1 o n c o l o together for y loncologia insieme per l*aquila g bruera, d di giacomo & e...

1

www.cinbo.org

O n c o l oTogether for y

L’Oncologia

insieme per

L*Aquila

G Bruera, D Di Giacomo

& E Ricevuto

Medical Oncology

Department Experimental Medicine

University of L’Aquila

Mediterranean School of OncologyMediterranean School of OncologyChieti, april 21st 2010

COLORECTAL CANCERCOLORECTAL CANCERRound Table

TOWARD A PERSONALIZED THERAPY

Economic Implications of k-ras testing

2

K-ras genotype in Colorectal CancerK-ras genotype in Colorectal Cancer

Structural alteration Point mutations Prevalence of mutations 40% Hot-spot sites 34, 35, 37, 38 Functional relevance Gain of function Diagnostic strategy Direct Sequencing

Scanning for known mutations

Clinical implications Predictive anti-EGFR anti-VEGF

Prognostic in metastatic disease

3

SequencingSequencingDirect sequencingDirect sequencingPyrosequencingPyrosequencing

ScanningScanning Unknown mutationsUnknown mutations Known mutationsKnown mutationsSNap-shotSNap-shotReal-time PCRReal-time PCR

k-ras Mutations Detection Molecular diagnostic strategies

4

Cod.13 Cod.12Cod.12 Cod.13

senso antisenso

KRAS 29.09

KRAS 26.09

Cod.12 Cod.13 Cod.13 Cod.12

senso antisenso

5

K-ras testingCosts of genetic analysis

Direct Sequencing ~ 26 E/sample

SNaPshot ~ 26 E/sample

6

MCRC I line treatment: activity and efficacy

ORR(%)

PFS(months)

OS(months)

Mono ≤ 20 5 ≤ 14

Doublet 20.0-47.0 5.9-9.0 15.1-21.5

Triplet 39.0-66.0 8.3-10.6 20.3-26.1

Poker-Bev 82 12 28

Bruera and Ricevuto, Jan’10

7

Cetuximab in MCRC according to k-ras genotypeCetuximab + Irinotecan/5-FU/FA: Efficacy (Van Cutsem et al, NEJM 2008)

ITT KRAS wt KRAS mtParameters FOLFIRI

N. 599

Cetuximab+FOLFIRIN. 599

FOLFIRIN. 176


FOLFIRIN. 87


Overall response (%)CRPRSD

0.33847

0.54637

04344

15831

04046

03647

ORR (%) (C.I. 95%)

39 (35-43) 47 (43-51) 43 (36-51) 59 (52-67) 40 (30-51) 36 (27-46)

p-value 0.004 0.003 0.46

DCR (%) 85 84 87 90 86 83

Median PFS, months(C.I. 95%)

8.0(7.6-9.0)

8.9(8.0-9.5)

8.7(7.4-9.9)

9.9(8.7-14.6)

8.1(7.5-9.4)

7.6(6.7-9.4)

HR (C.I. 95%)p-value

0.85 (0.72-0.99)0.048

0.68 (0.50-0.94)0.02

1.07 (0.71-1.61)0.75

Median OS, months(C.I. 95%)

18.6(16.6-19.8)

19.9(18.5-21.3)

21 (19.2-25.7)

24.9 (22.2-27.8)

17.7(14.4-20.6)

17.5(15.6-20.2)

HR (C.I. 95%)p-value

0.93 (0.81-1.07)0.31

0.84 (0.64-1.11)0.22

1.03 (0.74-1.44)0.85

8

Cetuximab + Oxaliplatino/5-FU/FA: Efficacy (Bokemeyer et al, JCO 2009)

ITT KRAS wt KRAS mtParameters FOLFOX-4

N. 168

Cetuximab+FOLFOX-4N. 169

FOLFOX-4N. 73

Cetuximab+FOLFOx-4N. 61

FOLFOX-4N. 47

Cetuximab+FOLFOX-4N. 52

Overall response (%)CRPRSD

0.63545

14440

13641

35731

44536

03352

ORR (%) 36 46 37 61 49 33

p-value 0.064 0.011 0.106

DCR (%) 81 85 78 92 85 85

Median PFS, months(C.I. 95%)

7.2(6.0-7.8)

7.2(5.6-7.7)

7.2(5.6-7.4)

7.7(7.1-12)

8.6(5.5-9.5)

5.5(4-7.4)

HR (C.I. 95%) 0.93 (0.71-1.23) 0.57 (0.36-0.91) 1.83 (1.10-3.06)

p-value 0.617 0.016 0.019

Cetuximab in MCRC according to k-ras genotype

9

Efficacy of Panitumumab in KRAS wt patients (Phase III)

PRIME trial (I Line) (Douillard et al, ESMO 2009)

(II Line)(Peeters et al, ESMO 2009)

FOLFOX-4N.590

Panitumumab+FOLFOX-4N. 593

FOLFIRIN. 595

Panitumumab+FOLFIRIN. 591

ORR (%) 48 55 10 35

p-value 0.003 n.v.

Median PFS(months)

8.0 9.6 3.9 5.9

HR 0.80 (0.66-0.97) 0.73 (0.593-0.903)

p-value 0.0234 0.004

Median OS(months)

n.v. n.v. 12.5 14.5

HR n.v. 0.85 (0.702-1.039)

p-value n.v. 0.115

Panitumumab in MCRC according to k-ras genotype

10Ince et al, PNAS ‘05

Bevacizumabin MCRCaccording tokras genotype

11

Efficacyvariable

Wild-type Mutant

IFL+Placebo(n. 67)

IFL+BV(n.85)

p-valueHR

(95% CI)

IFL+Placebo(n. 34)

IFL+BV(n. 44)

p-valueHR

(95% CI)

Median OS(months)

17,6 27,7 0.040.58

(0.3-1.0)

13,6 19,9 0.260.69

(0.4-1.3)

Median PFS(months)

7,4 13,5 0.00010.44

(0.3-0.7)

5,5 9,3 0.00080.41

(0.2-0.7)

ORRn. (%)

25 (37,3)

51 (60)

0.006 14(41,2)

19(43,2)

0.86

Hurwitz HI, Ince W et al, The Oncologist 2009; 14:22-28

Bevacizumab in MCRC according to k-ras genotype

12

FIr-B/FOx in MCRC: Treatment Schedule

5-Fluorouracil (5-FU), time flat infusion of 12h, Irinotecan (CPT-11) / Bevacizumab (BEV), Oxaliplatin (l-OHP), as first line treatment of metastatic colorectal cancer:

fase II study.

Bev 5 mg/kg Bev 5 mg/kg

Bruera G et al, 2010 Submitted

13

FIr-B/Fox in MCRC: Activity and efficacy

Intent-to-treatAnalysis

As-treatedAnalysis

No % No %

Enrolled patients 50 100 50 100

Evaluable patients 49 98 43 86

Objective Response Partial Response Complete Response

40364

82 (CI±11)738

36324

84 (CI±11)759

Stable Disease 2 4 2 5

Progressive Disease 7 14 5 12

Median Progressio-free survival, months Range Progression events

123-46+

38 76

Median Overall Survival, months Range Deaths

283-4728 56

Liver metastasectomies No/Overall patients (50) No/Patients with liver metastases (33) No/Patients with liver-only metastases (21)

13263957


14

Kaplan-Meier survival estimate: Progression-free survival

Median Follow-up 21 months

Median PFS 12 months (3-46+)


15

Median Follow-up 21 months

Median OS 28 months (3-47)

Kaplan-Meier survival estimate: Overall survival


16

FIr-B/Fox in MCRC: Cumulative toxicityPatients Cycles

Number 50 247

NCI-CTC Grade 1 2 3 4 1 2 3 4

Nausea (%) 23 (46) 15 (30) 3 (6) - 81 (33) 23 (9) 4 (2) -

Vomiting (%) 10 (20) 6 (12) 2 (4) - 19 (8) 9 (4) 2 (1) -

Diarrhea (%) 20 (40) 12(24) 14 (28) - 76 (30) 28 (11) 15 (6) -

Hypoalbuminemia (%) 2 (4) 1 (2) - - 2 (1) 1 (0.5) - -

Constipation (%) 17 (34) 1 (2) - - 22 (9) 1 (0.5) - -

Stomatitis/mucositis (%) 16 (32) 2 (4) 3 (6) - 29 (12) 3 (1) 3 (1) -

Erythema (%) 1 (2) - 1 (2) - 3 (1) - 1 (0.5) -

Asthenia (%) 13 (26) 20 (40) 3 (6) - 48 (19) 38 (15) 3 (1) -

Neurotoxicity (%) 36(72) 5 (10) - - 126(51) 6 (2) - -

Hypertension (%) 15 (30) 4 (8) 1 (2) - 27 (11) 4 (2) 1 (0.5) -

Hypotension (%) 1 (2) - - - 1 (0.5) - - -

Hematuria (%) 2 (4) 1 (2) - - 3 (1) 1 (0.5) - -

Gengival recession/gengivitis (%) 7 (14) - - - 10 (4) - - -

Rhinitis (%) 38 (76) - - - 110(44.5) - - -

Epistaxis (%) 31 (62) 2 (4) - - 68 (27.5) 2 (1) - -

HFS (%) 2 (4) - - - 2 (1) - - -

Headache (%) 6 (12) - - - 9 (4) - - -

Hypokalemia (%) 3 (6) - 1 (2) - 3 (1) - 1 (0.5) -

Hypertransaminasemy (%) 3 (6) 2 (4) 1 (2) 1 (2) 9 (4) 6 (2) 1 (0.5) 1 (0.5)

Hyperpigmentation (%) 6 (12) 2 (4) - - 14 (6) 5 (2) - -

Fever without infection (%) 10 (20) - - - 10 (4) - - -

Alopecia (%) 5 (10) 9 (18) 3 (6) - 11 (4) 17 (7) 7 (3) -


17


As-treatedAnalysis

No % No %




22193

88 (CI±14)7612

20173

87 (CI±14)7413

Stable Disease 2 8 2 9


Median Progression-free survival, months Range Progression events

143-46+

20 77


318-4713 50


9365682

Medical Oncology, L’Aquila, 2010, preliminary unpublished data

FIr-B/Fox in MCRC: k-ras wld-type patients

18


As-treatedAnalysis

No % No %




14131

82 (CI±19)766

13121

93 (CI±19)867

Stable Disease - - - -


Median Progression-free survival, months Range Progression events

124-37+

13 76


198-4410 59


31830

37.5


FIr-B/Fox in MCRC: k-ras mutant patients

19

_____ KRAS wt

_____ KRAS mt

P = 0.063


FIr-B/Fox in MCRCOS in k-ras wild-type and mutant patients

20

MCRC Treatment CostsMono

(E/cycle)Doublet(E/cycle)

Triplet(E/cycle)

Poker(E/cycle)

CT F FIri FOx FIr/FOx

76,441576,921430,22

2919,78

CT+Bev F-Bev FIri-Bev FOx-Bev FIr-B/FOx

4118,445618,925472,22

6961,30

CT+Cet Iri-Cet FIri-Cet FOx-Cet FIr-C/FOx-C

7740,887817,327670,62

9160,18

21

MCRC Treatment CostsMono

(E/cycle)Doublet(E/cycle)

Triplet(E/cycle)

Poker(E/cycle)


0.051

0.91.85


2.63.563.47

4.4


4.94.954.86

5.8

22

MCRC k-ras wt : I line treatment options

Mono(E/cycle)

Doublet(E/cycle)

Triplet(E/cycle)

Poker(E/cycle)


0.051

0.91.85


2.63.563.47

4.4


4.94.954.86

5.8

23

Mono(E/cycle)

Doublet(E/cycle)

Triplet(E/cycle)

Poker(E/cycle)


0.051

0.91.85


2.63.563.47

4.4


4.94.954.86

5.8

MCRC k-ras wt : II line treatment options

24

I line Cost

II line Cost

Total(E)

CT FIri FOx

1 CT+Cet Iri-Cet FIri-Cet FOx-Cet

4.95 5.95(9383)

CT+Bev FIri-Bev FOx-Bev

3.56 CT+Cet Iri-Cet FIri-Cet FOx-Cet

4.95 8.51(13420)

CT+Cet Iri-Cet FIri-Cet FOx-Cet

4.95CT+Bev FIri-Bev FOx-Bev

3.56 8.51(13420)

MCRC k-ras wt : I-II line treatment options

25

I line Cost

II line Cost

Total(E)

CT FIri FOx

1 CT+Cet Iri-Cet FIri-Cet FOx-Cet

2.87 3.87(6103)



2.87 6.43(10140)


4.95CT+Bev FIri-Bev FOx-Bev

2.06 7.01(11054)

MCRC k-ras wt : I-II line treatment options (58%)

26

I line Cost

II line Cost

Total(E)

CT FIr/FOx

1,85 CT+Cet Iri-Cet FIri-Cet FOx-Cet

2,87 4,72(7443)



2,87 6,43(10140)


4,95CT+Bev FIri-Bev FOx-Bev

2,06 7,01(11054)


27

I line Cost

II line Cost

Total(E)

CT FIr/FOx


2,87 4,72(7443)

CT+Bev FIr-B/FOx


2,87 7,27(11464)


4,95CT+Bev FIri-Bev FOx-Bev

2,06 7,01(11054)


28

I line Cost

II line Cost

Total(E)

CT FIr/FOx


2.87 4.72(7443)

CT+Bev FIr-B/FOx

4.40 CT+Cet Iri-Cet FIri-Cet FOx-Cet FIr-C/FOx-C

2.87

3.36

7.27(11464)

7.76(12237)

CT+Cet FIr-C/FOx-C

5.80 CT+Bev FIri-Bev FOx-Bev

2.06 7.86(12395)


29

I line Cost

II line Cost

Total(E)

CT FIri FOx FIr/FOx

10,9

1,85

CT Ox Iri CT+Bev FIri-Bev FOx-Bev

0,520,58

2,06

1,521,48

(2365)3,91

(6166)


3.56 CT FOx FIri

0,520,58 4,14

(6528)

MCRC k-ras mut : I-II line treatment options (58%)

30

I line Cost

II line Cost

Total(E)

CT FIri FOx FIr/FOx

10,9

1,85

CT Ox Iri CT+Bev FIri-Bev FOx-Bev

0,520,58

2,06

1,521,48

(2365)3,91

(6166)

CT+Bev FIr-B/FOx

4,40 CT ? 4,40

(6938)


31

K-ras testing: conclusions (1)

Low cost of genetic analysis Useful for differentiation between selection of

treatment options High-cost in k-ras wild-type Moderate-cost in k-ras mutated

Urgent need to consider randomized studies comparing triplet CT versus doublet/triplet CT associating anti-targets (anti-EGFR, anti-VEGF) according to kras genotype

32

K-ras testing: Perspectives

Consideration of 4-drugs combinations also due to their relative increase in costs (<10%)

Further lines of treatment in k-ras mutated patients

Binomial testing in primary tumors and metastatic sites

Evaluation of tumoral cells heterogeneity

34

Ringrazio

Department of Pathology, Rouen University Hospital,

Northwest Canceropole (FR)

Dr. JC SabourinDr.ssa A. Lamy

Dr.ssa F. Blanchard

INSERM U614, Faculty of Medicine, Rouen(FR)

Prof. Mario Tosi

Prof. Tierry Frebourg

Dr.ssa G. Bougeard

Dr.ssa J. Tinat

Dpt. Medicina Sperimentale, Università di

L’Aquila

Prof. Enrico Ricevuto

Università “ G. D’Annunzio” Chieti-Pescara

Prof. S. Iacobelli

35

MCRC I line: ORR

MCRC I line ORR

References Trial Mono Doublets Triplets Poker

ORR (%)

KabbinavarJCO 2003

Bev+5FU/LV5FU/LV 17

40

HurwitzNEJM 2004

Bev+IFLIFL+Placebo 34.8

44.8

KabbinavarJCO 2005

Bev+5FU/LV5FU/LV(unfit for CPT)

15.226

HurwitzJCO 2005

Bev+5FU/LVIFL

4037

Falcone JCO 2007

FOLFOXIRIFOLFIRI 41

66

SouglakosBJC 2006

FOLFOXIRIFOLFIRI 33.6

43

Morelli Oncol Rep 2010

FIr/FOx 66.7

HochsterJCO 2008

mFOLFOX6+BevbFOL+BevCapeOx+BevmFOLFOX6bFOLCapeOX

412027

523946

GruenbergerJCO 2008

XelOx+BevLiver mets resectable(High risk early recurrence)

73.2

SaltzJCO 2008

XelOx+BevFOLFOX4+BevXelOxFOLFOX4

4747

4949

MasiESMO 2009

Bev+FOLFOXIRI 77

Van CutsemNEJM 2009

Cet+FOLFIRIFOLFIRI(EGFR+)

38.746.9

BokemeyerJCO 2009

Cet+FOLFOX4FOLFOX4(EGFR+)

3646

FolprechtLancet Onc 2009

Cet+FOLFOX6Cet+FOLFIRI(Liver mets unresectable)

6857

TaberneroJCO 2007

Cet+FOLFOX4 79

GarufiESMO 2009

POCHER 79

DouillardESMO 2009

Panitumumab+FOLFOX4FOLFOX4(KRAS wt)

4855

Bruera 2010 submitted FIr-B/FOx 84

36

MCRC I line: PFS

MCRC I line PFS


PFS (months)

KabbinavarJCO 2003

Bev+5FU/LV5FU/LV 5.2

9

HurwitzNEJM 2004


10.6

KabbinavarJCO 2005


5.59.2

HurwitzJCO 2005

Bev+5FU/LVIFL

8.86.8

Falcone JCO 2007


9.8

SouglakosBJC 2006


8.4


FIr/FOx 12

HochsterJCO 2008


8.76.95.9

9.98.310.3

GruenbergerJCO 2008


SaltzJCO 2008


8.48.4

9.49.4

MasiESMO 2009

Bev+FOLFOXIRI 13.4

Van CutsemNEJM 2009


8.08.9

BokemeyerJCO 2009


7.27.2



TaberneroJCO 2007

Cet+FOLFOX4 12.3

GarufiESMO 2009

POCHER 13

DouillardESMO 2009


3.9


37

MCRC I line: OS

MCRC I line OS


OS (months)

KabbinavarJCO 2003

Bev+5FU/LV5FU/LV 13.8

21.5

HurwitzNEJM 2004


20.3

KabbinavarJCO 2005


12.916.6

HurwitzJCO 2005

Bev+5FU/LVIFL

18.315.1

Falcone JCO 2007


22.6

SouglakosBJC 2006


21.5


FIr/FOx 20

HochsterJCO 2008


19.217.917.2

26.120.424.6

GruenbergerJCO 2008


SaltzJCO 2008


19.919.9

21.321.3

MasiESMO 2009

Bev+FOLFOXIRI

Van CutsemNEJM 2009


18.619.9

BokemeyerJCO 2009




TaberneroJCO 2007

Cet+FOLFOX4 30

GarufiESMO 2009

POCHER

DouillardESMO 2009



38

Cumulative toxicity

Results Toxicity

Patients Cycles

Number 50 247

NCI-CTC Grade 1 2 3 4 1 2 3 4

Anemia (%) 7 (14) 4 (8) - - 16 (6) 4 (2) - -

Leucopenia (%) 13 (26) 17 (34) - - 49 (20) 26(10.5) - -

Neutropenia (%) 9 (18) 14 (28) 5 (10) - 35 (14) 32 (13) 8 (3) -

Trhombocitopeny (%) 7 (14) 1 (2) - - 16 (6) 1 (0.5) - -

1 o n c o l o together for y loncologia insieme per l*aquila g bruera, d di giacomo & e...

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median pfs months

months median pfs

months median os

esample slide

sensoantisenso slide

ci median os months

ras testing slide

kras genotype slide