Disclosure Information

Kim, Tae Won

Relationships with Companies

Honoraria: Roche, Amgen, Merk Serono, Bayer, Sanofi

Research Fund:Merck Serono, AstraZeneca, Pfizer, Bayer, Sanofi

Long-term results of the ADORE trial:ADjuvant Oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) versus 5-fluorouracil and leucovorin (FL) after preoperative chemoradiotherapy and surgery for locally advanced REctal cancer

Yong Sang Hong 1, Sun Young Kim 1, Ji Sung Lee 2, Byung-Ho Nam 3, Jeong Eun Kim 1, Kyu-pyo Kim 1, Joon Oh Park 4, Young Suk Park 4, Ji Yeon Baek 5, Tae-You Kim 6, Keun-Wook Lee 7, Joong Bae Ahn 8, Kyung Hae Jung 1,

and Tae Won Kim 1 on behalf of ADORE investigators

2KIM, TAE WON

1 Asan Medical Center, University of Ulsan College of Medicine, Seoul; 2 Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul; 3 HERINGS, The Institute of Advanced Clinical and Biomedical Research, Seoul; 4 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; 5 National Cancer Center, Goyang; 6 Seoul National University Hospital, Seoul National University College of Medicine, Seoul; 7 Seoul National University Bundang Hospital,

Seoul National University College of Medicine, Seongnam; 8 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

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Treatment of Locally Advanced Rectal Cancer

Preoperative chemoradiotherapy

• Both pre- and post-operative oxaliplatin based chemotherapy improved disease-free survival,1 but is still investigating. At present, fluoropyrimidine (capecitabine or 5-fluorouracil) monotherapy is the current standard strategy during pre-operative chemoradiotherapy. 2-4

• Adjuvant FOLFOX after preoperative chemoradiotherapy was based on the extrapolation of results obtained for colon cancer patients. 5,6

cT3-4N0 or N+Clinical staging by Rectal MRI

Total Mesorectal Excision

Adjuvant Chemotherapy

Controversies for adjuvant chemotherapy

1 Rodel et al. Lancet Oncol 2015; 2 O’Connell et al. J Clin Oncol 2014; 3 Gerard et al. J Clin Oncol 2012; 4 Aschele et al. J Clin Oncol 2011; 5 Andre T, et al. NEJM 2004; 6 Haller D, et al. J Clin Oncol 2011

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4KIM, TAE WON

Study design and Rationale

Adjuvant FOLFOXOxaliplatinLeucovorin5-Fluorouracil

85 mg/m2 on day 1200 mg/m2 on day 1400 mg/m2 bolus on day 12400 mg/m2 CIV for 46 hours

Every 2 weeks X 8 cycles

Adjuvant FL

R

Leucovorin5-Fluorouracil

20 mg/m2/day from days 1 to 5380 mg/m2/day from days 1 to 5

Every 4 weeks X 4 cycles

Stratified by- ypStage (II vs III)- Participating centers

ypStage II (ypT3-4N0)

ypStage III (ypTanyN1-2)

Preoperative chemoradiotherapy

with fluoropyrimidines

Total Mesorectal

Excision

Screening procedure based on the postsurgical pathologic stages

Clinical practice according to the institutional standards

Key inclusion criteria• Preoperative chemoradiotherapy with fluoropyrimidines alone;

oxaliplatin or other combined regimens were not allowed.

• Total mesorectal excision (TME) was mandatory.• Curative surgery (no microscopic residual tumor), ≤ 8 weeks prior to randomization.

Exclude ypStage 0-I, or stage IV

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Statistical ConsiderationsPrimary endpoint: disease-free survival (DFS)

• This study was a randomised phase II trial based on the parallel concurrent historical comparison.

• Patients number was calculated based on the expected 3-year DFS for the FOLFOX arm was 78%, and was 70% for the FL arm, the historical control.

• 160 patients per treatment arm were required to ensure one-sided type I error of 5% and a power of 80%, after assuming an 8% of drop-out rate.

Secondary endpoints

• Adverse events• Patterns of failure• Overall survival• Quality of life

The 3-year DFS, adverse events, and quality of life were reported at ASCO 2014 #3502 and published.1

1 Hong et al. ASCO 2014 #3502, Lancet Oncol 2014

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Patient Disposition

10 consent withdrawal4 ineligible 12 consent withdrawal

321 patients randomly assigned(ypT3-4N0 or ypTanyN1-2)

160 allocated to FOLFOX 161 allocated to FL

146 received FOLFOX 149 received FL

First patient in: Nov 2008

Last patient in: Jun 2012

Data cut-off for primary outcomes: Dec 2013

Data cut-off for long-term results: Jan 2018

Median follow-up: 74.1 months (IQR, 56.2 – 88.0)

* From 6 participating centers in Korea

Intent-to-treat (ITT)population

Safety population

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1 Hong et al. ASCO 2014 #3502, Lancet Oncol 2014

65 events at cut-off39 deceased

46 events at cut-off32 deceased

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Patient Characteristics (1)FOLFOX(n=160)

FL(n=161)

Age (years), median (range) 55 (27–81) 54 (25–79)

Age ≥ 65 31 19.4% 24 14.9%

GenderMale 118 73.8% 116 72.0%

Female 42 26.3% 45 28.0%

ECOG performance status0 26 16.3% 30 18.6%

1 134 83.8% 131 81.4%

Distance of the primary tumorfrom the anal verge

≤ 4 cm 48 30.0% 45 28.0%

4 ~ 8 cm 81 50.6% 89 55.3%

> 8 cm 31 19.4% 27 16.8%

Tumor differentiationWell differentiated 13 8.1% 20 12.4%

Moderately differentiated 133 83.1% 130 80.7%

Poorly differentiated /signet ring cell / mucinous 11 6.9% 9 5.6%

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Patient Characteristics (2)FOLFOX(n=160)

FL(n=161)

Preoperative radiotherapyDose (cGy), median (IQR) 5,000 (5,000–5,040) 5,000 (5,000–5,040)

Duration (weeks), median (IQR) 5.1 (4.9–5.7) 5.0 (4.6–5.4)

Concurrent chemotherapy during preoperative radiotherapy

5-Fluorouracil ± leucovorin 107 66.9% 108 67.1%

Capecitabine 46 28.8% 43 26.7%

UFT 7 4.4% 10 6.2%

Interval between end of preoperative chemoradiotherapy and surgery (weeks), median (IQR) 7.0 (6.1–8.0) 7.0 (6.0–8.0)

Type of surgery

Abdominoperineal resection 24 15.0% 24 14.9%

Low anterior resection 135 84.4% 135 83.9%

Hartmann’s procedure 1 0.6% 2 1.2%

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Patient Characteristics (3)FOLFOX(n=160)

FL(n=161)

ypStage

ypStage II 58 36.3% 65 40.4%

ypStage III 102 63.8% 96 59.6%

Lymphovascular invasion

Absent 120 75.0% 120 74.5%

Present 37 23.1% 41 24.5%

missing 3 1.9% 0 0%

Grade of tumor regression

Total regression 5 3.1% 2 1.2%

Near total regression 31 19.4% 22 13.7%

Moderate regression 85 53.1% 84 52.2%

Minimal or no regression 38 23.8% 52 32.3%

missing 1 0.6% 1 0.6%

Time from surgery to randomization (weeks), median (IQR) 3.4 (3.0 – 4.3) 3.6 (3.1 – 4.6)

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Treatment Exposure and Adverse Events

Treatment Exposure

FOLFOX(n=146)

FL(n=149)

Completed planned cycles 141 (96.6%) 141 (94.6%)

Relative dose intensity

5-FU bolus 86.6% 95.0%

5-FU continuous infusion 87.6% -

Oxaliplatin 93.2% -

Grade 3 or 4 Adverse Events

FOLFOX(n=146)

FL(n=149)

p value

Hematologic

Leucopenia 12 8.2% 8 5.4% 0.363

Neutropenia 52 35.6% 38 25.5% 0.076

Febrile neutropenia 1 0.7% 4 2.7% 0.371

Thrombocytopenia 1 0.7% 0 0% 0.495

Anemia 0 0.0% 1 0.7% 1.000

Non-hematologic

Nausea 2 1.4% 1 0.7% 0.620

Vomiting 1 0.7% 1 0.7% 1.000

Stomatitis 0 0.0% 2 1.3% 0.498

Diarrhea 2 1.4% 4 2.7% 0.684

Sensory neuropathy 1 0.7% 0 0% 0.495

p value calculated by Fisher’s exact test

1 Hong et al. ASCO 2014 #3502, Lancet Oncol 2014

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Disease-free survival, ITT population

11KIM, TAE WON

% d

isea

se-f

ree

100

80

60

40

20

0

FOLFOX

FL

12010896847260483624120

Months, disease-free survivalNumber at risk

FL 161 114 99 91 82 72 51 29 12 2 0

FOLFOX 160 131 108 103 97 81 61 37 15 1 0

FOLFOX (n=160) FL (n=161)

Events 46 65

6-year DFS rate 68.2% 56.8%

Crude HR (95% CI) 0.63 (0.43 – 0.92), p=0.018

Stratified HR (95% CI) * 0.63 (0.43 - 0.93), p=0.018* Stratified by predefined stratification factors (ypStage and participating centers)

∆11.4%

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Disease-free survival, ypStage III%

dis

ease

-fre

e100

80

60

40

20

012010896847260483624120

Months, disease-free survival

FOLFOX

FL

Number at risk

FL 96 60 53 49 41 33 27 17 8 1 0

FOLFOX 102 83 68 63 58 46 37 23 8 0 0

FOLFOX (n=102) FL (n=96)

Events 35 47

6-year DFS rate 63.2% 48.3%

Crude HR (95% CI) 0.58 (0.37 – 0.90), p=0.014

Stratified HR (95% CI) * 0.59 (0.38 - 0.92), p=0.019* Stratified by predefined stratification factors (ypStage and participating centers)

∆14.9%

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Disease-free survival, ypStage II

FOLFOX

FL

% d

isea

se-f

ree

100

80

60

40

20

012010896847260483624120

Months, disease-free survivalNumber at risk

FL 65 54 46 42 41 39 24 12 4 1 0

FOLFOX 58 48 40 40 39 35 24 14 7 1 0

FOLFOX (n=58) FL (n=65)

Events 11 18

6-year DFS rate 77.8% 69.5%

Crude HR (95% CI) 0.67 (0.32 –1.42), p=0.293

Stratified HR (95% CI) * 0.64 (0.30 - 1.36), p=0.245

* Stratified by predefined stratification factors (ypStage and participating centers)

∆8.3%

Number of patient Stratified HR 95% CI p value p value for

interaction

ITT population 321 0.63 0.43 – 0.93 0.018

Gender 0.798

Male 234 0.62 0.39 – 0.98 0.039

Female 87 0.69 0.34 - 1.39 0.297

Age 0.903

< 65 years 266 0.64 0.42 – 0.97 0.034

≥ 65 years 55 0.60 0.21 – 1.67 0.325

Pathologic stage 0.856

ypStage II 123 0.64 0.30 – 1.36 0.245

ypStage III 198 0.59 0.38 – 0.92 0.019

Pathologic T stage 0.939

ypT0-2 48 0.61 0.19 – 2.00 0.415

ypT3-4 273 0.58 0.39 – 0.88 0.010

Pathologic N stage 0.167

ypN0 123 0.70 0.33 – 1.50 0.362

ypN1a 72 1.27 0.55 – 2.92 0.574

ypN1b 63 0.35 0.14 – 0.83 0.017

ypN2 63 0.47 0.22 – 0.99 0.048

Subgroup analysis for disease-free survival (1)

0.1 0.2 0.5 1 2 4

Favours FOLFOX Favours FL

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Subgroup analysis for disease-free survival (2)

0.1 0.2 0.5 1 2 4

Favours FOLFOX Favours FL

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Number of patient Stratified HR 95% CI p value p value for

interaction

Location of Tumor 0.444

≤ 4 cm 93 0.59 0.31 – 1.12 0.107

4 ~ 8 cm 170 0.78 0.44 – 1.36 0.380

> 8 cm 58 0.37 0.14 – 1.01 0.052

Tumor differentiation 0.296

Well differentiated 33 0.42 0.09 – 1.98 0.272

Moderately differentiated 263 0.74 0.48 – 1.14 0.174

Poorly differentiated/mucinous/signet ring cell 20 0.28 0.08 – 0.97 0.045

Grade of tumor regression 0.297

Total or near total regression 60 0.95 0.39 – 2.33 0.908

Moderate regression 169 0.72 0.42 – 1.23 0.230

Minimal or no regression 90 0.40 0.19 – 0.85 0.016

Lymphovascular invasion 0.285

Absent 240 0.55 0.34 – 0.88 0.013

Present 78 0.86 0.44 – 1.69 0.662

Perineural invasion 0.282

Absent 241 0.53 0.33 – 0.86 0.010

Present 77 0.84 0.43 – 1.63 0.598

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Overall survival, ITT population

FOLFOX

FL

% s

urvi

ved

100

80

60

40

20

012010896847260483624120

Months, overall survivalNumber at risk

FL 161 144 137 126 120 104 79 50 22 2 0

FOLFOX 160 146 139 134 123 105 79 48 23 1 0

FOLFOX (n=160) FL (n=161)

Events 32 39

6-year OS rate 78.1% 76.4%

Crude HR (95% CI) 0.80 (0.50 – 1.27), p=0.338

Stratified HR (95% CI) * 0.73 (0.45 - 1.19), p=0.210

* Stratified by predefined stratification factors (ypStage and participating centers)

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Subgroup analysis for overall survival (1)

0.1 0.2 0.5 1 2 4

Favours FOLFOX Favours FL

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Number of patient Stratified HR 95% CI p value p value for

interactionITT population 321 0.73 0.45 – 1.19 0.210

Gender 0.748

Male 234 0.69 0.40 – 1.22 0.203

Female 87 0.83 0.33 – 2.09 0.690

Age 0.923

< 65 years 266 0.75 0.44 – 1.26 0.271

≥ 65 years 55 0.70 0.20 – 2.46 0.576

Pathologic stage 0.800

ypStage II 123 0.83 0.33 – 2.10 0.691

ypStage III 198 0.72 0.41 – 1.25 0.242

Pathologic T stage 0.414

ypT0-2 48 1.31 0.26 – 6.62 0.741

ypT3-4 273 0.65 0.39 – 1.07 0.093

Pathologic N stage 0.303

ypN0 123 0.82 0.30 – 2.19 0.688

ypN1a 72 1.44 0.48 – 4.28 0.514

ypN1b 63 0.42 0.11 – 1.53 0.188

ypN2 63 0.42 0.18 – 0.96 0.040

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Subgroup analysis for overall survival (2)

0.1 0.2 0.5 1 2 4

Favours FOLFOX Favours FL

KIM, TAE WON

Number of patient Stratified HR 95% CI p value p value for

interaction

Location of tumor 0.429

≤ 4 cm 93 0.52 0.22 – 1.23 0.137

4 ~ 8 cm 170 1.01 0.52 – 1.97 0.981

> 8 cm 58 0.53 0.15 – 1.87 0.325

Tumor differentiation 0.286

Well differentiated 33 0.73 0.15 – 3.68 0.707

Moderately differentiated 263 0.87 0.49 – 1.52 0.615

Poorly differentiated/mucinous/signet ring cell 20 0.27 0.07 – 1.03 0.055

Grade of tumor regression 0.111

Total or near total regression 60 2.17 0.56 – 8.33 0.260

Moderate regression 169 0.91 0.43 – 1.89 0.790

Minimal or no regression 90 0.42 0.19 – 0.98 0.043

Lymphovascular invasion 0.931

Absent 240 0.69 0.37 – 1.29 0.244

Present 78 0.73 0.33 – 1.60 0.432

Perineural invasion 0.109

Absent 241 0.53 0.28 – 1.02 0.058

Present 77 1.22 0.57 – 2.62 0.615

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Patterns of recurrenceFOLFOX

(n=160)

FL(n=161)

Events 46 28.8% 65 40.4%

Locoregional recurrence 7 4.4% 15 9.3%

Distant metastasis 41 25.6% 53 32.9%

Lung 27 16.9% 33 20.5%

Liver 9 5.6% 17 10.6%

Lymph node 6 3.8% 13 8.1%

Bone 2 1.3% 6 3.7%

Peritoneum 1 0.6% 2 1.2%

Other * 2 1.3% 3 1.9%

Sum of distant metastases

1 organ 36 22.5% 38 23.6%

2 organs 4 2.5% 11 6.8%

≥ 3 organs 1 0.6% 4 2.5%* Other sites of metastasis included the brain (1), bladder (1), ovary (1), pleura (1) and abdominal wall (1)

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Treatment after recurrence

Initial treatment after recurrenceFOLFOX

(n=46)

FL(n=65)

Surgery of curative intent 19 41.3% 28 43.1%

Radiofrequency ablation 3 6.5% 4 6.2%

Stereotactic radiosurgery 1 2.2% 0 0%

Surgery of palliative intent 2 4.3% 5 7.7%

Palliative chemotherapy only 16 34.8% 20 30.8%

No treatment or lost to follow-up 5 10.9% 8 12.3%

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Conclusion

• Adjuvant FOLFOX demonstrated disease-free survival improvements compared with FL, in pathologic ypStage II-III patients after preoperative chemoradiotherapy with fluoropyrimidines alone and surgery.

• Subgroup analyses might provide potential candidates of adjuvant oxaliplatin-based chemotherapy in these patients.

KIM, TAE WON

• Selection of adjuvant chemotherapy should be considered based on the postoperative pathologic stages after preoperative chemoradiotherapy and surgery.

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Special Thanks

To all the patients and their families

To Sanofi Korea for providing study drugs and funds

To the investigators and research coordinators at the 6 institutions in Korea

KIM, TAE WON