prodige 24/cctg pa.6, an unicancer gi trial: a multicenter ... · prodige 24/cctg pa.6, an...

PRODIGE 24/CCTG PA.6, an Unicancer GI trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX

versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas.

T. Conroy, P. Hammel, M. Hebbar, M. Ben Abdelghani, A.C. Wei, J-L. Raoul, L. Choné, E. François, P. Artru, J. Biagi, T. Lecomte, E. Assenat, R. Faroux, M. Ychou, J. Volet, A. Sauvanet, C. Jouffroy,

P. Rat, F. Castan, J-B. Bachet, for the CCTG and the UNICANCER-GI /PRODIGE Group

Institut de Cancérologie de Lorraine, Nancy; Hôpital Beaujon, Clichy; Hôpital Huriez, Lille; Centre Paul Strauss, Strasbourg; Princess Margaret Hospital, Toronto; Institut Paoli-Calmettes, Marseille; University hospital, Nancy; Centre Antoine-Lacassagne, Nice; Hôpital Jean-Mermoz,

Lyon; Kingston General Hospital, Kingston; Hôpital Trousseau, Tours; University Hospital, Montpellier; CHD Vendée, La Roche-sur-Yon; Institut du Cancer de Montpellier, Montpellier; Centre Hospitalier Universitaire, Dijon; Hôpital Pitié-Salpétrière, Paris;

Canadian Cancer Trials Group, Kingston, Canada; R&D UNICANCER, Paris; France

Thierry Conroy

Background• 6 months Gemcitabine (Gem) and/or fluoropyrimidine (S-1 in Japan) are standard adjuvant

treatments for resected pancreatic cancer (PC) patients Neuhaus P. et al. ASCO Annual Meeting 2008; #LBA4504Uesaka K et al. Lancet 2016;388:248-57Neoptolemos JP et al. Lancet 2017; 389:1011-24.

• However 71%-76% of patients still relapse within 2 years despite these treatments and thereis an obvious need for a better drug or drugs’ combination

Neoptolemos JP et al. JAMA. 2010;304:1073-81 Oettle H et al. JAMA. 2013;310:1473-81Sinn M et al. J Clin Oncol. 2017;35:3330-7

• FOLFIRINOX is more effective than Gem as first-line treatment in metastatic PC for patients with good Performance Status

Conroy T et al. N Engl J Med 2011;364:1817-25

• The « modified » FOLFIRINOX regimen with no bolus fluorouracil is associated with lesshematological toxicities and less diarrhea rate but maintained efficacy.

Mahaseth H et al. Pancreas. 2013;42:1311-5

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PRODIGE 24/CCTG PA.6 trial: study design

Stratification: - center- resection margin (R0 vs R1)- CA19-9 level (≤ 90 vs 91-179 U/mL)- pN0 (< 12 vs ≥ 12 examined nodes)

vs pN1

- R0 or R1 resected pancreatic cancer- postoperative CT-scan mandatory- CA19-9 level < 180 U/mL within 12

weeks after surgery

RANDOMIZE - 6 months of chemotherapy

- CT scans: every 3 months

NCT01526135 mFolfirinoxOxaliplatin 85 mg/m², Leucovorin 400 mg/m², Irinotecan 180 mg/m²*, all at D1 Fluorouracil continuous IV infusion 2.4 g/m² over 46 hours Every 2 weeks; 12 cycles *Reduced to 150 mg/m² after patient 162

Gemcitabine1000 mg/m2, qw 3/4 weeks; 6 cycles

for both arms:

1:1

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Key Inclusion Criteria

• Histologically confirmed resected pancreatic ductal adenocarcinoma

• Macroscopically complete resection (R0 or R1 resection)

• Patients able to receive chemotherapy within 12 weeks after resection

• ECOG performance status 0 or 1

• Patients aged from 18 to 79 years

• No prior radiotherapy or chemotherapy

• Adequate hematologic/blood chemistry levels

• Patient information and written informed consent

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Key Exclusion Criteria

• Metastatic disease, or macroscopic incomplete tumor removal (R2 resection)

• Postoperative CA 19-9 ≥ 180 U/ml assessed within 21 days of randomization

• Symptomatic heart failure or coronary heart disease

• Major comorbidity, active infection, history of HIV or uncontrolled diabetes

• Inflammatory bowel disease, or occlusion or sub-occlusion of the intestine or

severe postoperative uncontrolled diarrhea

• Concomitant occurrence of another cancer, or significant history of cancer

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Endpoints

n Primary: Disease-Free Survival (DFS)

n Secondary:

• Toxicity (NCI-CTC version 4.0 grading)• Overall survival (OS)• Cancer specific survival (SS)• Metastasis-free survival (MFS)

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Statistical considerations

Required sample size:

• 490 patients required to reach 342 events for final analysis, based on the use of the log-

rank test with a two-sided significance level of 5%

Hypothesis:

n Study designed to have 80% power to detect an increase of 10% in 3 year-DFS (17% to

27%) corresponding to a hazard ratio (HR) = 0.74

n DFS defined as the first occurrence of any tumor recurrence or metastases, second

cancer or death from any cause

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Independent Data Monitoring Committee meetings

• March 12, 2014: early tolerance analysis on the first 30 patients who received 2 cycles of mFOLFIRINOX at full doses; application of a protocol-planned irinotecan dose reductionfrom 180 mg/m2 to 150 mg/m2 due to a grade 3-4 diarrhea rate of 20% (5 grade 3 and 1 grade 4)

• December 8, 2015: no further changes after toxicity analysis of first month of treatment after Irinotecan dose reduction in subsequent patients

• July 6, 2016: Planned interim analysis after 113 events; trial continuation without change

• February 5, 2018: IDMC consultation for communication strategy. Analysis of the primary endpoint: 302 events/342 expected; IDMC statement of analysis and publication ASAP

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Recruitment and Analysis

• Recruitment: April 2012-October 2016

• Final accrual: 493 patients in 77 French and Canadian centres

• Current analysis database lock: 13 April 2018

• Number of events observed: 314 (91.8% of the planned sample size)

• Median follow-up: 33.6 months (95% CI, 30.3-36.0)

• Quality control: surgical procedures, all pathology reports and postoperative CT-scans

were centrally reviewed to confirm eligibility criteria and to assess major prognostic factors

• Intent-to-Treat Population (ITT) analysis: all randomized patients, whether treated or not,

eligible or not.

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Flow ChartmFolfirinox Gemcitabine Total

Total randomized

Intent-to-treat population

247

247 (100 %)

246

246 (100 %)

493

493

Did not fulfill all major eligibility criteria

Untreated patients (consent withdrawal)9* (3.6 %)

9 (6)6** (2.4 %)

3 (1)

15 (3.0 %)

12 (2.4 %)

Received allocated treatment 238 (96.4 %) 243 (98.8 %) 481 (97.6 %)

Safety population 238 (96.4 %) 243 (98.8%) 481

* 8 patients with metastatic disease, and/or 2 with high level of CA 19.9** 5 patients with metastatic disease, and 1 with high level of CA 19.9

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Patients baseline characteristics

CharacteristicsmFolfirinox

N=247Gemcitabine

N=246p

Median age (yrs)[range]

63 [30-79]

64 [30-81] 0.09

Gender male 57.5 % 55.6 % 0.67

ECOG PS 01

49.8 %50.2 %

52.5 %47.5 %

0.55

Diabetes 25.3 % 26.6 % 0.44

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Pancreatic tumors baseline characteristics

CharacteristicsmFolfirinox

N=247Gemcitabine

N=246p

Median size of primary tumor [mm, range] 30 [8-90] 30 [6-120] 0.50

T1-2/T3-4 (%) 12.5/87.5 9.8 /90.2 0.33

N0/N1 (%) 22.3 /77.7 24.5 /75.5 0.60

Stage: I/IIA/IIB/III-IV (%) 4.9/17.4 /74.1/3.6 5.7/19.1 /72.8/2.4 0.81

Tumor grading :well/moderately/poorly differentiated (%)

30.6/54.1/15.3 33.9/53.7/12.5 0.58

Whipple resection procedure (%) 82.1 76.8 0.53

R1 resection (%) 40.1 45.7 0.24

Venous resection (%) 21.3 28.2 0.08

Lymphovascular emboli (%) 73.7 63.1 0.02

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Safety: hematologic AEs

Grade 3-4 adverse events, % per patient

mFolfirinox

N=238

Gemcitabine

N=243p

Anemia 0.0% 0.4% 1.00

Neutropenia 28.4 % 26.0 % 0.56

G-CSF use 59.9 % 3.7 % <0.001

Febrile neutropenia 2.9 % 3.7 % 0.65

Lymphopenia 1.3 % 2.9 % 0.34

Thrombocytopenia 1.3 % 4.5 % 0.03

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Safety: main nonhematologic AEs

AE, % per patientmFolfirinox N=238 Gemcitabine N=243

p-valueall gradesAll grades Grade 3/4 All grades Grade 3/4

Diarrhea 84.4 % 18.6 %* 49 % 3.7 % < 0.001

Sensory peripheral neuropathy 61.2 % 9.3 % 8.7 % - < 0.001

Fatigue 84 % 11 % 77.6 % 4.6 % 0.003

Vomiting 46 % 5 % 29 % 1.2 % < 0.001

Mucositis 33.8 % 2.5 % 14.9 % 0 % < 0.001

Alopecia 27 % - 19.5 % - 0.07

Hand-foot syndrome 5 % 0.4 % 0.8 % - 0.023* 8.6% during cycle 1; 6.3% during cycle 2; 3% at cycles 3-5; 1% at cycles 6-12Grade 3-4 diarrhea is significantly related to a higher number of lymph nodes examined, p = 0.02.

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Safety: main nonhematologic AEs

AE, % per patientmFolfirinox N=238 Gemcitabine N=243

p-valueall gradesAll grades Grade 3/4 All grades Grade 3/4

Headache 8.4 % - 19.4 % - 0.001

Fever 16.5% 0.4 % 32.4 % 0.4 % < 0.001

Flu-like symptoms 1.3 % - 5.0 % 0.4 % 0.018

ALT increase 64 % 4.2 % 73.5 % 5.0 % 0.006

AST increase 67 % 3.8 % 69 % 3.3 % 0.033

Toxic death 0 - 1 -

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Six-month treatment completionmFolfirinox

No = 238

Gemcitabine

No = 243P

All cycles of chemotherapy 66.4% 79.0% 0.002

Planned administrations

Median No. administrations

1212 [1-12]

1818 [1-18] ─

No. administrations delayed 14.4% 3.9% < 0.001

Relative dose-intensity > 0.70 48.7% 91.4% < 0.001

Early stop due to :

- relapse

- toxicity- Principal Investigator’s decision

- patient decision

80 (33.6%)

15 (6.3%)21 (8.8%)

7 (2.9%)13 (5.4%)

51 (21.0%)

26 (10.7%)11 (4.5%)

2 (0.8%)2 (0.8%)

0.002

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Disease-Free SurvivalNo DFS events: 314Median DFS:

• 21.6 mths [95%CI: 17.7-27.6] with mFolfirinox

• 12.8 mths [95%CI: 11.7-15.2] with Gemcitabine

3-year DFS: • 39.7% [95%CI: 32.8-46.6]

with mFolfirinox• 21.4% [95%CI: 15.8-27.5]

with Gemcitabine

0.00

0.25

0.50

0.75

1.00

Dis

ease

-free

sur

viva

l

247 210 156 118 80 60 46 29 21 11 2B:mFolfirinox246 205 127 85 59 34 24 15 10 7 3A:Gemcitabine

Number at risk

0 6 12 18 24 30 36 42 48 54 60Time (months)

A :Gemcitabine B:mFolfirinox

HR=0.58 CI95%[0.46-0.73]stratified HR=0.58 [95%CI: 0.46-0.73],p<0.0001

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Prognostic factors for DFSUnivariate analysis Multivariate analysis N=434 Events=280

Factor HR [95 % CI] p-value Factor HR [95 % CI]* p-value**

mFolfirinox group 0.58 [0.46-0.73]* < 0.001 mFolfirinox group 0.59 [0.46-0.75] < 0.001

Moderately or poorlydifferentiated tumor

1.34 [1.04-1.71] 0.02 Moderately or poorlydifferentiated tumor

1.42 [1.09-1.86] <0.001

pN+ 1.67 [1.25-2.22] < 0.001 Portal vein resection 1.43 [1.05-1.94] <0.001

R1 resection 1.45 [1.16-1.81] 0.001

VMS resection 1.52 [1.05-2.20] 0.027

Portal resection 1.43 [1.07-1.92] 0.014

6 months treatment 0.60 [0.37-0.96] 0.03

*Stratified on lymph node status, resection margins, and postoperative CA19-9 ** Likelihood-ratio test

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Forest plot for DFS

Metastasis-free Survival

No MFS events: 273

Median:

• 30.4 months

[95%CI: 21.7-NR] with mFolfirinox

• 17.7 months

[95%CI: 14.2-21.5] with Gemcitabine

0.00

0.25

0.50

0.75

1.00

Met

asta

sis

free

surv

ival


Number at risk

0 6 12 18 24 30 36 42 48 54 60Time (months)


HR=0.59 CI95%[0.46-0.75]stratified HR=0.59, [95%CI: 0.46-0.75],

p<0.0001

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Overall Survival

Median overall survival:

• 54.4 months [95%CI: 41.8-NR] with mFolfirinox

• 35.0 months [95%CI: 28.7-43.9] with Gemcitabine

3-year overall survival:

No OS events=192• 63.4% (mFolfirinox) vs 48.6 % (Gem)

0.00

0.25

0.50

0.75

1.00

Ove

rall

surv

ival


Number at risk

0 6 12 18 24 30 36 42 48 54 60Time (months)


HR=0.64 CI95%[0.48-0.86]stratified HR=0.64, [95%CI: 0.48-0.86], p=0.003

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Specific Survival

3-year specific survival:No OS events=18066.2% (mFolfirinox) vs 51.2 % (Gem)

Disease Specific Survival is the time delay between the date of randomization and the patient’s death due to the treated cancer or a treatment-related complication.

0.00

0.25

0.50

0.75

1.00

Spe

cific

sur

viva

l


Number at risk

0 6 12 18 24 30 36 42 48 54 60Time (months)


HR=0.63 CI95%[0.47-0.85]stratified HR=0.63 [95%CI: 0.47-0.85]p=0.003

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Conclusions

• Adjuvant chemotherapy with mFOLFIRINOX in resected PC patients is superior to Gem, with significantly improved Disease-Free Survival, Metastasis-free Survival, Specific Survival and Overall Survival

• Its superiority is observed in all predefined subgroups

• mFOLFIRINOX is more toxic than Gem, but is a safe regimen with manageable toxicities

• mFOLFIRINOX should now be considered a new standard of care after pancreatic cancer resection in patients with good performance status, at least in Western countries

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• Sponsor: R&D Unicancer, Paris

• Funders: Trial supported by a Clinical Research Hospital Program grant (PHRC 2012) from the French Ministry of Health/Institut National du Cancer and by 3 charitable organisations:

- French national Ligue against cancer- Canadian Cancer Society- 7 Days in May

PRODIGE 24/CCTG PA.6 acknowledgements

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Acknowledgements

n To our patients and their families who trusted us

n To all investigators of the 77 active centers, including surgeons, pharmacists, biometrics unit membersand research staffs for quality of the data

n To the PRODIGE intergroup (Unicancer GI, FFCD, GERCOR groups) and to the CCTG group for their help

n To talented physicians and statisticians who helped to plan, realize and finalize this trial

n To IDMC members (B. Asselain, MD, JL. Van Laethem, MD, A. Sa Cunha, MD) for their wise advices

n To quality control members: M. Fau, MD, A. Lambert, MD, A. Leroux, MD, J. Thomas, MD

n Thanks to Sanofi-aventis Canada for oxaliplatin supply in the Canadian centers

Thierry Conroy

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