Colon

COLON

Fotios Loupakis, MD PhD SuperNovae in Oncologia

Pisa, September 2017

Regione del Veneto

U.O.C. Oncologia Medica 1

Dipartimento di Oncologia Clinica e Sperimentale

Istituto Oncologico Veneto – IRCCS, Padova

ADJUVANT

3 ^vs 6

• Academic collaboration of clinicians and statisticians from six randomized phase III trials (12 countries)

– SCOT (UK, Denmark, Spain, Australia, Sweden, New Zealand),

TOSCA (Italy), Alliance/SWOG 80702 (US, Canada), IDEA France, ACHIEVE (Japan), HORG (Greece)

• Total of 12,834 patients with stage III disease included in analysis

– High number of patients needed to make sure with high confidence that we are not sacrificing efficacy of therapy for decreased toxicity

IDEA Concept

• Objective:

Reduce side-effects of therapy without giving up (too much) anti-cancer efficacy of therapy

• Non-inferiority design:

As agreed upon by patient advocates and oncologists, shorter duration of therapy should not sacrifice more than 12% of benefit of adjuvant therapy

In statistical terms: upper 95% confidence interval of Hazard Ratio (HR) of

disease free survival (DFS) should not exceed ^1.12

Stage III Colon

Cancer R

3 months

6 months FOLFOX ^* or CAPOX ^*

* Investigator’s choice, no randomization

12,834 patients

DESIGN

FOLFOX CAPOX

Adverse Events 3m Arm 6m Arm p-value

¹

3m Arm 6m Arm p-value

¹

Overall G2 G3-4

32%

38%

32%

57%

<.0001

41%

24%

48%

37%

<.0001

Neurotoxicity G2

G3-4

14%

3%

32%

16%

<.0001

12%

3%

36%

9%

<.0001

Diarrhea G2

G3-4

11%

5%

13%

7%

<.0001

10%

7%

13%

9%

0.0117

0 5 10 15 20 25 30 35 40 45 50

3m 6m

G2/3 G4

0 5 10 15 20 25 30 35 40 45 50

3m G2/3 6m

The Main Point

0 1 2 3 4 5 6 Years from Randomization

10 20 30 40 50 60 70 80 90 100

0 1 2 3 4 5 6

Years from Randomization 0

10 20 30 40 50 60 70 80 90

Percent Without Event

6 Months 3 Months Duration

6424 5446 4464 3000 1609 826 321

6410 5530 4477 3065 1679 873 334

Duration 3-yr DFS

3m 74.6 %

6m 75.5 %

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

N Patients At risk

DFS HR = 1.07 95% CI, 1.00 to 1.15

DFS results

Hazard Ratio 1.12

3m TRT better 6m TRT better

Not proven

1.0

Non-Inferiority Margin

Statistical Conclusions

DFS HR = 1.07 95% CI, 1.00 to 1.15

TRT: treatment

Primary EP: not met

Regimen

CAPOX FOLFOX

Risk group

Low-risk

(T1-3 N1)

~60% 3 months ^(3-) 6 months

High-risk

(T4 and/or N2)

~40%

3 ^(-6) months 6 months

IDEA: conclusions

3 yr DFS rate (%) and HR by regimen and

risk group

Regimen

CAPOX FOLFOX CAPOX/FOLFOX

combined

3 yr DFS, %

(95% CI) HR

(95%

CI)

3 yr DFS, %

(95% CI)

HR (95%

CI)

3 yr DFS, %

(95% CI)

HR (95%

CI)

3 m 6 m 3 m 6 m 3 m 6 m

Risk grou p

Low- risk

(T1-3 N1)

~60%

85.0

(83.1- 86.9)

83.1

(81.1- 85.2)

0.85

(0.71- 1.01)

81.9

(80.2- 83.6)

83.5

(81.9- 85.1)

1.10

(0.96- 1.26)

83.1

(81.8- 84.4)

83.3

(82.1- 84.6)

1.01

(0.90- 1.12)

High- risk (T4 and / or N2)

~40%

64.1

(61.3- 67.1)

64.0

(61.2- 67.0)

1.02

(0.89- 1.17)

61.5

(58.9- 64.1)

64.7

(62.2- 67.3)

1.20

(1.07- 1.35)

62.7

(60.8- 64.4)

64.4

(62.6- 66.4)

1.12

(1.03- 1.23)

Risk groups combin ed

75.9

(74.2- 77.6)

74.8

(73.1- 76.6)

0.95

(0.85- 1.06)

73.6

(72.2- 75.1)

76.0

(74.6- 77.5)

1.16

(1.06- 1.26)

P-value interaction test:

Regimen: 0.0061 Risk group: 0.11

Non-inferior Not proven Inferior

Regimen

CAPOX FOLFOX

Risk group

Low-risk

(T1-3 N1)

~60% 3 months ^(3-) 6 months

High-risk

(T4 and/or N2)

~40%

3 ^(-6) months 6 months

IDEA: conclusions

METASTATIC

IMMUNO

A new era

www.fda.org accessed on May 23rd, 2017

Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: First Results From CheckMate 142

NIVO

Overman et al, Lancet Oncol 2017

• Primary endpoint: ORR per investigator assessment

• Secondary endpoint: ORR per blinded independent central review (BICR)

• Other endpoints: PFS, OS, biomarkers, safety and tolerability

Nivolumab 3 mg/kg Q2W

Stage 1^a

• Histologically confirmed metastatic/recurrent CRC

• dMMR/MSI-H per local laboratory

• ≥ 1 prior line of therapy

Nivolumab 3 mg/kg Q2W

Stage 2^b

Patients

Stage 2^d Stage 1^c

Nivolumab 3 mg/kg

+ ipilimumab 1 mg/kg Q3W for 4 doses

• Then nivolumab 3 mg/kg Q2W

Nivolumab 3 mg/kg

+ ipilimumab 1 mg/kg Q3W for 4 doses

• Then nivolumab 3 mg/kg Q2W

74 patients were treated in monotherapy stages 1 and 2

Study Design

Overman et al, Lancet Oncol in press

dMMR/MSI-H per Local Laboratory

(N = 74) BICR ORR, n (%)

95% CI

20 (27.0) 17.4, 38.6 Best overall response, n (%)

CR PR SD PD

Unable to determine

2 (2.7) 18 (24.3) 28 (37.8) 20 (27.0) 6 (11.1) Disease control for ≥ 12 weeks, n (%)

^a

46 (62.2)

Activity

Overman et al, Lancet Oncol 2017

Change in tumor burden over time

Overman et al, Lancet Oncol 2017

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0

- 1 0 0 - 7 5 - 5 0 - 2 5 0 2 5 5 0 7 5 1 0 0

W e e k s

ChangeinSumofTargetLesionsSize(%)

O n

T r e a t m e n t O f f T r e a t m e n t

C o m p l e t e o r P a r t i a l R e s o p o n s e

F i r s t O c c u r r e n c e o f N e w L e s i o n

C h a n g e T r u n c a t e d t o 1 0 0 %

a

On treatment Off treatment CR or PR

First occurrence of new lesion

b b

Progression-Free Survival

Overman et al, Lancet Oncol 2017

PFS per Investigator Median [95% CI], months

12-month rate [95%

CI], %

9.6 [4.3, NE]

48.4 [33.6, 61.7]

PFS per BICR

12-month rate [95%

CI], % 45.6 [32.2, 58.1]

0 3 6 9 12 15 18 21 24

Months

74 48 22 14 12 10 7 3 0

No. at risk 0 10 20 30 40 50 60 70 80 90 100

Probability of PFS (%)a

Overman et al, Lancet Oncol 2017

Overall Survival

3 6 9 12 15 18 21 24 27

74 64 54 24 21 21 14 10 3 0

0 10 20 30 40 50 60 70 80 90 100

Probability of Survival (%)a

Median OS [95% CI], months

12-month OS rate [95%

CI], %

NR [17.1, NE]

73.8 [59.8, 83.5]

Months No. at risk

0

BRAF Mutation Status

Inves ti gat or -A ss es se d B es t C hang e in T ar get Lesi on S iz e (% )

Mutant Wild type

Impact of BRAF mut on response to Nivo

Overman et al, Lancet Oncol in press

Rare Intermediate Numerous

Investigator-Assessed Best Change in Target Lesion Size (%)

Abundance of PD-L1 Expressing Tumor- Associated Immune Cells

≥ 1%

< 1%

Investigator-Assessed Best Change in Target Lesion Size (%)

Tumor PD-L1 Expression

Impact of PD-L1 expression

Overman et al, Lancet Oncol in press

Overman et al, Lancet Oncol in press

Safety

Patients, n (%)

All Patients (N = 74)

Any grade Grade 3–4

Any TRAE 51 (68.9)

^a

15 (20.3)

TRAEs reported in ≥ 10% of patients

Fatigue Diarrhea Pruritus

Lipase increased Rash

17 (23.0) 16 (21.6) 10 (13.5) 9 (12.2) 8 (10.8)

1 (1.4) 1 (1.4)

0 6 (8.1)

0

NIVO+IPI

*Ongoing Response include responders who had neither progressed nor initiated subsequent therapy at the time of analysis and excludes responders censored prior to 8 weeks of the clinical data cutoff date if a patient is still in the first 24 weeks follow-up period, otherwise, the window is 14 weeks

Checkmate 142 Nivo+Ipi: study design

Overman et al, ASCO 2017

*Ongoing Response include responders who had neither progressed nor initiated subsequent therapy at the time of analysis and excludes responders censored prior to 8 weeks of the clinical data cutoff date if a patient is still in the first 24 weeks follow-up period, otherwise, the window is 14 weeks

Nivo+Ipi: main results

Overman et al, ASCO 2017

dMMR/MSI-H (N = 84)^a Investigator

ORR, n (%)

[95% CI]

46 (54.8) [43.5, 65.7]

Best overall response, n (%) CR

PR SD PD

Not determined Not reported

2 (2.4) 44 (52.4) 26 (31.0) 9 (10.7)

2 (2.4) 1 (1.2)

Disease control for ≥ 12 weeks, n (%)

^b

66 (78.6)

Median TTR, months (range) 2.8 (1.1–14.0)

Median DOR, months, [95% CI] NR [0.0+, 15.9+]

Median PFS, months [95% CI], months NR [11.47–NE]

Median OS, months [95% CI] NR [NE–NE]

*Ongoing Response include responders who had neither progressed nor initiated subsequent therapy at the time of analysis and excludes responders censored prior to 8 weeks of the clinical data cutoff date if a patient is still in the first 24 weeks follow-up period, otherwise, the window is 14 weeks

Nivo+Ipi: waterfall plot

Overman et al, ASCO 2017

Nivolumab + Ipilimumab (N=84)

6 mo PFS rate, % [95% CI]

77.4 (66.5, 85.1)

Median PFS, mo [95% CI]

NA (11.47, NE)

No. events 21/84

Overman et al, ASCO 2017

Nivo+Ipi: Progression-free Survival

Nivolumab + Ipilimumab (N=84)

OS rate, % [95% CI]

6 mo 89.1 (80.2, 94.2

9 mo 87.6 (78.1, 93.1)

Median OS, mo [95%

CI]

NA (NE, NE)

Overman et al, ASCO 2017

Nivo+Ipi: Overall Survival

dMMR/MSI-H per Local Laboratory (N = 84)

^a

Patients, n (%) Any Grade Grade 3 or 4

Any TRAE 57 (67.9) 24 (28.6)

Serious TRAE 15 ( 17.9) 14 ( 16.7)

TRAEs reported in ≥ 10% of patients

Diarrhea 20 (23.8) 1 (1.2)

Fatigue 14 (16.7) 1 (1.2)

Aspartate aminotransferase increase 14 (16.7) 8 (9.5)

Pyrexia 13 (15.5) 0

Pruritus 13 (15.5) 2 (2.4)

Alanine aminotransferase increase 12 (14.3) 7 (8.3)

Nausea 12 (14.3) 0

Hyperthyroidism 11 (13.1) 0

Hypothyroidism 11 (13.1) 0

Safety

Overman et al, ASCO 2017

Final Chapter

ALICE

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