Riccardo Giampieri Scuola di Specializzazione Oncologia

Università Politecnica delle Marche Ancona

How to manage patients with mutated KRAS tumors

•Hot-spot point mutations within codons 12 or 13 of the KRAS gene constitutively active KRAS protein

•Constitutively active KRAS protein cancer cell growth and survival through the RAF-MEK-ERK and PI3K-AKT pathways independently from EGFR signaling

K-ras mutation

A controversial starting point…

Patient harbouring K-ras mutated tumors:

Easy patient! Difficult patient!

?

Why easy patient?

- We know what DO NOT give to this patient

- We know what CAN be given to this patient

- Treatment sequence is almost always set without difficulties

What DO NOT give: preclinical data

- Anti-EGFR monoclonal antibodies + DiFi colon cancer cell lines + k-ras mutation or not

Benvenuti et al. Cancer Res 2007

Moroni Lancet Oncol 2005 n=31

Lièvre Clin Cancer Res 2006 n=30

Di Fiore Br J Cancer 2007 n=59

Frattini Br J Cancer 2007 n=27

Benvenuti Cancer Res 2007 n=48

Khambata-Ford J Clin Oncol 2007 n=80

De Roock ASCO Proc 2007 n=37

Finocchiaro ASCO Proc 2007 n=81

Response rate:analysis of 8 studies available in PubMed or from ASCO Proceedings:

Responders (n=82)

wt (93.0%)

RAS mutated (7.0%)

wt (56.1%)

RAS mutated (43.9%)

Non-Responders (n=312)

p = 0.000000635 (Fisher’s exact test)

Pre-treated patients and response rate differencies

FOLFOX FOLFOX+Cetuximab 168 pts 169 ptsRR (%) 36 46 p=0.06

Kras status PFS (mo.) RR (%) C+Ffox Ffox C+Ffox Ffox

Wt 7.7 7.1 61 37

Mutated 5.5 8.6 33 49

Bokemeyer C, ASCO 2008

First line: OPUS trial (randomized phase II)

Bokemeyer C. ASCO 2008, J Clin Oncol 2009; 27(5)

OPUS trial k-ras mutant population: response rates

FOLFOX N=47

ERBITUX + FOLFOX

N=52

CR 4.3% 0%

PR 44.7% 32.7%

SD 36.2% 51.9%

PD 10.6% 13.5%

NE 4.3% 1.9%

RR 48.9% 32.7%

95% CI (exact)

[34.1%, 63.9%]

[20.3%, 47.1%]

ERBITUX + FOLFOXFOLFOX

49

33

p=0.106Odds Ratio = 0.507(95% CI: 0.223 –1.150)

0

10

20

30

40

50

60

Res

pons

e ra

te (%

)

No benefit for Erbitux

p = 0.106

Stratification by: – Region– ECOG PS

FOLFIRI

Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2

as 46-h continuous infusion) + LV (every 2 weeks)

Cetuximab + FOLFIRI

Cetuximab (IV 400 mg/m2 on day 1,then 250 mg/m2 weekly)

+ irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2

as 46-h continuous infusion)+ LV (every 2 weeks)

REGFR-detectable

mCRC

Primary endpoint– Progression-free survival time

(as assessed by blinded independent review)

Secondary endpoints– ORR (independent review)– OS– Quality of life (EORTC QLQ-C30)– Safety

First line: CRYSTAL trial (phase III)

17.7 17.5 [14.4–20.6] [15.6–20.2]

1.03 [0.74–1.44]

0.85

KRAS wild-type

FOLFIRI(n=176)

Cetuximab+ FOLFIRI

(n=172)

FOLFIRI(n=87)

Cetuximab+ FOLFIRI

(n=105)

KRAS mutant

Parameter

Median OS[95% CI]

Hazard ratio[95% CI]

P-value

ITT

FOLFIRI(n=599)

Cetuximab+ FOLFIRI

(n=599)

18.6 19.9 [16.6–19.8] [18.5–21.3]

0.93 [0.81–1.07]

0.30

Median follow up time: 30 months

21.0 24.9[19.2–25.7] [22.2–27.8]

0.84 [0.64–1.11]

0.22

Overall survival analysis based on K-ras status

Overall survival analysis based on K-ras status

Continuous* XELOX or FOLFOX Arm A

RFirst-line mCRC (n= 2,445) Arm B

Continuous XELOX or FOLFOX +

cetuximab

Arm CIntermittent‡ XELOX or FOLFOX

*Treatment until disease progression or unacceptable toxicity‡Stop and Go treatment (12 weeks then restart at progression)

MRC Sponsored study supported by Merck

109 UK and Irish Hospitals

65% XELOX; 35% FOLFOX(patient/physician choice)

Maughan, et al. ESMO 2009

First line: COIN trial (phase III)

Maughan, et al. ESMO 2009

COIN trial: response rates based on K-ras status

All patients KRAS wild-type KRAS mutant

FOLFOX/XELOX(n=815)

Cetuximab +

FOLFOX/XELOX(n=815)

FOLFOX/XELOX(n=367)

Cetuximab +

FOLFOX/XELOX(n=362)

FOLFOX/XELOX(n=268)

Cetuximab +

FOLFOX/XELOX(n=297)

ORR at 12 weeks (%) 45 49 50 59 41 40Odds ratio 1.17 (p=0.124) 1.44 (p=0.015) 0.97 (p=0.877)

Best overall response (%)

51 53 57 64 46 43

Odds ratio 1.08 (p=0.428) OR=1.35 (p=0.049) OR=0.88 (p=0.449)

The 045 Phase I: Study Design

FOLFIRI: irinotecan 180 mg/m2 over 30–90 min; FA 400 mg/m2 over 2 hours; 5-fluorouracil 200 mg/m2 as bolus and 2400 mg/m2 over 46 hours given every 2 weeks

CONTROL ARM (GROUP A)10-patient cohort

ERBITUX (400 mg/m2 on day 1,then 250 mg/m2 weekly)

EXPERIMENTAL ARM (GROUP B)

10-patient cohortsERBITUX at escalating doses for

successive cohorts: 400, 500, 600, 700 mg/m2 once every second week

6 weeks’ treatmentComplete PK profile obtained during this period

FOLFIRI added to patients’ current ERBITUX regimen

Evaluate best overall response

Progression-free survival

PART I

PART II

1º endpointDLT assessment

2º endpoints

Tabernero et al. ASCO GI 2008 (Abstract No. 435)

Study AIO 045 Maybe it is dose related…

KRAS status

Monotherapy Combination therapyWild-type

n=29Mutation

n=19Wild-type

n=29Mutation

n=19RR, n (%)[95% CI]

8 (27.6)[12.7–47.2]

0 (0)[0–17.7]

16 (55.2)[35.7–73.6]

6 (31.6)[12.6–56.6]

p=0.015 p=0.144

Median PFS, months[95% CI] — —

9.4[7.0–11.3]

5.6[3.3–12.2]

HR: 0.47, p=0.0475

• KRAS mutations were detected in 19 samples (40%) of KRAS evaluable population

Tabernero J, et al. ASCO GI 2008 (Abstract No. 435)

… Of course not

Panitumumab anyone?

KRAS wild-type

Amado et al. J Clin Oncol 2008;26

Panitumumab single agent

Amado RG, et al. J Clin Oncol 2008;26:1626-34

181 Trial (PFS) (2°line FOLFIRI+/-panitumumab)

Peeters et al. J Clin Oncol 2010

181 Trial (OS)

Peeters et al. J Clin Oncol 2010

PRIME trial (PFS)(1°line FOLFOX+/-Panitumumab)

Douillard et al. J Clin Oncol 2010

PRIME trial (OS)

Douillard et al. J Clin Oncol 2010

So, we can’t give THAT…But WHAT can we give?

Bevacizumab: IFL+/- Bevacizumab and K-ras status (PFS)

Hurwitz et al. The Oncologist 2009

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

Duration of PFS (Months)

Prop

ortio

n Pr

ogre

ssio

n-Fr

ee

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

Duration of PFS (Months)

Prop

ortio

n Pr

ogre

ssio

n-Fr

ee

Group: Mutant (n = 78) Group: Wild-type (n = 152)Median

PFS (mo)

IFL + placebo 5.5 IFL + BV 9.3

Median PFS (mo)

IFL + placebo 7.4 IFL + BV 13.5

HR :0.44; P < .0001HR: 0.41; P = .0008

Bevacizumab: IFL+/- Bevacizumab and K-ras status (OS)

Hurwitz et al. The Oncologist 2009

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30Duration of Survival (Months)

Prop

ortio

n Su

rviv

ing

Group: Mutant (n = 78) Group: Wild-type (n = 152)

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30Duration of Survival (Months)

Prop

ortio

n Su

rviv

ing

Median OS (mo)

IFL + placebo 13.6 IFL + BV 19.9

Median OS (mo)

IFL + placebo 17.6 IFL + BV 27.7

HR: 0.58; P = .04HR: 0.69; P = .26

• Primary endpoint– 6-month PFS

• Secondary endpoints– OS, PFS, toxicity, secondary resection of liver or lung metastases

Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD)R = randomisation; WT = wild-type; MT = mutant

Bevacizumab + CAPIRI(n=120)

[KRAS WT=44; KRAS MT=21]

Bevacizumab + CAPOX (n=127)

[KRAS WT=56; KRAS MT=21]

Previously untreated mCRC

(n=247)R

AIO 0604 study: design of the trial

Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD)

AIO 0604 study: CAPIRI arm

Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD)

AIO 0604 study: CAPOX arm

Masi, et al. Lancet Oncology 2010

Avastin 5 mg/kg

Irinotecan165 mg/m2

Oxaliplatin85 mg/m2

L-LV200 mg/m2

5-FU continuous infusion3200 mg/m2

Day 1 Days 2–3

Cycles repeated every 2 weeks for 12 cyclesfollowed by maintenance Avastin until PD

FOIB study: design

K-rasa B-rafb

WT(n=34)

MT(n=21)

WT(n=45)

MT(n=10)

Responders, n (%) 28 (82) 15 (71) 34 (75) 9 (90)

Non-responders , n (%) 6 (18) 6 (29) 11 (25) 1 (10)

a Responders vs non-responders: p=0.503 (Fischer’s exact test)b Responders vs non-responders: p=0.430(Fischer’s exact test)

Masi et al. Lancet Oncology 2010

FOIB study: retrospective analysis on K-ras status, RR

Masi et al. Lancet Oncology 2010

Time (months)

100

75

50

25

0

Progression-free (%)

0 10 20 30

K-ras WT: median PFS: 13.4 monthsK-ras MT: median PFS: 12.6 months

Log-rank test: p=0.433

HR=0.78 95% CI: 0.38–1.51

FOIB study: retrospective analysis on K-ras status, PFS

Possible 1°line therapeutic options

– Bevacizumab+FOLFOX (XELOX)– Bevacizumab+FOLFIRI (XELIRI)– FOLFOXIRI

To sum up…

So… Where is the “Difficult” part?

Starting in a “knee-deep in trouble” situation…

K-ras is not only a PREDICTIVE factor…

It is also a PROGNOSTIC factor

Of a WORSE prognosis

K-ras prognostic: RASCAL

CRYSTAL study OS:K-ras also prognostic?

K-ras mutated: a name fits all?

7 more frequent mutations >98%

Rare mutations2%

The only mutation with prognostic value?

RASCAL II

Br J Cancer 2001

The G13D case: someone begs to differ…

So… not every Kras mutated tumor doesn’t respond to anti-EGFR…?

NORDIC VII: trial design

NORDIC VII: PFS according to K-ras status

NORDIC VII: OS according K-ras status

Cetuximab+ FOLFIRI

Cetuximab+ FOLFOX4

Cetuximab+ FOLFIRI

Cetuximab+ OxFp

Cetuximab + FOLFOX 6 or FOLFIRI

Cetuximab+ FOLFIRI

Cetuximab+ FOLFOX 6

Cetuximab+ capecitabine

Cetuximab (continuous)

+ FLOX

Cetuximab+ capecitabine + oxaliplatin

+ bevacizumab

2009 2009 2008 2009 2009 2008 2008 2009 2010 2009

Difference (wt-mt)

Response Rate

NORDIC VII: Comparison with other studies (OS)

Cetuximab+ FOLFIRI

Cetuximab+ FOLFOX4

Cetuximab+ FOLFIRI

Cetuximab+ OxFp

Cetuximab+ FOLFIRI

Cetuximab+ FOLFOX 6

Cetuximab+ capecitabine

Cetuximab (continuous)

+ FLOX

Cetuximab+ capecitabine + oxaliplatin

+ bevacizumab

2009 2009 2008 2009 2008 2008 2009 2010 2009

9,98,3

9,48,6 8,4

9,1 8,67,9

10,5

7,4

5,5 5,66,5

8,17,2

6,0

9,28,1

0

2

4

6

8

10

12

CRYSTAL OPUS EMR62202-045

COIN CECOGCORE 1

CECOGCORE 1

Rivera NORDIC VII(cont)

CAIRO 2

PFS,

mon

ths

KRAS wt KRAS mt

Difference (wt-mt)

PFS

NORDIC VII: Comparison with other studies (PFS)

CAPIRI + cetuximab(n=93)

CAPOX + cetuximab(n=92)

Previously untreated mCRC

(n=185)R

Stintzing, et al. ESMO 2010 (Abstract 582PD)

• Primary endpoint– response rate

• Secondary endpoints– TTP, disease control rate, tolerability

AIO KRK-0204: CAPIRI/CAPOX+Cetuximab

• CAPOX + cetuximab and CAPIRI + cetuximab are feasible, with acceptable toxicity profiles

• Both regimens are effective, with comparable efficacy

• KRAS status did not influence ORR

• KRAS WT patients showed only a trend towards longer OS and PFS vs KRAS MT patients

Stintzing, et al. ESMO 2010 (Abstract 582PD)

AIO KRK-0204: Conclusions

What is then the MOST predictive factor for anti-EGFR efficacy?

Douillard, et al. ASCO 2010

PRIME trial: efficacy by SKIN TOXICITY

Thanks for the attention…