary resections of initially unresectable

metastatic sites in left/right as well as BRAF mutated mCRC.