gustavo fernandes centro de oncologia-hospital...

Estrategias de tratamiento individualizadas para maximiz ar lasobrevida en CCR metastásico, actualización de la evidenci a

Gustavo FernandesCentro de Oncologia-Hospital Sírio-LibanêsUnidade Brasília

Disclosure

� I have received honoraria from: Roche, Amgen, Sanof iand Novartis during the last 2 years.

Bevacizumab 4

In the past 3 decades, advances in the treatment of mCRC have led to improved OS…

Median OS

Tim

e (m

onth

s)

BSC5-FU

30

20

10

0

Irinotecan 1

Capecitabine 2

Oxaliplatin 3

Cetuximab 5,6

1980s 1990s 2000s 2010

Panitumumab 7

Aflibercept 8

Regorafenib 9*

1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004; 3. Rothenberg, et al. JCO 20034. Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM 20097. Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012

Solving the puzzle of how to use the available agen ts effectively to treat mCRC is a key challenge

5-FU/LV Capecitabine Irinotecan

Oxaliplatin Bevacizumab

Panitumumab

Cetuximab

AfliberceptRegorafenib*

What have we learned?� The limits of what can be achieved with chemotherap y in mCRC appear

to have been reached – cure is uncommon

� A number of biological agents are now available for use in the treatment of mCRC – based on tumour biology and mechanism of ac tion, these agents can be expected to improve survival rather t han cure

� Maximising overall survival and maintaining quality of life are the primary goals for the majority of patients with mCR C who cannot be cured

Key question: what data do we have for biological a gents to indicate how they influence survival?

The OS benefit and approved uses of biological agents differ

Approved inData to show OS

benefitEU US

Bevacizumab1L, 2L, 1L+2L

1L, 2L, 1L+2L

Yes

Cetuximab* 1L, 2L, 3L 1L, 2L, 3L Yes

Panitumumab* 1L, 2L, 3L 3L Yes

Aflibercept 2L 2L Yes

Regorafenib‡ Not approved

3L+ Yes

*Approved for use only in patients with KRAS wild-type mCRC



benefit

Data to show OS benefit in

EU USKRAS WT

+ MT KRAS WT


1L, 2L, 1L+2L

Yes Yes Yes

Cetuximab* 1L, 2L, 3L 1L, 2L, 3L Yes Yes Yes

Panitumumab* 1L, 2L, 3L 3L Yes No Yes

Aflibercept 2L 2L Yes Yes No


3L+ Yes Yes Yes




benefit

Data to show OS benefit in

Data to show OS benefit combined with

EU USKRAS WT

+ MT KRAS WTOxali-based

Irino-based


1L, 2L, 1L+2L

Yes Yes Yes Yes Yes

Cetuximab* 1L, 2L, 3L 1L, 2L, 3L Yes Yes Yes No Yes

Panitumumab* 1L, 2L, 3L 3L Yes No Yes Yes No

Aflibercept 2L 2L Yes Yes No No Yes


3L+ Yes Yes Yes No No


Patients with unresectable metastases: largest patient group

� Unresectable liver metastases:

� R0 resection not possible 1

� Large metastases 2

� Poorly located metastases 1,2

� Multinodular disease 1,2

� (Unresectable) extrahepaticmetastases 1–4

� Insufficient remnant liver 1,4

� Bilobar metastases 3UnresectableBorderline resectableResectable

70%

20%

10%

1. Adam, et al. Oncologist 2012; 2. Adam, et al. Su rg Oncol 20013. Adam. Eur J Cancer 2004; 4. Adam, et al. Ann Onco l 2003

Patients with unresectable metastases: OS is the primary treatment goal

Resection

Overall survival / long-term disease control

Treatment strategy

Requiredoutcome

Curative surgery

10% 20% 70%

ClassificationUpfront

resectable Borderline resectable Unresectable

CT ±biologic

CT ±biologic

≈12%1≈8%1

Relapse14%2

4% 96%1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. A nn Surg 2007

What data are available to support selection of first-line therapy?

1st line

3rd line

FU FU + BevOptional 1st line

Oxaliplatin-based 1st line Irinotecan-based 1st lin e Chemo-triplet

4thline

Regorafenib*

2nd line

FU/Ox FU/Ox/IriFU/Ox + BevFOLFOX +Pan or Cet

(FOLF)IRI+ Pan/Cet

FU/Iri +Bev

Fu/Iri Pan/Cet ± Iri or FU/Bev

Pan/Cet ± Iri FU+Bev

FOLFIRI +Aflibercept

Regorafenib*

FU/Iri +Cet

FU/IriFU/Iri +

Bev

FU/Ox FOLFOX + Cet (Pan)

Pan/Cet ± Iri FU + Bev

Regorafenib*

Regorafenib* Regorafenib*

FU/Ox+Bev

Schmoll, et al. Ann Oncol 2012

In patients with unselected ( KRAS WT and MT) mCRC , OS data indicate that bevacizumab is a first-line option

NO169662

OS PFS OS PFS

19.921.3

15.6

20.3

6.2

10.69.4

HR=0.89p=0.0769

HR=0.54p<0.001

HR=0.66p<0.001

HR=0.83p=0.0023

1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008

8.0

All data based on prospective analyses

Med

ian

(mon

ths)

30

25

20

15

10

5

0

AVF2107g1

Both bevacizumab and EGFR inhibitors have shown efficacy when used first line in KRAS WT mCRC

OS PFS OS PFS OS PFS OS PFS

17.6

27.7

18.5

22.8

20.0

23.5

22.0

20.1

7.4

13.5

8.49.

9

7.28.

3

8.7

7.9

HR=0.86p=0.39

HR=1.14p=0.48

HR=1.07p=0.66

OS PFS OS PFS

HR=1.04p=0.67

HR=0.96p=0.60

HR=0.88p=0.17

17.9

17.0

8.6

8.6

19.7

23.9

8.610.0

1. Hurwitz, et al. Oncologist 2009; 2. Van Cutsem, et al. JCO 2011 3. Bokemeyer, et al. Ann Oncol 2011; 4. Tveit, et al . JCO 2012 5. Maughan, et al. Lancet 2011; 6. Douillard, et al . ASCO 2011

PRIME6CRYSTAL2*AVF2107g1* OPUS3* NORDIC VII4‡ COIN5‡

HR=0.58p=0.04

HR=0.44p<0.0001

HR=0.70p=0.0012 HR=0.57

p=0.0064

HR=0.80p=0.01

HR=0.80p=0.0093

*Data based on retrospective analyses‡Data obtained following protocol amendmentNR = not reported

Med

ian

(mon

ths)

30

25

20

15

10

5

0

Cross-trial safety summary of biological agents in mCRC *

AEs

Bevacizumab 1 + + + + + + + – – (+) – –

Cetuximab 2 – – – – – – + – + + + –

Panitumumab 3 – – – – – – – + + (+) + –

Aflibercept 4 ++ ++ + + + + ++ + – – – –

Regorafenib 5,6‡ – + + + + – – ++ ++ – – ++

– no clinically relevant increase+ clinically relevant increase++ clinically relevant increase and incidence diffe rent to other agents in class

1. Avastin SmPC 2013; 2. Erbitux SmPC 2013; 3. Vectibix SmPC 20134. Zaltrap SmPC 2013; 5. Stivarga SmPC 2013; 6. Stivarg a PI 2013*Based on information available in the SmPC

New trials in first line from ASCO 2013

AVEX

Untreated elderly patients with

mCRC(age ≥70 years)

(n=280)

Capecitabine

Bevacizumab+ Xeloda

PD

PD

R

» Phase III trial

» Primary endpoint: PFS

» Secondary endpoints: ORR, DOR, time to response, OS , safety, laboratory parameters, vital signs

» Sponsor: Roche

AVEX: Results

AVEX: Conclusions

� The addition of bevacizumab to capecitabinewas associated with significant improvements in PFS in the overall elderly mCRC population and within age subgroups

� The safety profile of bevacizumab + capecitabine was consistent across age groups.

PRIME

Previously untreated

mCRC

n=1,183

Panitumumab + FOLFOX4

(n=593)

(n=325 KRAS WT)

FOLFOX4

(n=590)

(n=331 KRAS WT)

R

PRIME: OS and PFS based on KRAS/NRASand BRAF analysis

Panitumumab+ FOLFOX4 FOLFOX4 HR; p value

RAS WT (n) (259) (253)

Median OS (months) 26.0 20.2 0.78; 0.04

Median PFS (months) 10.1 7.9 0.72; <0.01

RAS MT (n) (272) (276)

Median OS (months) 15.6 19.2 1.25; 0.04

Median PFS (months) 7.3 8.7 1.31; 0.01

RAS and BRAF WT (n) (228) (218)

Median OS (months) 28.3 20.9 0.74; 0.02

Median PFS (months) 10.8 9.2 0.68; <0.01

BRAF MT (n) (24) (29)

Median OS (months) 10.5 9.2 0.90; 0.76

Median PFS (months) 6.1 5.4 0.58; 0.12

Oliner, et al. ASCO 2013

WT = KRAS and NRAS WT in exons 2, 3 and 4; MT = MT in any of KRAS or NRAS exons 2, 3 or 4

PRIME: author’s conclusions

• A statistically significant OS benefit was observed in patients with RAS WT mCRC treated with panitumumab + FOLFOX4 vs FOLFOX4

• Panitumumab is unlikely to benefit patients with any RAS mutations

• BRAF mutation had no predictive value in this analysis

Oliner, et al. ASCO 2013

FIRE-3

FIRE-3

• Primary endpoint: ORR

• Secondary endpoints: PFS, OS, secondary R0 resectio n rate, safety

• Sponsor: University of Munich (Merck supported)

Untreated Untreated Untreated Untreated

KRASKRASKRASKRAS WT WT WT WT

mCRCmCRCmCRCmCRC

(n=750)(n=750)(n=750)(n=750)

BevacizumabBevacizumabBevacizumabBevacizumab

+ FOLFIRI+ FOLFIRI+ FOLFIRI+ FOLFIRI

CetuximabCetuximabCetuximabCetuximab

+ FOLFIRI+ FOLFIRI+ FOLFIRI+ FOLFIRI

RRRR

Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic

colorectal cancer: German AIO study KRK-0306 (FIRE-3).

Internal Use Only

FIRE-3: ORRCetuximab + FOLFIRI Avastin + FOLFIRI

ITT population (n=592) (n=297) (n=295)

ORR (95% CI), % 62.0 (56.2–67.5) 58.0 (52.1–63.7)

Odds ratio 1.18 (0.85-1.64)

p-value ǂ 0.183

CR 4.4 1.4

PR 57.6 56.6

SD 17.5 28.8

PD 7.1 5.4

Not evaluable 13.1 7.8

*Fisher’s exact test (one-sided)1. Heinemann, et al. ASCO 2013

•With a p value of 0.183, the futility of the primar y analysis was substantial 1

•The main reason for missing the primary endpoint wa s the higher than expected ORR in the Avastin arm

Internal Use Only

FIRE-3: PFS

Heinemann, et al. ASCO 2013

Patients at risk297 100 19 10 5 3295 99 15 6 4

PF

S e

stim

ate

1.0

0.75

0.50

0.25

0

Time (months)0 12 24 36 48 60 72

Cetuximab + FOLFIRI Avastin + FOLFIRI

Events, n/N (%) 250/297 (84.2) 242/295 (82.0)

Median, months 10.0 10.3

HR (95% CI)p-value

1.06 (0.88–1.26)p=0.547

10.0 10.3

Median PFS was similar between treatment arms

Internal Use Only

The separation of OS curves observed at approximate ly 24 months is highly unlikely to be attributable to the first-line treatment effect of ~5 months of biological treatment


The lack of a significant increase in PFS with cetu ximab-based therapy suggests that later-line therapies have been influential on the OS findings

Patients at risk297 218 111 60 29 9295 214 111 47 18 2

OS

estim

ate

1.0

0.75

0.50

0.25

0

Time (months)0 12 24 36 48 60 72

Cetuximab + FOLFIRI Avastin + FOLFIRI

Events, n/N (%) 158/297 (53.2) 185/295 (62.7)

Median, months 28.7 25.0

HR (95% CI)p-value

0.77 (0.62–0.96)p=0.017

28.725.0

Median duration of treatment~5 months (all 3 agents)

Median PFS~10.0 months

Grade ≥3 adverse events of special interest to Avastin


Significant differences in any-grade toxicity: *p<0.001; ǂp=0.046; §p=0.006

Adverse event, % Cetuximab + FOLFIRI (n=297)Avastin + FOLFIRI

(n=295) p-value (grade ≥3)

Any-grade Grade ≥3 Any-grade Grade ≥3

Hypertension 21.2* 6.4 38.3* 6.8 0.870

Proteinuria 2.7 0 2.0 0.3 0.498

Bleeding 21.2ǂ 0.7 28.5ǂ 0.3 >0.999

Abscesses/fistulae 1.4§ 0.3 5.4§ 1.0 0.372

GI perforation 0.3 0.3 0.7 0.7 0.623

Thrombosis (any) 9.4 6.1 11.5 6.1 >0.999

Thromboembolic event 7.4 5.1 7.1 5.8 0.720

Wound healing complications

2.0 0.3 2.7 1.4 0.216


Avastin did not lead to any significant difference in grade ≥3 adverse events of special interest to anti-VEGF treatment

Grade ≥3 adverse events of special interest to cetuximab


Adverse event, % Cetuximab + FOLFIRI (n=297)Avastin + FOLFIRI

(n=295) p-value (grade ≥3)

Any-grade Grade ≥3 Any-grade Grade ≥3

Acneiform exanthema 77.4* 16.8 7.8* 0.0 <0.0001

Desquamation 35.4* 6.7 11.5* 0.7 0.0001

Paronychia 37.4* 5.7 9.2* 0.0 <0.0001

Infusion-related allergic reaction

7.7* 4.0 0.0* 0.0 0.0004

Hypocalcaemia 27.6‡ 4.0 15.3‡ 2.4 0.351

Hypomagnesaemia 63.3* 4.4 39.7* 0.7 0.007

Significant differences in any-grade toxicity: *p<0.0001; ǂp=0.0003


Cetuximab resulted in significantly increased grade ≥3 adverse events of special interest to anti-EGFR therapy

FIRE-3: Evaluation of ORR

31

ORR

FOLFIRI + Cetuximab

%(95% CI)

FOLFIRI + Bevacizumab

%(95% CI)

Odds ratio p

ITTn= 592

62,0(56,2 – 67,5)

58(52,1 – 63,7)

1,18(0,85 – 1,64)

0,183

Assessablefor response

n= 52672,2

(66,2 – 77,6)63,1

(57,1 – 68,9)1,52

(1,05 – 2,19)0,017

p = Fisher’s exact test (one-sided)

FIRE-3: Results

KRAS-WTITT

Cetuximab+

FOLFIRI

Bevacizumab+

FOLFIRIHR p value

ORR 62% 57%

mPFS 10,3m 10,4m 1,04 0,69

mOS 28,8m 25,0m 0,77(95%CI 0,620-0,953)

0,0164

Sixty daymortality

1,01% 2,71%

FIRE-3: Conclusions

� Negative trial

� ORR was comparable between arms in the ITT analysis, but favored arm A in assessable pts

� Significantly superior OS was observed in KRAS -WT patients receiving cetuximab plus FOLFIRI as first-line treatment????

CALGB 80405

UntreatedKRAS WT mCRC(n=1,500)

Bevacizumab+ FOLFOXor FOLFIRI

Cetuximab+ FOLFOXor FOLFIRI

PD

PD

R

»Phase III trial

»Primary endpoint: OS

»Secondary endpoints: ORR, PFS, TTF, DOR, safety

Summary: 1L treatment decisions for patients with mCRC are complex

� The complexity of treatment decision-making is base d on patient characteristics as well as treatment availability

� Both bevacizumab, cetuximab and now panitumumab, are available and effective for first-line treatmen t of patients with unresectable mCRC

� What do you prefer?

Factors that affect treatment decisions1st line 2nd line

Treatment goal Pretreatment

Disease-related factorsInformation from pretreatment

(including reported toxicity)

Patient-related factors Disease-related factors

Biomarkers Patient-related factors

Anticipated toxicity Treatment goal

Biomarkers

Second -line treatment options: even greater complexity

1st line

3rd line



4th line

Regorafenib*

2nd line


(FOLF)IRI+ Pan/Cet

FU/Iri +Bev




Regorafenib*

FU/Iri +Cet

FU/IriFU/Iri +

Bev



Regorafenib*


FU/Ox+Bev

*Not approved by the EMA or for use in the Czech Re public Schmoll, et al. Ann Oncol 2012

VEGF inhibitors improve OS when combined with chemotherapy in 2L

E32001

(no prior bevacizumab)

Med

ian

(mon

ths)

20 ML181472

(prior bevacizumab)VELOUR3

(both prior bevacizumab and no prior bevacizumab)

OS PFS OS PFS OS PFS

10.8

6.9

4.7

7.3

12.9

9.811.2

4.1

5.7

12.113.5

1. Giantonio, et al. JCO 2007; 2. Bennouna, et al. Lancet Oncol 2013 3. Van Cutsem, et al. JCO 2012

4.7

HR=0.75p=0.0011

HR=0.61p<0.0001

HR=0.81p=0.0062

HR=0.68p<0.0001

HR=0.82p=0.0032

HR=0.76p<0.0001

All data based on prospective analyses

15

10

0

5

Bevacizumab and aflibercept have different toxicity profiles, which may influence treatment choice

E32001 (KRAS WT + MT) ML181472 (KRAS WT + MT) VELOUR3 (KRAS WT + MT)

Grade 3/4 AE, %

Bevacizumab+ FOLFOX4

(n=287)FOLFOX4(n=285)

Bevacizumab+ CT

(n=401)CT

(n=409)

Aflib+ FOLFIRI

(n=611)

Plac+ FOLFIRI

(n=605)

Diarrhoea – – 10 8 19.3 7.8

Neutropenia – – 16 13 36.7 29.5

Hypertension 6.2 1.8 2 1 19.3 1.5

Bleeding 3.4 0.4 2 <1 2.9 1.7

Proteinuria 0.7 0 – – 7.9 1.2

GI perforation – – 2 <1 0.5 0.3

ATE3.4§§§§ 2.5§§§§

5 3 1.8 0.5

VTE <1 1 7.9 6.3

Stomatitis/mucositis – – 13.7¶ 5¶

Hand-foot syndrome – – 2.8 0.5

*Pulmonary embolism; ‡Grade 3–5 AEs; §§§§Thromboembolism¶Stomatitis & ulceration

1. Giantonio, et al. JCO 2007; 2. Bennouna, et al. Lancet Oncol 20133. Van Cutsem, et al. JCO 2012

Is there a rationale to continue VEGF inhibition beyond disease progression?� Preclinical hypothesis: VEGF is expressed throughou t the

tumour lifecycle– tumours continually require VEGF to recruit new vas culature 1

– VEGF continues to be expressed throughout tumour progression, even as secondary pathways emerge 2–5

� Clinical hypothesis: in the observational studies B RITE and ARIES, OS was significantly improved with bevacizum ab beyond progression vs no bevacizumab beyond progression 6,7

1. Inoue, et al. Cancer Cell 2002; 2. Kim, et al. N ature 19933. Folkman. In: DeVita, Hellman, Rosenberg, eds. Ca ncer: Principles & Practice of Oncology.

Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins;20054. Mesiano, et al. Am J Pathol 1998; 5. Melnyk, et a l. J Urol 1999

6. Grothey, et al. JCO 2008; 7. Cohn, et al. WCGC 2 010

ML18147: the first reported phase III trial to inve stigate continuation of biological therapy after progressio n

Bevacizumab + standard 1L chemo (either oxaliplatin or

irinotecan-based)(n=820)

Standard 2L chemo (oxaliplatinor irinotecan-based) until PD

Bevacizumab (2.5mg/kg/week) + standard 2L chemo (oxaliplatinor irinotecan-based) until PD

PD

Key eligibility criteria � Histologically confirmed diagnosis of metastatic co lorectal cancer� ≥3 months of standard 1L bevacizumab plus chemotherapy� PD <3 months after last bevacizumab administration

� Phase III� Primary endpoint: OS from randomisation� Secondary endpoints: PFS, ORR, OS from start of 1L therapy

CT switch:Oxaliplatin �� IrinotecanIrinotecan �� Oxaliplatin

R

Arnold, et al. ASCO 2012; Bennouna, et al. Lancet O ncol 2013PD = disease progression

ML18147 demonstrated that bevacizumab is effective b eyond progression in unselected patients ( KRAS WT and MT mCRC)

OS

est

imat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 38 42 48

Bevacizumab + chemo (n=409)Chemo (n=410)

9.8 11.2

OS*

PF

S e

stim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 38 42

4.1 5.7

PFS*


HR=0.81(95% CI: 0.69–0.94)p=0.0062

HR=0.68(95% CI: 0.59–0.78)p<0.0001

*From randomisation Arnold, et al. ASCO 2012 Bennouna, et al. Lancet O ncol 2013

Outcomes were comparable with those with aflibercept in unselected patients ( KRAS WT and MT)

PFS OS

Median (months) HR P value

Median (months) HR P value

Bevacizumab ML18147 1 Continuation of BEV

Bevacizumab + chemotherapy

5.70.68 <0.0001

11.20.81 0.0062

Chemotherapy 4.1 9.8

Aflibercept VELOUR 2 Prior BEV

Aflibercept+ FOLFIRI

6.7 NR

Analysis showed no difference

compared to patients who

did not receive prior

BEV

12.5 NR

Analysis showed no difference

compared to patients who

did not receive prior

BEV

Placebo + FOLFIRI

3.9 NR 11.7 NR

1. Bennouna, et al. Lancet Oncol 2013; 2. Allegra, e t al. ASCO 2012NR = not reported

Second -line treatment options: bevacizumab or panitumumab?

1st line

3rd line



4th line

Regorafenib*

2nd line


(FOLF)IRI+ Pan/Cet

FU/Iri +Bev




Regorafenib*

FU/Iri +Cet

FU/IriFU/Iri +

Bev



Regorafenib*


FU/Ox+Bev

*Not approved by the EMA or for use in the Czech Re public Schmoll, et al. Ann Oncol 2012

ML18147: subgroup analysis shows that bevacizumab ha s OS benefit when continued beyond progression in KRAS WT mCRC

Van Cutsem, et al. WCGC 2012*From randomisation (exploratory analysis)

11.1 15.4

HR: 0.6995% CI: 0.53–0.90p=0.0052


ML181471.0

0.8

0.6

0.4

0.2

0

OS

est

imat

e*

0 6 12 18 24 30 36 42 48

Time (months)

In patients with KRAS WT mCRC, only bevacizumab has shown significant OS benefit 2L in phase III trials

NR2.8

4.0

11.1

15.4

11.610.9

4.5

6.4

HR=1.28p=0.1755

HR=0.77p=0.0954

HR=0.92p=0.37

1. Giantonio, et al. JCO 2007; 2. Van Cutsem, et al . WCGC 2012; 3. Langer, et al. ESMO 2008 4. Sobrero, et al. ASCO GI 2012; 5. Van Cutsem, et a l. JCO 2012

NR OS PFS

12.5

14.5

4.9

6.7

HR=0.69p=0.0052

HR=0.61p<0.0001

HR=0.82p=0.0023

EPIC3E32001 Study 181 4‡ML181472* VELOUR5

OS PFS OS PFS

*Exploratory analysis‡Retrospective analysis

20

15

10

5

0

Med

ian

(mon

ths)

Summary: complexity of treatment selection continues in the second -line setting� Second-line treatment selection shows further compl exity: not

only patient characteristics and treatment options need to be considered, but also use and outcome of first-line therapy

� Many options are available for use second line

� The available options have similar efficacy, but th eir toxicity differs

� Anti-VEGF agents have demonstrated OS benefit secon d-line, and continuing treatment after progression is there fore an option

Third and later lines of therapy: wide choice of biological agents

1st line

3rd line



4th line

Regorafenib*

2nd line

FU/Ox FU/Ox/IriFU/Ox+BevFOLFOX +Pan or Cet

(FOLF)IRI+ Pan/Cet

FU/Iri +Bev




Regorafenib*

FU/Iri +Cet

FU/IriFU/Iri +

Bev



Regorafenib*


FU/Ox+Bev

Schmoll, et al. Ann Oncol 2012

Regorafenib is the only option available to unselect ed patients ( KRAS WT and MT) beyond second line

*Not approved by the EMA or for use in the Czech Re public‡27% and 25% of pts had 1–2 prior therapies, 25% and 28% of pts had 3 prior therapies and 49% and 47% of pts had ≥4 prior therapies in the regorafenib and placebo arm s, respectively: §§§§Data reported only for KRAS WT and KRAS MT disease separately

1. Jonker, et al. NEJM 2007; 2. Amado, et al. JCO 2 008 3. Grothey, et al. Lancet 2012

Med

ian

(mon

ths)

OS PFSNR§

6.4 8.08.

9

5.0

1.9 1.7

HR=0.77p=0.0052

6.1

1.9

HR=0.77p=0.005

HR=0.68p<0.001

OS PFS

4.6

1.8

15

HR=0.49p<0.0001

Unselected ( KRAS WT and MT)

CORRECT3‡CO.171 Study 408 2

10

5

0

EGFR inhibitors and regorafenib are options for pati ents with KRAS WT disease in third or later lines

*Not approved by the EMA or for use in the Czech Re publicNR = not reported; ‡Retrospective analysis; §27% and 25% of pts had 1–2 prior therapies, 25% and 28% of pts had 3 prior therapies and 49% and 47% of pts had ≥4 prior therapies in the regorafenib and placebo ar ms, respectively

CORRECT4§CO.171‡ Study 408 2 ‡

OS PFS

7

8.08.

9

HR=0.65p=NR

HR=0.48p=NR5

2 2

OS PFS

8.1

8.08.

9

HR=0.67p=NR

7.6

2.81.7

OS PFS

9.5

8.0

4.8 3.7

1.9

KRAS WT

HR=0.45p<0.0001

HR=0.55p<0.001

HR=0.40p<0.001

1. Jonker, et al. NEJM 2007; 2. Amado, et al. JCO 2 008 3. Grothey, et al. Lancet 2012; 4. Van Cutsem, et a l. ASCO 2012

Med

ian

(mon

ths)

OS PFSNR

6.4 8.08.

9

5.0

1.9 1.7

HR=0.77p=0.0052

6.1

1.9

HR=0.77p=0.005

HR=0.68p<0.001

OS PFS

4.6

1.8

15

HR=0.49p<0.0001

Unselected ( KRAS WT and MT)

CORRECT3§CO.171 Study 408 2

10

5

0

Med

ian

(mon

ths)

15

10

5

0

The magnitude of benefit of EGFR inhibitors is grea test in the 3L setting in patients with KRAS WT mCRC

CR

YS

TA

L5

CO

IN3

PR

IME

4

NO

RD

IC V

II2

CO

.179

Stu

dy 4

088

N01

471

1-H

R

1L 2L 3L(single agent)

Adjuvant

0.7

0.5

0.3

0.2

–0.1

–0.2

–0.3

1817

PIC

CO

LO6

0.6

0.4

0.1

0

CetuximabPanitumumab

1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. JCO 2010; 5. Van Cutsem, et al . JCO 2011; 6. Seymour, et al. ASCO 20117. Sobrero, et al. ASCO GI 2012; 8. Karapetis, et al . NEJM 2008; 9. Amado, et al. JCO 2008

FavoursEGFR inhibitor

Favourscontrol

But only if bevacizumab is used first line

Bevacizumab + FOLFOX Bevacizumab + FOLFOX

Unresectable diseaseKRAS wild-type

PD1 PD1

Cetuximab + FOLFIRICetuximab + FOLFIRIBevacizumab + FOLFIRI

PD2 PD2

PD3 PD3

Cetuximab/panitumumab + BSCCetuximab/panitumumab + BSC Regorafenib* + BSC

3 effectivetreatment lines

Regorafenib* + BSC


First line

Second line

Third line

Fourth line

Biological therapies are available for fourth line

Con

tinuu

m o

f car

eC

ontin

uum

of c

are

No OS data to support 2L EGFR inhibitor use for

KRAS WT disease

No rationale to switch to aflibercept

Mandatory induction

→maintenance strategy to

minimise toxicity from oxaliplatin

PD1

PD2

PD3

First line

Second line

Third line

Fourth line

Bevacizumab + FOLFOX

What is the impact of using FOLFOX first line?

Bevacizumab + FOLFIRIEGFR inhibitors

have greatest efficacy in later lines

Cetuximab/panitumumab + BSCCetuximab/panitumumab + BSC Regorafenib* has efficacy when all other therapies

have been administered

Regorafenib* + BSC


Unresectable diseaseKRAS wild-type

Rationalising the complexity of treatment selection with TML

1st line

3rd line

FU FU + BevOptional 1st line (group 3 only)


4th line

Regorafenib*

2nd line

FU/Ox FU/Ox/IriFU/Ox+BevFOLFOX +Pan or Cet

FOLFIRI+ Pan/Cet

FU/Iri +Bev

Fu/IriPan/Cet ± Iri

or FU/Bev



Regorafenib*

FU/Iri +Cet

FU/Iri FU/Iri + Bev

FU/OxFOLFOX + Cet

(Pan)


Regorafenib*

Regorafenib Regorafenib*

FU/Ox+Bev

FU + Bev


Regorafenib*

FOLFOX + Cet (Pan)

TMLChemo A + Bev

PD

Chemo B* + Bev

PD

Anti-EGFR

PD

Regorafenib*Schmoll, et al. Ann Oncol 2012

FU/Ox+Bev

PD >3 months ǂ

(~90% of patients)

Bevacizumab + Chemo A* 1‒3First line

KRAS WT PD

PD

KRAS MT

Bevacizumab + Chemo B* 3Second line

Regorafenib §EGFR inhibitor 4Third line

Regorafenib §Fourth line

1.Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2 0083. Bennouna, et al. Lancet Oncol 2013

4. Karapetis, et al. NEJM 2008

*Clinical evidence suggests oxaliplatin or irinoteca n-based chemotherapy; ǂand if no significant bevacizumab-related toxicity;if PD is <3 months, therapy choice should be based on clinicaljudgement as evidence in this clinical setting is n ot yet established§Not approved by the EMA or for use in the Czech Rep ublic

Continuing bevacizumab after first progression is a rational approach regardless of KRAS status and first-line chemotherapy choice

Patient with unresectable mCRC

Conclusions� Bevacizumab has OS benefit in 1L, 2L and when contin ued

beyond progression after 1L therapy both in an unse lected population and in KRAS wild-type mCRC

� EGFR inhibitors have benefit in mCRC and this is see ms to be greatest in later lines

� Aflibercept has efficacy when used second line in un selected patients that failed first line oxaliplatin. Seems to be usefull in patients who had early progression.

� Regorafenib* can provide some benefit in third or f irst line.

� We have to move foreword….

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