for adjuvant treatment in stage III colon cancer? High vs

1

Can we refine the selection for adjuvant treatment in stage III colon cancer?

High vs Low Risk

Thierry André, MDService d’Oncologie MédicaleEt unité INSERM UMRS 938

‘Microsatellite Instability and Cancer’Sorbonne universitéHôpital Saint Antoine

Et GERCOR

2

Consultant and or Advisory board :

Amgen, BMS,Gritstone, HalioDx, MSD Oncology, Roche, Sevier

Honoraria :

Amgen, Bayer, BMS, MSD Oncology, Roche/Genentech, Xbiotech

Sanofi Aventis

Disclosure

3

AJCC V7

Gunderson et al, JCO 2009

4

Stage III Colon CancerCured with Surgery Alone

(55%)

Patients cured byFOLFOX or CAPOX

Patients cured by chemo: 20%

Moertel CG, N Engl J Med 1990 ; IMPACT investigators, Lancet 1995; André T, J Clin Oncol. 2009; Yothers G, J Clin Oncol 2011; Haller D, J Clin Oncol 2011

Patients with recurrence: 25 %

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OS with 10 yr Follow Up : ITTStage III

Hazard ratio 0,8095% CI 0,66 to 0,96

P = 0,015André T et al et al. JCO 2015

+ 8,1%+ 4,2%

MOSAIC 2015

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Year Overall Survival: Stage III

André T et al et al. JCO 2015

Stage III N1 (1 to 3 N+) Stage III N2 (≥ 4N+)

+ 6%

- 5;5%+

+ 13%+6%

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Stage III ACCENT Database Fluoropyrimidines ± Oxali (n=8993)

• Higher risk of recurrence over time was associated with higher T and N Stage• Oxaliplatin demonstrating more benefit in patients with more advanced T and

nodal stage• Addition of oxaliplatin to FU is associated with benefit for T4 and T3, however

this benefit exist but is little for T1 and T2 Shah MA et al et al. JCO 2016

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• Open SEER population-based data from 1992-2004

• The relative weights of the T and N stages were calculated by multiple linear regressions

• For colon cancer, Relative T and N stage weight were 0.58 and 0.42

• Conclusion: T stage affects colon cancer survival more significantly than the N stage

TNM7 TNM8

T4 Perforates serosa Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure

T4a Tumor penetrates to the surface of the visceral peritoneum

Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum)

T4b Tumor directly invades or is adherent to other organs or structures

Tumor directly invades or is adherent to other organs or structures

T4TNM8

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Prospective Pooled Analysis of Six Phase III Trials Investigating Duration of Adjuvant Oxaliplatin-based therapy (3 vs. 6 months) for Patients with Stage III Colon Cancer:

The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration

Grothey A et al. NEJM 2018André T et al. JCO 2018

Sobrero A et al. JCO 2018Ivenson T et al. Lancet Oncol 2018

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Study Schema

Stage III Colon Cancer Patients

R

3 months

6 months

Investigator’s choiceFOLFOX or CAPOX

Total planned accrual ≥ 10,500

1:1

FOLFOX: 5FU/LV + Oxaliplatin CAPOX: Capecitabine + Oxaliplatin

Grothey A et al. NEJM 2018

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Results: mITT Population


N patients 12,834

N1 72%

N2 28%

T1-2 13%

T3 66%

T4 21%

T1-T3 N1 59%

T4 or N2 41%

FOLFOX / CAPOX 60% / 40%

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DFS HR = 1.0795% CI, 1.00 to 1.15

Duration 3-yr DFS

6m 75.5 %

3m 74.6%

3-yr DFS diff. = -0.9%, 95% CI, (-2.4 to 0.6%)

DFS HR = 1.0795% CI, 1.00 to 1.15

Primary DFS Analysis (mITT)


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DFS Comparison by Regimen, cont.

FOLFOX CAPOX

HR 1.12

3m TRT better 6m TRT better

Inferiority

1.0

NI Margin

DFS HR = 1.1695% CI, 1.06 to 1.26

HR 1.12


Non-Inferiority

1.0

NI Margin

DFS HR = 0.9595% CI, 0.85 to 1.06

TRT: treatment

Interaction p-value = 0.0051Grothey A et al. NEJM 2018

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DFS Comparison by Risk Groups, cont mITT all patients independently of the

duration of chemotherapy

T1-3 N1 (59%)

T4 or N2 (41%)

IDEA, Shi Q et al , personal data

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Analysis by Risk Groups and Regimens

• Large difference in overall prognosis observed between (T1-3 N1) and (T4 or N2) cancers*– 3 year DFS ∆ 20%Analysis of 3m vs 6m adjuvant therapy for these groups

* Shah MA et al et al. JCO 2016

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DFS Comparison by Risk Groups, cont.

T1-3 N1 (58.7%) T4 or N2 (41.3%)

Interaction p-value = 0.11

HR 1.12


Non-Inferiority

1.0

NI Margin

DFS HR = 1.0195% CI, 0.90 to 1.12

HR 1.12


Inferiority

1.0

NI Margin

DFS HR = 1.1295% CI, 1.03 to 1.23

TRT: treatmentGrothey A et al. NEJM 2018

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N2

N1

Perc

ent W

ithou

t Eve

nt

--

4583 4006 3334 2262 1212 600 2344585 4064 3378 2337 1265 658 2511798 1409 1108 721 387 222 851769 1429 1072 712 408 214 83

mITT: DFS Comparison by N Groups: N1 vs N2


N1

N2

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T4

T1-3

Perc

ent W

ithou

t Eve

nt

--

5068 4397 3665 2518 1387 714 2855022 4412 3624 2519 1416 744 2941320 1023 777 466 213 108 351335 1082 826 527 251 123 37

mITT: DFS Comparison by N Groups: T1-T3 vs T4


T1-T3

T4

20

T4 or N2

T1-3 N1

Perc

ent W

ithou

t Eve

nt

--

3744 3313 2796 1934 1064 527 2113727 3336 2788 1949 1081 566 2212634 2099 1640 1044 531 292 1072622 2151 1655 1094 586 301 110

mITT: DFS Comparison by N Groups: Low Risk vs High risk


T1-T3 N1

T4 or N2

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mITT population T4 or N2 FOLFOX

mITT population T4 or N2 XELOX

1531 1242 937 648 396 228 1031523 1189 900 612 360 216 94

0 1 2 3 4 5 6

Years from Randomization

0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt

0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt

Stratified Non Inferiority P-value: 0.8825

1091 909 718 446 190 73 71111 910 740 432 171 76 13

0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt

0 1 2 3 4 5 6


0

10

20

30

40

50

60

70

80

90

100

Perc

ent W

ithou

t Eve

nt

Stratified Non Inferiority P-value: 0.0974

mITT: DFS T4 and/or N2 FOLFOX vs XELOX


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(3m/6m)HR

6m ArmPatients

3m ArmPatients

1.07

1.07

1.16

1.12

1.07

1.04

1.01

1769

841

1335

2622

4585

4181

3727

1798

849

1320

2634

4583

4219

3744

N2

T1/T2

T4

T4 or N2

N1

T3

T1-3 N1

N stage

T stage

Risk Group

0.5 1 1.12 1.5Hazard Ratio

Favors 3m Favors 6m

mITT: DFS Comparison by Stage, cont.

InteractionP-value

0.44

0.36

0.11


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mITT: DFS Comparison by Regimen, N, T and Low versus High risk


+2.4% - 1.1% +1.1% +0.2% +0.3% + 3.3% +0.2% +1.7%

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My Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer

Stage Recommended durationof adjuvant therapy

T1-3 N1CAPOX or

(FOLFOX)

Stop at 3 months if CAPOX T1-T3 N2 ?

Clinical decision point- Tolerability of therapy- Regimen FOLFOX or CAPOX- Patient preference- T4 or N2

If FOLFOX and or T4Continue oxaliplatin with stop if neuropathy ≥ grade 2and continue fluoropyrimidines

T4 and/or N2CAPOX or FOLFOX

3 months

6 months

3 months

End of therapy

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KRAS, BRAF, MSI assessments

• Important for clinical research: • Stratification factors for future clinical trials (Kras and

Braf)

• For daily practice: No interest for the indication and choice of adjuvant treatment

- except MSI / dMMR in elderly subjects because if a chemo is decided, indication to a combination of fluoropyrimidines and oxaliplatin is mandatory

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IDEA and after ?• 20 000 patients included in 8 studies for evolution of 3 drugs: irinotecan,

bevacizumab and cetuximab

• 1000 Millions of Dollars (cost of one adjuvant trial with2000 patients with a new drug ≥ 80-130 Millions $)

• A disaster for patients, physicians, and companies

• Difficult to find a new industrial partner !

• No indisputable signals emerging from results of trials performed in the metastatic setting, which argue to go in adjuvant settings 1

• We need study with selected population with a predictive test for new drugs

de Gramont A et al, Curr Colorectal Cancer Rep 2013

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What is the future?

28Song N et al. JAMA Oncol 2016

The consensus molecular subtypes of CRC

Clinical Outcome From Oxaliplatin Treatment in Stage II/III Colon Cancer According to Intrinsic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology Randomized Clinical Trial.

The stemlike subtype (CMS3 and 4) was associated with poor prognosis and lack of benefit from oxaliplatin (HR, 0.99 [95% CI, 0.73-1.34]; P = .96 [N = 367]).

29Pages F, et al, Lancet 2018

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Digital Droplet PCR for Circulating Tumor DNA

Pekin D. et al., Quantitative and sensitive detection of rare mutations using droplet-based microfluidics, Lab on Chip, 2011: 2156-66.Taly V. et al., Detecting biomarkers with microdroplet technology,Trends in Molecular Medicine, 2012;18:405-16.

31Tie J et al., abstr. 3516 ASCO 2018

• 95 patients with colon cancer stage III• Fluoropyrimidine alone: 23 % and Fluoropyrimidine + oxaliplatin : 77 %

Colon Cancer Stage III : tumoral circulating DNA

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New Trials for stage III in 2018

• Strong prognostic factor: ctDNA- DYNAMIC-III, Phase III for stage III guided by ctDNA

• Focus on T4 or N2 because 40% relapse and need only between 500 to 800 patients to answer the question

- IROCAS/PRODIGE study: FOLFOX6 vs FOLFIRINOX

• Predictive factor of efficacy- MSI/dMMR (NCT02912559 with atezolizumab)- Aspirin and mutation of PI3K (1 PRODIGE study in France with aspirin)- High Immuno-Score and Immuno-oncology ?

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Take home message stage III

• T stage affects colon cancer survival more significantly than the N stage

• Prognosis if stage III T1-T3 N1 : DFS is 83% with 3 or 6 months of fluoropyrimidines & oxaliplatin and 3 months of CAPOX will be the new standard

• Prognosis if stage III T4 or N2 : DFS is 62.7 % with 3 and 64.4% with 6 months of fluoropyrimidines & oxaliplatin: 6 months of CAPOX or FOLFOX are the standard, with stopping oxaliplatin in case of neuropathy grade ≥ 2

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Thank you for your attention

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for adjuvant treatment in stage III colon cancer? High vs