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clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer

KRAS Status in Response to Cetuximab

Retrospective analysis of CRYSTAL[1]

– PFS and ORR benefit of FOLFIRI + cetuximab only observed in mCRC patients with wild-type KRAS

1. Van Cutsem E, et al. ASCO 2008. Abstract 2.

Outcome Wild-Type KRAS(n = 348)

Mutated KRAS(n = 192)

Median PFS, mos

FOLFIRI + cetuximab 9.9 7.6

FOLFIRI 8.7 8.1

HR 0.68* 1.07†

ORR, %

FOLFIRI + cetuximab 59.3‡ 36.2

FOLFIRI 43.2 40.2

*P = .017; †P = .75; ‡P = .0025

E Idelevich, 2011


20060314FOLFIRI + Panitumumab in 1st-line Treatment of Metastatic CRC

Approx. 56 daysafter end of treatment

Köhne CH, et al. ASCO-GI 2010, #414, poster presentation;www.amgentrials.com; protocol ID: 20060314. ClinicalTrials.gov identifier: NCT00508404.

Study objectives: To estimate the effect of KRAS mutation status on efficacy and to describe the safety profile

Study endpoints: ORR (1°); PFS, Safety

FOLFIRI (Q2W) +panitumumab 6 mg/kg(Q2W, on day 1 of each cycle)

Metastatic CRC

(n=150)

End

of

treat

ment

Safety follow

up

End

of

study

ScreenIng

Enroll

ment

E Idelevich, 2011


20060314Best Objective Response

Panitumumab + FOLFIRI*

KRAS wt (n=85) KRAS mt (n=58)

Objective response, % Complete response 2 2 Partial response 54 36 Stable disease 34 52 Disease progression 7 7 Unevaluable 0 2 Not done 2 2

CR + PR,% (95% CI)

56.5(45.3, 67.2)

37.9(25.5, 51.6)

Difference, % (95% CI)

18.54(0.84, 34.63)

Unadjusted common treatment odds ratio(95% CI)

2.12(1.02, 4.45)

*Two patients did not have measurable disease per RECIST guidelines at baseline and were therefore not included in the analysis of response rate.

Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.

E Idelevich, 2011


Resection Rates – Patients with Liver Only Disease

0

20

40

KRAS wt(n=11/31)

KRAS mt(n=2/16)

35

Res

ecti

on r

ate

(%)

13

Overall resections

Hofheinz R, et al. ASCO 2010, #3545, poster presentation

KRAS evaluable

20060314E Idelevich, 2011


20060314Progression-free Survival Primary Analysis Set

Pro

por

tion

Eve

nt-F

ree

(%)

100

90

70

60

80

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 1210 11 1613 14 15

Eventsn (%)

Median (95% CI) months

KRAS wt (n=86)______ 44 (51) 8.9 (7.6–14.3)

KRAS mt (n=59)______ 48 (81) 7.2 (5.6–7.8)

HR = 0.46 (95%CI: 0.31–0.70)

Months

Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.

E Idelevich, 2011


20060314SummaryThis was the first study to investigate the effect of tumour KRAS status on response to panitumumab plus FOLFIRI in the 1st-line treatment of mCRC

KRAS wt tumours were more likely to respond to treatment with panitumumab plus FOLFIRI (56.5%vs 37.9%)

PFS was longer in patients with KRAS wt tumours

Resection rate was higher in the KRAS wt population

Safety was as expected for an anti-EGFR inhibitor plus irinotecan-based chemotherapy in this setting

Köhne CH, et al. ASCO-GI 2010, #414, poster presentation;Hofheinz R, et al. J Clin Oncol 2010; 28(15S): #3545, poster presentation.

E Idelevich, 2011


20050181FOLFIRI ± Panitumumab in 2nd-line Treatment of Metastatic CRC

PRO, patient-reported outcomesPeeters M, et al. J Clin Oncol 2010;28:4706-4713;ClinicalTrials.gov identifier: NCT00339183; www.amgentrials.com; protocol ID: 20050181.

Metastatic CRC

(n=1100)R

1:1

Stratification by:• ECOG score: 0-1 vs. 2• Prior oxaliplatin exposure for mCRC• Prior bevacizumab exposure for mCRC

End

of

treat

ment

Long

term follow

up

Disease assessment every 8 weeksDisease assessment every 8 weeks

Study endpoints: PFS/OS (co-1°); ORR, Safety, PRO

FOLFIRI (Q2W) +panitumumab 6 mg/kg

(Q2W)

FOLFIRI (Q2W)

E Idelevich, 2011


20050181Objective Response in Patients with KRAS wt Tumours (Central Review)

p < 0.001(descriptive); All responses were confirmed no earlier than 28 days after the response criteria were first met

Peeters M, et al. J Clin Oncol 2010;28:4706-4713.

0

10

20

30

40

Panitumumab+ FOLFIRI

(n=297)

FOLFIRI(n=285)

Ob

ject

ive

Res

po

nse

Rat

e (%

)

35

10

More than 3x as many patients responded to panitumumab

E Idelevich, 2011


20050181Panitumumab Improved Median PFS by 51% in Patients with KRAS wt Tumours

20181614121086420

Pro

gre

ssio

n-F

ree

Pro

bab

ility

1.0

0.9

0.7

0.6

0.8

0.5

0.4

0.3

0.2

0.1

0.0

Months

Eventsn (%)

Median (95% CI) months

Panitumumab + FOLFIRI (n=303)___ 178 (59) 5.9 (5.5–6.7)

FOLFIRI (n=294)___ 203 (69) 3.9 (3.7–5.3)

2.0

HR = 0.73 (95%CI: 0.59–0.90)

p = 0.004

Peeters M, et al. J Clin Oncol 2010;28:4706-4713.

E Idelevich, 2011


20050181Summary This is the first randomised study prospectively analysed by KRAS status in 2nd-line mCRC

In patients with KRAS wt tumours, panitumumab significantly improved PFS when added to FOLFIRI

Overall survival was numerically improved (not significant)

The response rate was improved by more than 3x (35% vs 10%)

Safety was as expected for an anti-EGFR antibody in combination with FOLFIRI

Peeters M, et al. J Clin Oncol 2010;28:4706-4713.Peeters M, et al. ASCO-GI 2010, #282, oral presentation

E Idelevich, 2011

asickmann

exact wording in Peeters et al., 2010: "acceptable safety profile"

Metastatic colon cancer patients (100%)

Non curable PotentiallyDown-sizable

12%63%

Non - resectable 75% Resectable 25%

Paul Brousse Experience - 1439 Patients (1988–1999)

Adam R et al Ann Surg. 2004;240:644-658

Treatment of Metastatic CRC

1980 1985 1990 1995 2000 2005 RR % MS

5Fu

Capecitabine

20-25 13

Irinotecan

Oxaliplatin

EGFR inhibitors

Bevacizumab

40 -50 20-22

~60 >24

Months

Endpoints for assessment of systemic therapy for potentially resectablepotentially resectable

disease• Systemic therapy is enabling resection - Highest RR maximizes resection rate (Folprecht et al)

• Endpoints - PFS is primary efficacy endpoint (ECNTG, 2007) - Secondary endpoints * Response Rate * Liver related toxicity * Achievement of R0 resection of all disease

Are biological essential? - if acceptable toxicity, higher RR, improved

resection rates and ultimately improved PFS are demonstrated (European Journal of Cancer, 43 (2007), 2037-2045)

Response rates: recent phase 3 trialsRegimen Response Rate Reference_________________________________________________________________________FOLFOX 36% NS;FOFOX+cetuximab 46% (OPUS, Bokemeyer)_____________________________________________________________________________________

FOLFIRI 43% p=0.004;FOLFIRI+cetuximab 59% (CRYSTAL,van Cutsem)______________________________________________________________________________________

FOLFOX 38% NS;

FOLFOX+bevacizzumab 38% (XELOX-1/NO16966 Saltz)

______________________________________________________________________________________

FOLFOX 47% NS; p=0.06

FOLFOX+panitumumab 55 (PRIME, J-Y Douillard)

______________________________________________________________________________________

FOLFIRI 36% p=0.001;

FOLFOXIRI 60% (Falcone)

______________________________________________________________________________________

FOLFOX+bevacizumab 41% NS;

FOLFOX+bevacizumab+cetuximab 39% (PACCE; Hecht)

______________________________________________________________________________________

CAPOX+bevacizumab 44% NS;

CAPOX+becizumab+cetuximab 44% (CAIRO2; Punt)

______________________________________________________________________________________

Standard Doublets ~ 40% Response Rate (RR)

Response rates: recent phase 3 trialsRegimen Response Rate Reference______________________________________________________________________________________

FOLFOX 36% NS;FOFOX+cetuximab 46% (OPUS, Bokemeyer)______________________________________________________________________________________


FOLFOX 38% NS;


______________________________________________________________________________________


FOLFOX+panitumumab 55% (PRIME, J-Y Douillard)

______________________________________________________________________________________



______________________________________________________________________________________



______________________________________________________________________________________



______________________________________________________________________________________

Adding EGFR inhibitors or using triplet chemotherapy increases RR

Response rates: recent phase 3 trialsRegimen Response Rate Reference_____________________________________________________________________________________FOLFOX 36% NS;FOFOX+cetuximab 46% (OPUS, Bokemeyer)_____________________________________________________________________________________


FOLFOX 38% NS;


______________________________________________________________________________________


FOLFOX+panitumumab 55% (PRIME, J-Y Douillard)

______________________________________________________________________________________



______________________________________________________________________________________



______________________________________________________________________________________



______________________________________________________________________________________

Bevacizumab does not increase Response Rate (RR)

Kras-dependent RR in First-Line Trials RR (K-ras w.t.) RR (K-ras mut)RR (K-ras w.t.) RR (K-ras mut)____________________________________________________________________________________________________________________________________OPUS OPUS (Bokemeyer)

FOLFOX 37% 49%FOLFOX+erbitux 61% 33%__________________________________________________________________CRYSTALCRYSTAL (van Cutsem)FOLFIRI 43% 40%FOLFIRI+erbitux 59% 38% 38%____________________________________________________________________________________________________________________________________

PRIMEPRIME (J-Y Douillard)FOLFOX 47% 40%FOLFOX+vectibix 55% 40%__________________________________________________________________2006031420060314 (Köhne CH)FOLFIRI+vectibix 56,5% 37.9%__________________________________________________________________

Response Rate

• In K-ras In K-ras wild typewild type patients patients - FOLFOX or FOLFIRI+EGFR inhibitors has shown

55%- 60% response rate

• FOLFOXIRI - 60% response rate in small phase 3 trial

What is the optimal chemotherapy for the neoadjuvant treatment of unresectable liver

metastases?

• In patients with K-ras unknown or mutant - FOLFOX remains a standard treatment - FOLFOXIRI is an option (resectability, RR + PFS), but unknown toxicity profile in larger series - FOLFOX + bevacizumab is safe, but neither improves response rates nor resection rates

• In patients with wildtype K-ras - FOLFOX or FOLFIRI + EGFR inhibitors improve

resection rates - FOLFIRI + cetuximab improves resection rate compared FOLFIRI

Treatment of unresectable mCRC

• Patients needing or desiring an aggressive approach:

- patients with potentially resectable metastases

- patients with clearly symptomatic disease in whom tumor regression is needed

KRAS wild type patients:

- CT + panitumumab, CT+cetuximab

-evidence for response is greater for cetuximab in neoadjuvant

approach

KRAS mutant patients:

- CT + bevacizumab

- FOLFOXIRI may be an option if contraindications for bevacizumab and downsizing is desired

Van Cutsem E, et al. WCGIC 2009 Expert Opinion

Treatment of unresectable mCRC Specific issues

• Treat with biologicals until progression or toxicity, or until metastases become resectable

• Continue treatment until progression with biologicals, even if one of the cytotoxic partners (oxaliplatin, irinotecan) is stopped

• No clear evidence to administer biologicals beyond progression

• Correlation of rash and activity after anti-EGFR antibodies has no immediate practical implications in clinical practice


Stage IV Colon CancerStage IV Colon CancerGroup I Group II Group III Group IVGroup I Group II Group III Group IV

Curable Curable Potentially Symptomatic Asymptomatic Potentially Symptomatic Asymptomatic

disease disease curablecurable non curablenon curable non curablenon curable

disease disease diseasedisease disease disease

!

Non curable Non curable

First line strategy of metastatic CRC

Dose the patient need (or desire) aggressive therapy?


Yes ~ 85% No ~ 15%

5FU/Cape +/- bev K-RAS

Unavailable WT MUT

Doublet + bev Doublet + EGFR inhibitors Doublet + bevacizumab

Doublet + bev

+ inh.EGFR(WT))

Optimal Chemotherapy for the neoadjuvant treatment of non- resectable liver metastases –

Do we have to include biologics in this setting?

Conversion Therapy Considerations: Practical Management • Role of FOLFOX better established than FOLFIRI - Better toxicity profile, more clinical data• FOLFOXIRI attractive …• Limit duration of pre-operative therapy to 3-4 months - Don’t treat to best response, but to resectability - Decrease hepatotoxicity• Role of biologics is evolving - Bevacizumab is not mandatory! - If Bevacizumab is used, d/c 6 wks before planned surgery• EGFR inhibitors could emerge as best option in K-ras wild type CRC

Aggressive Multi-disciplinary

Approach

Take-home Messages

Thank you!

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