Claus-Henning Köhne

University Clinic Oncology and Haematology

North West German Cancer Center (NWTZ)

Chemotherapy and Targeted Agents in First Line mCRC

ESMO Preceptorship Barcelona 2017

ESMO Consensus 1st line approach

ESMO Consensus 1st line approach

Cytoreduction is

best disease

control !

I always treat a

patient to achieve

tumor shrinkage!Artificial differentiation of cytoreduction &

disease control

Modified ESMO Consensus 1st line approach

In any case

Check for secondary resectability!

Pending to be included:

MSI, Her2/neu

Cremolini et al. Lancet Oncol 2015

Survival according to molecular subgroups

RASw.38%

RAS mut38%

RAS mut MSI8%

BRAF mut8%

RAS wt MSI8%

Her2/neu

~5%

EGFR in RAS wt disease

Influence of KRAS and RAS mutational status on survival

Randomised trials of EGFR antibodies

1st line infusional 5-FU regimens

Trial Therapy OS (mo)

KRAS wt

OS (mo)

RAS wt

OS (mo)

RAS mut

CTx +EGFR CTx +EGFR CTX +EGFR

CRYSTAL

(n=666)

FOLFIRI

+/- Cetux*20.0 23.5 20.2 28.4 17.7 16.4

PRIME

(n=656)

FOLFOX

+/- Pani*19,4 23.8 20.2 26.0 19.2 15.6

OPUS

(n=197)

FOLFOX

+/- Cetux*18,5 (22.8) 17.8 19.8 17.8 13.5

Chinese

(138)

Chemo

+/- Cetux21.0 30.9 - - - -

TAILOR

(n=354)

FOLFOX

+/- cetux17.8 20.7

Van Cutsem E, et al. J Clin Oncol. 2011;29(15):2011-2019. Ye LC, et al. J Clin Oncol. 2013;31(16):1931-1938. Douillard

JY, et al. J Clin Oncol. 2010;28(31):4697-4705. Bokemeyer C, et al. Ann Oncol. 2011;22(7):1535-1546.

An EGFR antibody added to a doublet significantly

increases RR, and prolongs PFS and OS compared to

a doublet alone. This prolongation of OS is clinically

relevant

4 out of 5 trails showed a significant survival increase

EGFR antibodies for RASwt mCRC in 1st line

EGFR or VEGF in RAS wt disease

Head-to-Head comparison

Head to Head comparison Cetuximab vs Bevacizumab 1st line RASwt

1st Line mCRC RAS wt

Trial Doublet Biological OS HR P-value

FIRE 3

(n=400) FOLFIRI

Cetuximab 33.1

0.70 <0.006

Bevacizumab 25.0

PEAK

(n=170)FOLFOX

Panitumumab 36.9

0.76 0.15Bevacizumab 28.9

CALGB* 80405

(n=390)FOLFOX

Cetuxumab 32.5

0.86 0.2

Bevacizumab 29.0

3 different trials are displayed

Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.. Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.

Lenz H-J, et al. Eur J Cancer. 2014;50(Suppl): Abstract 501O. Venook JAMA 2017

FIRE 3 & CALGB Overall Survival in RASwt diesase

Heinemann et al. Lancet Oncol 2014

(HR 0·70, 95% CI 0·53–0·92;

p=0·011)

Venook et al. JAMA 2017

© 2017 American Medical Association. All rights reserved.

eFigure 4. Overall Survival (OS) by Treatment Biologic among patients on the mFOLFOX6 Chemotherapy Regimen (Oxaliplatin 85 mg/m2 over 120 minutes, leucovorin 400 mg/m2 over 2 hours followed by 5FU 400 mg/m2 bolus then 5FU 2400 mg/m2 by 46-48 hour infusion)*

*Tick marks denote the last known follow-up time for patients with no death date reported.

*HR and P-value are adjusted for prior adjuvant therapy, prior radiotherapy, protocol chemotherapy and randomization pre- or post-amendment restricting eligibility to KRAS wt.

Arm N

(Events)

OS Median

(Interquartile

Range)

Adjusted

HR

(95% CI)

Adjusted

P*

Chemotherapy +

Bevacizumab

409

(329)

27.7

(14.2-45.4) 0.83

(0.71-0.98) 0.03

Chemotherapy +

Cetuximab

426

(317)

30.1

(13.5-53.6)

Downloaded From: http://jamanetwork.com/ by a University Medical Center Hamburg - Eppendorf User on 07/16/2017

© 2017 American Medical Association. All rights reserved.

eFigure 2. Forest plots for comparisons of Overall Survival (OS) by Treatment Regimen Overall and within each level of Sex, Race and Chemotherapy. Hazard ratios and 95% Confidence Intervals are provided

Downloaded From: http://jamanetwork.com/ by a University Medical Center Hamburg - Eppendorf User on 07/16/2017

CALGB 80405 Survival

mFOLFOX only

Venook et al. JAMA 2017 Supplement 2

PRIME – OS – 1st line

HR, hazard ratio; OS, overall survival; Pmab, panitumumab

Overall survival (months)

100

80

60

40

20

0

Ka

pla

n-M

eie

r e

stim

ate

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

169 159 39

49

164 151 36

42

147 137 26

34

136 120 18

28

124 103 17

23

107 86 15

20

97 76 13

14

86 64 11

11

77 56 8

9

66 44 6

8

56 32 5

7

46 24 4

6

39 21 4

5

30 19 4

4

16 11 3

1

11 6 1

1

3 1 1

0

0 1 0

No. of subjects: 1: 2:

3: 4:

Censor indicated by vertical bar

48P

rob

abili

ty o

f O

S

Time (months)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 362412

Median OS (95% CI), months

Pmab +

FOLFOX FOLFOX HR (95% CI)

Left 328 30.3 23.6 0.73 (0.57–0.93)

Righ

t 88 11.1 15.4 0.87 (0.55–1.37)

1: Pmab + FOLFOX left

2: FOLFOX left

3: Pmab + FOLFOX right

4: FOLFOX right

Median OS (95% CI), months

Cet+

FOLFIRIFOLFIRI HR (95% CI)

Left 280 28.7 21.70.65 (0.50-0.86)

P=0.002

Righ

t84 18.5 15.0

1.08( 0.65-1.81)

P=0.78

1: Cet + FOLFIRI left

2: FOLFIRI left

3: Cet + FOLFIRI right

4: FOLFIRI right

The role of sideness for a doublet +/- EGFR

PRIME: FOLFOX +/- Panitumumab CRYSTAL: FOLFIRI +/- Cetuxumab

Teijpar et al. Jama Oncol 2016Peeters et al. ESMO 2016

∆ 6.7 mo ∆ 10.2 mo

5 o

f 9

| JN

CI J N

atl C

an

cer Inst, 2

01

5, V

ol.1

07

, No.3

ARTICLE

Table 2. Unadjusted analyses of survi val outcom es by pr im ary tum or locat ion and stud y*

Cohort

OS events

No. (%)

Median OS, m onths (95% CI)

HR (95% CI) P PFS events No. (%)

Median PFS, m onths (95% CI)

HR (95% CI) PRight -sided tum ors Left -sided tum ors Right -sided tum ors Left -sided tum ors

PROVETTA

All el igible pat ien ts

(n  = 200)

77 (38.5%) 24.8 (19.1 to 29.8) 42.0 (32.1 to 53.5) .44 (.28 to .70) <.001 147 (73.5%) 9.9 (8.3 to 11.7) 12.1 (11.1 to 15.8) .52 (.36 to .75) <.001

Nonm ucinous/BRAF

w i ld-type subgr oup

(n  = 155)

54 (34.8%) 28.8 (20.1 to 33.0) 47.6 (32.1 to 53.5) .52 (.30 to .93) .02 112 (72.3%) 10.0 (8.8 to 13.1) 13.0 (11.5 to 15.9) .54 (.34 to .84) .01

AVF2107g

Evaluable pat ien ts

(n  = 559)

264 (47.2) 14.6 (12.0 to 16.9) 20.4 (18.7 to 24.2) .55 (.43 to .70) <.001 363 (64.9) 7.1 (5.6 to 8.1) 8.5 (8.2 to 10.3) .68 (.55 to .83) <.001

CT arm (n  = 282) 144 (51.1) 13.6 (10.6 to 16.7) 18.0 (15.7 to 21.7) .62 (.44 to .86) .01 206 (73.0) 5.4 (4.4 to 5.8) 8.0 (5.7 to 8.3) .72 (.55 to .96) .02

CT + bevacizum ab arm

(n  = 277)

120 (43.3) 15.9 (12.7 to 19.6) 24.2 (19.5 to NE) .49 (.34 to .70) <.001 157 (56.7) 8.7 (8.1 to 10·.6) 11.1 (9.4 to 13.8) .62 (.45 to .85) .01

NO16966

Evaluable pat ien ts

(n  = 1268)

994 (78.3) 18.0 (16.5 to 19.8) 23.0 (21.5 to 24.4) .71 (.62 to .82) <.001 1127 (88.9) 7.6 (7.0 to 8.3) 8.9 (8.5 to 9.3) .90 (.79 to 1.03) .12

CT arm s (n  = 827) 664 (80.3) 17.0 (14.7 to 18.5) 22.0 (20.5 to 23.7) .67 (.57 to .80) <.001 751 (90.8) 7.0 (6.0 to 7.9) 8.3 (7.9 to 8.8) .87 (.74 to 1.03) .10

CT + bevacizum ab arm s

(n  = 441)

330 (74.8) 20.6 (17.6 to 24.7) 24.7 (22.2 to 27.6) .78 (.61 to .99) .04 376 (85.3) 8.6 (7.6 to 10.2) 10.0 (9.2 to 10.8) .95 (.76 to 1.19) .64

* Cox proport ional hazards regression analyses. Al l stat ist ical tests w ere tw o-sided. CI = con f dence in terval; CT = chem otherapy; HR = hazard rat io; OS = overal l survival; PFS = progression-free survival.

by guest on October 9, 2016 http://jnci.oxfordjournals.org/ Downloaded from

Loupakis et al. JNCI J Natl Cancer Inst 2015

Prognostic value of primary tumor side : Doublet +/- VEGF

p-value ? p-value ?

Is Bevacizumab improving OS over FOLFOX/XELOX

in left or right sided tumors?

• This question has probably been addressed in this study, but has not been reported

• We don’t know whether Bev is working in left or right sided tumors

• It is unlikely that sideness plays a role for Bevacizumab

Left Right

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity o

f O

S

12 6024 36 48

Months

0 72

Median OS (95% CI), months

Cet + FOLFIRI Bev + FOLFIRI HR (95% CI)

Left 306 38.3 28.00.63

P=0.002

Right 88 18.3 23.01.31

P=0.28

Median OS (95% CI), months

Cet + FOLFIRI Bev + FOLFIRI HR (95% CI)

Left 325 39.3 32.70.77

P=0.04

Right 149 13.7 29.21.36

P=0.10

EGFR vs. VEGF all plus Doublet and influence of side of primary

FIRE-3 CALBG 80405

Teijpar et al. JAMA Oncol 2016 Venook et al. ESMO 2016

Right Left

DCTripplet?/ Doublet

+/-VEGF?

Doublet＋EGFR

CyRDoublet＋

EGFRDoublet＋

EGFR

Right Left

DCDoublet+

VEGFDoublet＋

EGFR

CyRTriplet+

VEGFDoublet＋

EGFR

Right Left

DCDoublet+VEGF

Doublet＋EGFR

CyR

Doublet＋EGFR

Triplet+VEGF

Doublet＋EGFR

Different perspective about Sidedness from EU and US

Key opinion leaders have changed their thought

DC: Disease Control CyR: Cytoreduction

Treatment of RAS wt mCRC

RAS mutant disease

Randomised trials of VEGF antibodies in 1st line mCRC

irrespectively of RAS mutational status

Trial N Pat Therapy ORR PFS (mo) OS (mo)

Bevacizumab plus less effective chemotherapy

AGITG 313 Capecitabine+/- Beva 31% vs. 38% 5.7 vs. 8.5 18.9 vs. 18.9

UK 280 Capecitabine+/- Beva (>70y) 48% vs. 57% 5.1 vs. 9.1 16.8 vs. 20.7

AVF2107g 813 IFL +/- Bev 35% vs. 45% 6.2 vs. 10.5 15.6 vs. 20.3

Bevacizumab plus effective chemotherapy

NO16966 700 FOLFOX+/- Beva 38% vs. 38% 8.6 vs. 9.4 20.3 vs. 21.2

700 CAPOX+/- Beva 38% vs. 38% 5.1 vs. 9.1 16.8 vs. 20.7

ITACA 376 Doublet+/- Beva 48% vs. 49% 8.4 vs. 9.6 20.6 vs. 20.6

0FOLFIRI +/- Bev

FOLFOXIRI / +/- Bev Such a studies were never done

NO16966 PFS CTx +/- Bevacizumab :

XELOX and FOLFOX subgroups

FOLFOX+placebo

FOX+bevacizumab

Cassidy et al. ASCO 2007; Saltz et al. JCO 2008, Table 1A appendix

9.37.4

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25Months

PF

S e

sti

mate

XELOX+placebo

XELOX+bevacizumab

FOLFOX

FOLFOX+

Bev XELOX

XELOX

+Bev

N Pat 351 349 350 350

PFS mo 8.6 9.4 7.4 9.3

HR

97.5% CI

0.89

0.73 - 1.08

0.77

0.63 – 0.94

p-value 0.19 0.0026

OS (mo) 20.3 21.2 19.2 21.4

HR

97.5% CI

0.94

0.75 to 1.16

0.84

0.68 – 1.04

P-value n.s. n.s.

RASwt or mut: Doublet vs. Triplet

RASwt or mut disease

Regimen N RR PFS OS Author

FOLFIRI 122 41% 6.9 16.7 Falcone JCO 2007

+/- Oxaliplatin 122 66% 9.9 23.6

FOLFIRI / Bev 256 53% 9.7 25.8 Falcone NEJM 2015

+/- Oxaliplatin 252 65% 12.2 29.8

FOLFOX / Bev 39 62% Grünberger Ann Oncol 2015

+/- Irinotecan 41 81%

FOLFOX / Bev 121 60% 9.8 n.a. Schmoll ESMO 2016

+/- Irinotecan 121 79% 12 n.a.

• Unroven / unclear role of bevacizumab

Cremolini et al. Lancet Oncol 2015

Triplet is not better than doublet Group Events/No. OS (95% CI), months

RAS/BRAF WT (Arm

A)51/79 25.2 (20.8-29.8)

RAS/BRAF WT (Arm

B)40/79 32.2 (26.1-46.1)

RAS MT (Arm A) 68/97 21.3 (19.6-23.0)

RAS MT (Arm B) 65/97 23.2 (18.1-28.4)

BRAF MT (Arm A) 11/12 12.4 (10.2-20.2)

BRAF MT (Arm B) 8/10 7.8 (4.7-13.5)

Doublet is not better than FP+Bev

What is the best treatment for RAS mutant disease?

FOLFIRI/Bev +/- Oxaliplation FP/Bev +/- Irinotecan

Modest et al. ESMO 2017

Discussion Presented at ESMO 2017

Bevacizumab efficacy in 1st line (IFL ± Bev) andpooled analysis of 1st & 2nd line studies

Overall survival

HR 95% CI P-value

KRAS

wt

Pooled analysis

N=364 0.70 0.54-0.91 0.007

KRAS

mut

Pooled analysis

N=166 0.85 0.60-1.22 0.38

Hurwitz et al. The Oncologist 2009 and 2013

TML study : Chemo ± bevacizumab continued in 2nd line

Survival difference mainly driven by KRASwt subgroup

Kubicka et al. Ann Oncol 2014

PFS CTx +Bev HR p-value

KRASwt 4.5 6.4 0.61 <.0001

KRASmut 4.1 5.5 0.70 0.0027

OS CTx +Bev HR p-value

KRASwt 11.1 15.4 0.69 0.0052

KRASmut 10.0 10.4 0.92 0.5

PFS

OS

RASwt RASmu

SAGLB.AFL.17.03.0196e (06/17)

ESMO Guidelines: No Guidance on KRAS Exon 2 WT/MUT Alone

Aflibercept Comparable to Other Anti-VEGF Agents in KRAS Exon 2 WT and MUT

WTMUT

Wirapati P, et al. J Clin Oncol. 2017;35 (suppl; abstr 3538); Ince WL et al. J Natl Cancer Inst. 2005;97:981-9; Kubicka S et al. Ann Oncol.

2013;24:2342‒2349; Obermannova et al. Ann Oncol. 2016;27:2082‒2090; Wirapati P, et al. J Clin Oncol. 2017;35 (suppl; abstr 3538).

Retrospective evaluation of a limited dataset can only be hypothesis generating

KRAS

RASmut disease

The best treatment for RASmut disease is unknown

A Doublet may still be the best

Developing new treatments is a medical need

BRAF mutant disease

Cremolini et al. Lancet Oncol 2015

N=28 N=70 N=30

1st line 1st line 2nd line

FOLFIRI/Bev +/- Oxaliplatin Doublet +/- Cetuximab Doublet+/- Afflibercept

Cremolini et al. Lancet Oncol 2015 Bokemeyer C..Köhne, et al. J Clin Oncol

2010;28(Suppl. 15):Abstract No. 3506

Tejpaer et. al. WVGIC 2017

Treatment BRAF mut tumors

1st line experience

N=70

SAGLB.AFL.17.03.0196e (06/17)

BRAFOS PFS

Retrospective evaluation of a limited dataset can only be hypothesis generating

BRAF/plcboBRAF/afli

Adapted from Wirapati P, et al. J Clin Oncol. 2017;35 (suppl; abstr 3538).

BRAF

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0 5 10 15 20 25 30 35

0.0

0.2

0.4

0.6

0.8

1.0

events

1911

months

median surv

5.5 [ 3.5,10.6]10.3 [ 5.3, NA]

number at risk:

20 12 5 2 1

16 12 8 4

BRAF/afli vs BRAF/plcbo: HR = 0.416 [0.158, 1.09] p = 0.076

A)

three way/arm

BRAF/plcboBRAF/afli

OS

/

/

/

/

/

/

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/

0 5 10 15 20 25

0.0

0.2

0.4

0.6

0.8

1.0

PF

S

events:

1711

median surv:2.2 [ 1.4, 8.3]5.5 [ 2.7, NA]

number at risk:

20 4 2 116 8 2 1

BRAF/afli vs BRAF/plcbo: HR = 0.589 [0.22, 1.58] p = 0.29

B)

three way/arm

BRAF/plcboBRAF/afli

BRAF/plcboBRAF/afli

months

Summary BRAF mCRC

▪ Patients with BRAF mut disease have a poor prognosis

▪ Consider Intensive chemotherapy (FOLFOXIRI)

▪ EGFR inhibitors have a role

▪ VEGF inhibitors may have a role

▪ Combinations with EGFR, BRAF & MEK inhibitors are emerging

▪ Randomised trials are ongoing

▪ At the moment no drug or combination can be preferred or

excluded

Modified ESMO Consensus 1st line approach

In any case

Check for secondary resectability!

Options:

Triplet +/- Bev

Doublet +/- EGFR

BRAF / MEK / EGFR

BRAF / EGFR / Irinotecan

BRAFmt

Generally:

Doublet

No evidence for VEGF in

1st line

RASmut

Generally

Left: Doublet + EGFR

Right: Doublet / Tripplet

+/- VEGF?

CyR: Doublet+EGFR

RASwt

Trial name N Prevalence of MSI-H/dMMR

Overlapping

BRAF V600E

mutation

Pooled dataset1 3,063 5.0% 34.6%

AIO Colorectal Study Group2 104 4 % Not reported

Australia and United States3 NA Not reported 30%

Review Article4 NA 3% - 5% Not reported

GI-SCREEN-JAPAN5 853 1.9% 40%

NCCE6 277 1.9% 40%

1. Venderbosch S, et al. Clin Cancer Res. 2014;20(20):5322-5330. 2. Müller CI, et al. Int J Colorectal Dis. 2008;23(11):1033-1039. 3. Goldstein J, et al. Ann

Oncol. 2014;25(5):1032-1038. 4. Cohen R, et al. Curr Ocol Rep. 2016;18(3):18. 5. Kajiwara T, Yoshino T, et al. J Clin Oncol. 2016;34(suppl): Abstract 3591.

6. Kawazoe A, Yoshino T, et al. J Clin Oncol. 2016;34(suppl 4): Abstract 629.

Prevalence of MSI-H or dMMR mCRC:Cross-Trial Comparison

Note: GI-SCREEN-JAPAN is the Nationwide Cancer Genome Screening Project for Gastrointestinal Cancer in Japan

dMMR, mismatch repair-deficient

Retrospective IIR MSI-H

CALGB 80404: MSI Status Does Not Impact OS (29/418, 6.9%)

Months From Randomization

31.8 months (29.0-35.2)N = 38930.3 months (22.6-NE)N = 29

Median OS (95% CI)

MSSMSI-H

0 12 24 36 48 60 72

0.00

0.25

0.50

0.75

1.00

Pro

po

rtio

n W

ith

ou

tE

ve

nt

Innocenti F, et al. J Clin Oncol. 2017;35(suppl 4): Abstract 3504.

BRAF+ 52%

BRAF+ 11%

HRadj 0.84 (95% CI 0.51-1.39), P = .50

Le et al. NEJM 2015

Regimen N RR Disease Control PFS

Dabrafenib (BRAF)

+ Panitumumab (EGFR)20 10% 90%

Dabrafenib (BRAF)

+Panitumumab (EGFR)

+Trametinib (MEK)

35 26% 96%

Irinotecan

+Cetuximab (EGFR)47 4% 22% 2.0

Irinotecan

+Cetuximab (EGFR)

+Vemurafennib (BRAF)

44 16% 67% 4.3

BRAFmut disease results from Phase II trials

Chloe Atreya at 2015 ASCO

Kopetz et al. ASCO 2017

Response and Disease Control

Patients, n (%)

dMMR/MSI-H per

Local Laboratory

(N = 74)

dMMR/MSI-H per

Central Laboratory

(n = 53)

Investigator BICR Investigator BICR

ORR, n (%)

95% CI

23 (31.1)

20.8, 42.9

20 (27.0)

17.4, 38.6

19 (35.8)

23.1, 50.2

17 (32.1)

19.9, 46.3

Best overall response, n (%)

CR

PR

SD

PD

Unable to determine

0

23 (31.1)

29 (39.2)

18 (24.3)

4 (5.4)

2 (2.7)

18 (24.3)

28 (37.8)

20 (27.0)

6 (11.1)

0

19 (35.8)

21 (39.6)

10 (18.9)

3 (5.7)

1 (1.9)

16 (30.2)

21 (39.6)

12 (22.6)

3 (5.7)

Disease control for ≥ 12 weeks, n (%)a 51 (68.9) 46 (62.2) 39 (73.6) 37 (69.8)

BICR, blinded independent central review.a Patients with CR, PR, or SD for ≥ 12 weeks.

Presented by: Dr Michael J. Overman

Overall Survival

Presented by: Dr Michael J. Overman

NR, not reached. a dMMR/MSI-H assessed by local laboratory.

3 6 9 12 15 18 21 2724

74 64 54 24 21 21 14 10 3 0

0

10

20

30

40

50

60

70

80

90

100

Pro

bab

ilit

y o

f S

urv

ival

(%)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

Progression-Free Survival

Presented by: Dr Michael J. Overman

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]

BICR, blinded independent central review; NE, not estimable. a Investigator assessed dMMR/MSI-H by local laboratory.

0 3 6 9 12 15 18 21 24

Months

74 48 22 14 12 10 7 3 0No. at risk

0

10

20

30

40

50

60

70

80

90

100

Pro

bab

ilit

y o

f P

FS

(%

)a

Nivolumab in pretreated MSI-H mCRC - Checkmate 142

Patients, n (%)

dMMR/MSI-H per

Local Laboratory

(N = 74)

dMMR/MSI-H per

Central Laboratory

(n = 53)

Investigator BICR Investigator BICR

ORR, n (%)

95% CI

23 (31.1)

20.8, 42.9

20 (27.0)

17.4, 38.6

19 (35.8)

23.1, 50.2

17 (32.1)

19.9, 46.3

Overman-M ASCO 2017

Overm

an M,

et al.

J Clin

Onco

l. 2017

;35(su

ppl 4S

): Abs

tract

519.

ORR 5

5%, D

CR 79

%

50 -50 -100075 25 -25 -75

（（（

100 Best Reduction From Baseline inTarget Lesion

（

（ （ （（ （ （（ （（ （（ （（ （（（ （（

（ （（ （（ （ （（ （（ （（（ （（ （（（（（（ （（（ （ （ （

（Co

nfirme

d CR o

r PR p

er inv

estiga

tor

Tumor

Resp

onse

(Nivo

lumab

+ Ipil

imum

ab)

-100100(%

)

050 -50

Confir

med C

R/PR

Ref: N

IVOmo

nother

apy

ORR 3

1.1%,

DCR 6

8.9%

Time

00.0

213

1.0 0.4

69

1215

18

Probability of Progression-Free Survival

0.8 0.20.9 0.30.6 0.10.7 0.5

（mo

nths（

NE, no

t estim

able; N

R, not

reach

ed.

PFSr

ate（

95（CI)

, （

6-mont

h77（

66.5, 8

5.1（

9-mont

h77（

66.5, 8

5.1（

Media

n PFS（

95（CI)

, mont

hsNR

（11.

5, NE（

PFS (

Nivolu

mab +

Ipilim

umab

)

027

0100 Probability of PFS 2040608090 10305070(%)

36

912

1518

2124

PFSr

ate（

95（CI)

, （

12-mo

nth48.

4（33.

6, 61.7

（

Media

n PFS（

95（CI)

, mont

hs9.6

（4.3

, NE（

Ref: N

IVOmo

nother

apy

Overm

an M,

et al.

J Clin

Onco

l. 2017

;35(su

ppl 4S

): Abs

tract

519.

Time

00.0

213

1.0 0.4

69

1215

18

Probability of Overall Survival

0.8 0.20.9 0.30.6 0.10.7 0.5

（mo

nths（

NE, no

t estim

able; N

R, not

reach

ed.

OSrat

e（95（

CI（, （

6-mont

h89（

80.2, 9

4.2（

9-mont

h88（

78.1, 9

3.1（

Media

n OS（

95（CI)

, mont

hsNR

（NE

, NE（

OS (N

ivolum

ab + I

pilim

umab

)

OSrat

e（95（

CI（, （

12-mo

nth73.

8（59.

8, 83.5

（

Media

n OS（

95（CI)

, mont

hsNR

（17.

1, NE（

03

27

0100

69

1215

1821

Probability of survival

2040608090 10305070(%)

24

Ref: N

IVOmo

nother

apy

Overm

an M,

et al.

J Clin

Onco

l. 2017

;35(su

ppl 4S

): Abs

tract

519.

• Hold drug

• Steroids -> taper down

• Hospitalize if >= Grade 3

• If unresolved symptoms

• Consider infliximab

• Contact Organ specialist

Champiat et al. Ann Oncol 2016

Ch

ange

in t

arge

t le

sio

nfr

om

bas

elin

e (

%)

HER2 3+ HER2 2+ Patients on treatment PD NEW LESION

Waterfall plot

(best % tumor shrinkage)

Spaghetti plot

(tumor shrinkage trend)

Ch

ange

in t

arge

t le

sio

nfr

om

bas

elin

e (

%)

Trastuzumab/Lapatinib

Responses by HER2 IHC Score (46/849 5.4%)

RR 34%

Trastuzumab iv 4mg/kg load and then 2mg/kg/qwLapatinib po 1000 mg/qd

*3 patients are not shown: 122026 (IHC 2+,not yet assessed);

121011 (IHC 3+) and 121013 (IHC 3+) early clinical PDs.

Thank you for your attention