chemotherapy and targetd agents in 1st line...

Claus-Henning Köhne

University Clinic Onkology and Haematology

North West German Cancer Center (NWTZ)

Chemotherapy and targetd agents in 1st line mCRC

ESMO Preceptorship Colorectal Cancer Prague July 2016, Czech Republic

ESMO Consensus 1st line approach

mut mutmut mut


mut mutmut mut

Cytoreduction isbest disease

control !

I alwys treat apatient to achieve

a response!

mCRCFit for chemotherapy patients

Molecular profiling

RAS wt

RAS mut

?

CTx+EGFR

CTx+VEGF

IntensiveCTx

BRAF mut

CTx+VEGF

Her2/neuMSI

Check-pointInhibition?

Her2/neu targetingagents

• BRAF / MEK / EGFR?• EGFR?• VEGF?

?

Molecular profiling adviced by ESMO and NCCN guidelines

mCRCFit for chemotherapy patients

Molecular profiling

IntensiveCTx

BRAF mut

• BRAF / MEK / EGFR?• EGFR?• VEGF?

?

Molecular profiling adviced by ESMO and NCCN guidelines

FOLFOXIRI in molecular subgroups analysesProgression free survival

0.4 0.6 0.8 1

Experimental better(FOLFOXIRI + Bev)

Control Better(FOLFIRI+Bev)

Factor N HR p

• Promising regimen for BRAF mut• Equally effective for KRAS wt & mut

Falcone et al. ASCO 2014

OS

est

imat

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

180 6 12 24 6030 36 42 48 54

KRAS wt/BRAF wt

HR (95% CI): 0.840 (0.710–0.993); p=0.041

FOLFIRI/FOLFOX4 +cetuximab (n=349): mOS 24.8 mo

FOLFIRI/FOLFOX4 (n=381): mOS 21.1 mo

KRAS wt/BRAF mt

HR (95% CI): 0.633 (0.378–1.060); p=0.079

FOLFIRI/FOLFOX4 + cetuximab (n=32): mOS 14.1 mo

FOLFIRI/FOLFOX4 (n=38): mOS 9.9 mo

Bokemeyer C..Köhne, et al. J Clin Oncol 2010;28(Suppl. 15):Abstract No. 3506

Time (months)

Pooled analysis of OS in patients with KRAS wt tumors according to BRAF mutation status

2012年年年年CSCO年会年会年会年会北京北京北京北京

BRAF mut

Trial BRAF mut Treatment HR P-value

GONO N=28 FOLFIRI + Bev

0.55 0.323FOLFOXIRI + Bev

CRYSTAL/OPUS

N=70 Doublet

0.633 0.079

Doublet+Cet

...... there are insufficient data to justify the exclusion of anti-EGFR mAbtherapy for patients with RAS WT/BRAF MT mCRC.

C- or P-based therapy did not increase the benefit of standard therapy orthe BSC in RAS-wt/BRAF-mut CRC patients. .........

Loupakis F, et al. N Engl J Med. 2014;371(17):1609-1618. , Bokemeyer C, …. Köhne CH, et al. Eur J Cancer. 2012;48(10):1466-1475.

A Rowland, et al. British Journal of Cancer 112, 1888-1894 (09 June 2015) , Pietrantonio et al .Eur J Cancer. 2015 Mar;51(5):587-94.

Can Targeting EGFR Overcome Resistance to BRAF + MEK Inhibitors in BRAFm CRC?

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

Best Response With Confirmation <br />Percent Change from Baseline at Maximum Reduction in Tumor Measurement

Presented By Chloe Atreya at 2015 ASCO Annual Meeting


mut mutmut mut

Randomised trials of VEGF antibodies in

less effective chemotherapy (FU/FA alone or IFL) – 1st line

1st Line mCRC

Trial Therapy ORR PFS (mo) OS (mo)

AGITG

(n=313)

Capecitabine

+/- Beva

–31% vs. 38%

��

5.7 vs. 8.5

HR = 0,63

–18.9 vs. 18.9

HR = 0,86

UK

(n=280)

Capecitabine

+/- Beva (>70y)

��

48% vs. 57%

��

5.1 vs. 9.1

HR = 0.53

–16.8 vs. 20.7

HR = 0.79

AVF2192g

(n=209*)

FU/LV

+/- Beva

��

15% vs. 26%

��

5.5 vs. 9.2

HR = 0,567

–12.9 vs. 16.6

HR = 0,855

AVF2107g

(n=211)#

IFL vs.

FU/FA+ Bev37% vs. 40% 6.7 vs. 8.8 15.1 vs.18.3

AVF2107g

(n=813)

IFL

+/- Bev��

35% vs. 45%

��

6.2 vs. 10.5

HR = 0.54

��

15.6 vs. 20.3HR = 0.65

�� sig. diff;. Sig; – no sig. diff # exploratory * rand phase II,

Randomised trials of VEGF antibodies in effective chemotherapy (FOLFOX) – 1st line

1st Line mCRC

Trial Therapy ORR PFS (mo) OS (mo)

NO16966

(n=700)

FOLFOX

+/- Beva

–38% vs. 38%

–8.6 vs. 9.4

n.s.

–

20.3 vs. 21.2

n.s.

(n=700) CAPOX

+/- Beva

–

38% vs. 38%

��

5.1 vs. 9.1

HR = 0.77

–

16.8 vs. 20.7

n.s.

ITACA

(n=376)

FOLFOX or

FOLFIRI

+/- Beva

–

48% vs. 49%

–

8.4 vs. 9.6

n.s.

–

20.6 vs. 20.6.6

n.s.

EORTC

requestFOLFIRI +/- Bev Such a study was regarded as un-ethical by pharma industry

�� sig. diff;. Sig; – no sig. diff

NO16966 PFS CTx +/- Bevacizumab : XELOX and FOLFOX subgroups

FOLFOX+placeboFOX+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

ma

te

XELOX+placeboXELOX+bevacizumab

FOLFOXFOLFOX+

Bev XELOXXELOX+Bev

N Pat 351 349 350 350

PFS mo 8.6 9.4 7.4 9.3

HR97.5% CI

0.890.73 - 1.08

0.770.63 – 0.94

p-value 0.19 0.0026

OS (mo) 20.3 21.2 19.2 21.4

HR97.5% CI

0.940.75 to 1.16

0.840.68 – 1.04

P-value n.s. n.s.

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35

Overall survival (months)

Over

all

su

rviv

al

esti

mate

No treatment n=253

No Avastin post PD n=531

Avastin post PD n=642

Post-progression therapy:

12.6 19.9 31.8

BRITE: Bevacizumab increases survival post first-progression?

Grothey, et al. JCO 2008PD = progressive disease

Hidden Biases in an Observational Study of BevacizumabBeyond Progression

- Ondansetron beyond progression -

Kopetz et al. JCO 2009

OS

es

tim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 3642 48

CT (n=410)BEV + CT (n=409)

9.8 mo 11.2 mo

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)

p=0.0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)

p=0.0211 (log-rank test)

Overall survival : Bevacizumab beyond PD in mCRC

23.9 – 11.2 = 12.7 mo

22.5 - 9.8 = 12.7 mo

2nd line (CTx ± Bev)1st line (CTx+Bev)

9.8 mo

11.2 mo

22.5 mo

∂ 1.4 mo

23.9 mo

Overall survival composite from 1st and 2nd line treatment

VEGF Inhibition in Second or Later Line Therapy

Second-line VEGFLast-line

multi VEGF TKI

TML 18147 E3200 VELOUR RAISE CORRECT

BEV in 1st line All pts No pts Yes / No All ptsAll pts

(+ EGFR,if KRAS wt)

2nd line Chemotherapy

FOLFIRI or FOLFOX

FOLFOX FOLFIRI FOLFIRI Last line BSC

VEGF inhibitor Bevacizumab Bevacizumab Aflibercept Ramucirumab Regorafenib

OS

11.2 v 9.8 mo

HR 0.81

P = .0062

12.9 v 10.8 mo

HR 0.75

P = .0011

13.5 v 12.1 mo

HR 0.82

P = .003

11.7 vs. 13.3 mo

HR 0.84

P = .022

6.4 vs. 5.0 mo

HR 0.77

P = .0052

Bennouna J, et al. Lancet Oncol. 2013;14(1):29-37. Giantonio BJ, et al. J Clin Oncol. 2007;25(12):1539-1544. Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506. Grothey A, et al. Lancet. 2013;381:303-312.

FOLFIRI vs. FOFOXIRI

Regimen N RR PFS OS Author

FOLFIRI 122 41% 6.9 16.7 Falcone

FOLFOXIRI 122 66% 9.9 23.6 JCO 2007

FOLFIRI+Bev 256 53% 9.7 25.8 Falcone

FOLFOXIRI+Bev 252 65% 12.2 29.8 NEJM 2015

Lancet Oncol 2015

• FOLFOXIRI more effective than FOLFIRI• Unroven role of bevacizumab

FOLFOXIRI in different molecular subgroups

Cremolini et al. Lancet Oncol 2015

ESMO Consensus 1st line

approach

mut mutmut mut

Bevacizumab efficacy in 1st line (IFL ± Bev) andanalysis of 1st line studies

Overall survival

HR 95% CI P-value

KRAS

wt

IFL ± Bev

N=1520.58 0.3-1.0 0.04

KRAS

mut

IFL ± Bev

N=780.69 0.4-1.3 0.26

Hurwitz et al. The Oncologist 2009 and 2013

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

Overall survival

KRAS wt KRAS mut

Kubicka et al. Ann Oncol 2014

OS

KRAS wt

N=314

KRAS mut

N=297

CTx 11.1 10.0

CTx + Bev 15.4 10.4

HR 0.69 0.92

P-value .0052 0.497

EGFR antibody 69% 8%

CORRECT: BSC +/- RegorafenibOverall survival

Grothey et al. Lancet Oncol 2013

FIRE 3 results - No survival benefit for VEGF in RAS mutant disease -

RAS wt(n=201)

RAS mutant(n=188)

FOLFIRI + Bevacizumab

FOLFIRI + Cetuximab

FOLFIRI + Bevacizumab

HR/Odds ratio

p

ORR

(95%-CI)56 %48 – 64

38.1 %28.5 – 48.6

50.5 %39.9 – 61.2

0.600.34-1.08

0.11

PFS

(95% CI)10.2 mo9.3 – 11.5

7.5 mo5.7 – 8.5

9.68.5 – 10.9

1.250.93-1.68

0.14

OS(95% CI)

25.0 mo23.0 – 28.1

20.2 mo16.4 – 23.4

20.617.1 – 26.3

1.050.77 – 1.44

0.75

Similar observations in TML and CORRECT studies. Survival of all pts benefit driven by KRASwt.

Stintzing et al. ESMO 2014

CALGB 40805 Overall Survival RAS wt vs RAS mt*

RAS wt RAS mt

ArmN

(Events)

Median†

(95% CI)

HR

(95% CI)

p

N

(Events)

Median†

(95% CI)

HR

(95% CI)

p

Chemo +

Bev

256

(178)

31.2

(26.9-34.3)0.9

(0.7, 1.1)

p=0.40

42

(33)

22.3

(15.3, 29.0)0.74

(0.4, 1.1)

p=0.21Chemo +

Cetux

270

(177)

32.0

(27.6-38.5)

53

(41)

28.7

(20.2, 34.7)

†Median, months *(NRAS, KRAS exon 3+4 NOT KRAS exon 2)

Evidence on Bevacizumab in 1st line

Unselected patients both RASwt and RASmut

� Cape or FU: higher RR, longer PFS, no sig. difference on OS

� Doublets: No improvement on RR, PFS or OS

� Both: Median OS around 20 months for doublets and

fluoropyrimidines alone

Selected patients

� RASwt value of Bev uncertain, may be effective

� RASmut uncertain, most likely no effect


mut mutmut mut

30

Better selection extended the OS benefitwith cetuximab + FOLFIRI

HR=0.69 (0.54–0.88)p=0.0024

∆ = 8.2 months

HR=0.796 (0.67–0.95)p=0.0093

HR=0.878 (0.77–1.00)p=0.0419

∆ = 3.5 months∆ = 1.3 months

Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019;Van Cutsem E, et al. J Clin Oncol 2015;33:692–700;

Cetuximab + FOLFIRI (n=178)

FOLFIRI (n=189)

0.0

0.2

0.4

0.6

0.8

1.0

Months5442 48186 12 24 30 36

28.4

20.2

0

Months

5442 48

23.5

20.0

0.0

0.2

0.4

0.6

0.8

1.0

180 6 12 24 30 36

Months5442 48

0.0

0.2

0.4

0.6

0.8

1.0

180 6 12 24 30 36

OS

esti

mate

19.9

18.6


FOLFIRI (n=599)


FOLFIRI (n=350)

RAS wt2KRAS exon 2 wt1ITT(unselected)1

Influence of KRAS and RAS mutational status on survivalRandomised 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.

FIRE 3: KRAS vs. RAS analysis

KRAS wt RAS wt

Cetuximab + CT

Bevacizumab + CT

P-valueCetuximab +

FOLFIRIBevacizumab +

FOLFIRIP-value

RRindependend read

67% 56% 0.016 72% 56% 0.003

PFS 10.0 mo 10.3 mo 0.547 10.3 mo 10.2 mo 0.77

0.75

1.0

0.50

0.25

12 24 36 48 60 72 months since start of treatment

199 201

No. at risk

147 147

79 82

46 34

23 11

7 1

0.0

Pro

ba

bil

ity

of

su

rviv

al

∆ = 8.1 months

FOLFIRI+Cetuximab 33.1 mo

FOLFIRI + Bevaciziumb

25.0 mo

HR 0.70 P<0.006

Overall Survival by Arm(All RAS Wild Type FOLFOX Patients)

ArmN

(Events)

Median

(95% CI)

HR

(95% CI)p

Chemo

+ Bev

192

(137)

29.0

(24.0-32.8) 0.86

(0.6-1.1)0.2

Chemo

+ Cetux

198

(129)

32.5

(26.1-40.4)

Lenz et al. ESMO 2014

Head to Head comparison Cetuximab ves Bevacizumab 1st line

1st Line mCRC RAS wt

Trial Doublet Biological OS HR P-value

FIRE 3

(n=400) FOLFIRI

Cetuximab 33.10.70 <0.006

Bevacizumab 25.0

PEAK

(n=170)FOLFOX

Panitumumab 36.90.76 0.15

Bevacizumab 28.9

CALGB 80405

(n=390)FOLFOX

Cetuxumab 32.50.86 0.2

Bevacizumab 29.0

• FIRE 3 and PEAK are in line with earlier randomised trials of doublet +/- EGFR or doublet +/- VEGF

• CALGB needs more analysis must be considered preliminary and in someaspects inconsistent

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.

Khattak et al. Clinical Colorectal Cancer 2015

Head to Head Comparison EGFR vs. VEGF inhibition1st line mCRC in all RAS wt

Objective Response rate Progression free survival Overall survival

Anti-EGFR Anti-EGFR Anti-EGFR

Heinemann, et al. ASCO 2014

Effect of Location on PFS and OS

FOLFIRI + Cet

FOLFIRI + Bev

3%*

44%

20%

77%

*tumors of the transversum were excluded from further analysis

33%

Presented by: Alan Vernook

Side N (Events)Median

(95% CI)HR(95% CI) p

Left 356 (280)31.4

(28.3-33.6)1.32

(1.05-1.65)0.01

Right 150 (121)24.2

(17.9-30.3)

Left

Right

Side N (Events)Median

(95% CI)

HR

(95% CI)p

Left 376 (270)36.0

(32.6-40.3)1.87

(1.48-2.32)<0.0001

Right 143 (121)16.7

(13.1-19.4)

CALGB 80405: OS by Sidedness KRAS exon 2 wt (prognostic)

Bevacizumab Cetuximab

Right

Left

CALGB 80405: Overall Survival by Sidedness and Biologic

in KRAS exon 2 wt

Presented by: Alan Vernook

31.4 (28.3-33.6)

36.0 (32.6-40.3)

24.2 (17.9-30.3)

16.7 (13.1-19.4)

HR 0.817 (0.69-0.96)

P=0.018

HR 1.269 (0.98-1.63)

P=0.065

Retrospective analyses of prognostic and predictive relevance of primary tumorlocation in patients with RAS–wild-type metastatic colorectal cancer in CRYSTAL

and FIRE-3

Teijpar et al. JAMAOncol submitted/in press

Right-sided primaries are more likely to have concomitant genetic features associated with poor outcomes

Presented By Michael Lee at 2016 ASCO Annual Meeting

Table 6: Field testing ESMO-MCBS v1.0: Colorectal Cancer

COLORECTAL CANCER

Medication Trial name Setting

Primar

y

outco

me

PFS

control PFS gain PFS HR

OS

control OS gain OS HR QoL Toxicity

ESM0-

MCBS ref

FOLFOX4 +/-panitumumab PRIME 1st line metastatic (Post

hoc KRAS, NRAS BRAF WT) PFS 7.9 mth 2.3 mth 0.72 (0.58-0.90) 20.2 mth 5.8 mth 0.78 (0.62-0.99) 4 [62]

Panitumumab + mFOLFOX6

vs bevacizumab

+mFOLFOX6

PEAK 1st line metastatic (KRAS-

WT) PFS NS 24.3 mth 9.9 mth 0.62 (0.44-0.89) 4* [103]

FOLFIRI +/- cetuximab CRYSTAL

1st line metastatic

stratified for KRAS-WT

(Post hoc KRAS, NRAS WT)

PFS 8.4 mth 3.0 mth 0.56 (0.41-0.76)

20.2 mth 8.2 mth 0.69 (0.54-0.88)

4 [65]

Cetuximab vs best

supportive care

Refractory metastatic KRAS-

WT OS 1.9 mth 1.8 mth 0.4 ( 0.30-0.54) 4.8 mth 4.7 mth 0.55 ( 0.41-0.740

4 [104]

FOLFOX4 +/-panitumumab PRIME 1st line metastatic KRAS-

WT PFS 8 mth 1.6 mth 0.80 (0.66-0.97) 19.4 mth 4.4 mth 0.83 (0.70-0.98)

3 [60, 61]

FOLFIRI +/- cetuximab CRYSTAL 1st line metastatic

stratified for KRAS-WT PFS 8.4 mth 1.5 mth 0.70 (0.56-0.87)

20 mth 3.5 mth 0.80 (0.67-0.95) 3 [63, 64]

ILF +/- bevacizumab 1st line metastatic OS 15.6 mth 4.7 mth 0.66 (0.54–0.81) 3 [105]

FOLFIRI +/- panitumumab 2nd line metastatic KRAS-

WT PFS 3.9 mth 2 mth 0.73 (0.59-0.90)

3 [106]

FOLFOX+/- bevacizumab vs

bevacizumab alone E3200

2nd line metastatic after

FOLFIRI OS 10.8 mth 2.1 mth 0.75 (0.63–0.89)

2 [107]

Panitumumab, vs best

supportive care

3rd line metastatic

stratified for KRAS PFS 7.3 wk 5 wk 0.45 (0.34-0.59)

2 [108]

FOLFIRI bevacizumab vs

FOLFOXIRI bevacizumab

1st line metastatic PFS 9.7 mth 2.4 mth 0.75 (0.62-0.90) NS 2 [109]

TAS-102 vs placebo CONCOURSE 3rd line or beyond

metastatic OS 5.3 mth 1.8 mth 0.68 (.058-0.81)

2 [110]

Regorafenib vs placebo CORRECT 3rd line metastatic OS 5 mth 1.4 mth 077 (0.64-0.94) 1 [111]

2nd line chemotherapy +/-

bevacizumab ML18147

2nd line beyond progression

on bevacizumab OS 9.6 mth 1.5 mth 0·81 (0·69–0·94)

1 [112]

FOLFIRI+/- aflibercept VELOUR 2nd line after oxaliplatin

based treatment OS 4.7 mth 2.2 mth 0.76 (0.66-0.87) 12 .1 mth 1.5 mth 0.82 (0.71–0.94)

1 [113]

FOLFIRI +/-Ramucirumab RAISE

2nd line metastatic after

bevacizumab, oxaliplatin,

fluoropyrimidine

OS

11.7 mth 1.6 mth 0.84 (0.73-0.97)

1 [114]

*unbalanced crossover

by g

uest o

n Ju

ne 1

6, 2

01

5h

ttp://an

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aded

from

EGFR all RAS wt

EGFR KRAS wt

VEGF in all lines

Magnitude of clinical benefitThe ESMO approach

deVries et al ESMO 2015, Cherny et al. Ann Oncol 2015

Future options

• Checkpoint inhibitors?

• Her2/neu targeted therapy?

Mutations per tumor

0 500 1000 1500 2000

Mismatch repair tumors

Mutagen Associated tumors

Sporadic Adult Solid Tumors

Pediatric Tumors

Liquid Tumors

Mutations per tumor

Mismatch-repair proficient colon cancers

Mismatch-repair deficient colon

cancers

RR 0%

RR 62%

RR 60%

Pembrolizumab in preatreated patients

Best Reduction in Target Lesion Size <br />in Patients With MSI-H

Presented By Michael Overman at 2016 ASCO Annual Meeting

RR 25.5%

PFS

5.3 mo

OS 17.1 mo

RR 33.3%

PFS

n.r.

OS n.r.

ResultsMSI-H

Checkmate142

Ch

an

ge

in t

arg

et

lesi

on

fro

m b

ase

lin

e (

%)

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

*3 patients are not shown: 122026 (IHC 2+,not yet assessed); 121011 (IHC 3+) and 121013 (IHC 3+) early clinical PDs.

Waterfall plot

(best % tumor shrinkage)

Spaghetti plot(tumor shrinkage trend)

Ch

an

ge

in t

arg

et

lesi

on

fro

m b

ase

lin

e (

%)

Trastuzumab/LapatinibResponses by HER2 IHC Score

RR 34%


mut mutmut mut

Consider left/right

Test for RAS / BRAF

Test for HER2/neu / MSI

*

*not supported by data

*** ##

#left sided RASwt EGFR

right sided?

chemotherapy and targetd agents in 1st line...

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