Monoclonal Antibodies EGFR Inhibitors for Metastatic Colorectal Cancer: Where are we and What’s next

Discussion of Abstracts 4032-4035

Jeffrey Meyerhardt, MD MPHDana-Farber Cancer Institute

Boston, MA

Monoclonal EGFR Inhibitor History for CRC at ASCO

2001 – Abstract 7 (Saltz) Irinotecan + Cetuximab ~20% response rate in irinotecan-refractory patients

2002 – Abstract 504 (Saltz) Single agent Cetuximab ~11% response rate in irinotecan-refractory patients

2003 – Abstract 1012 (Cunningham) BOND trial

Monoclonal EGFR Inhibitor History for CRC at ASCO

2004 – Abstract 3512 (Tabernero) – Cetuximab + FOLFOX 50 patients -> 70% RR

2004 – Abstract 3513 (Rougier) – Cetuximab + FOLFIRI 23 patients -> 44% RR but TTP 10.9 months

2005 – Abstract 3508 (Saltz) – Cetuximab + Bevacizumab with or without Irinotecan2005 – Abstract 3520 (Malik) – Single agent panitumumab

Monoclonal EGFR Inhibitor History for CRC at ASCO

2006 – Abstract 3509 (Venook) – CALGB 80203 2 x 2 trial – FOLFIRI v FOLFOX +/- Cetuximab Efficacy

FOLFOX FOLFOX + Cetuximab

FOLFIRI FOLFIRI + Cetuximab

N 58 53 58 55Response rate

40% 60% 36% 44%

Venook et al Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3509

PFS 9.8 m 8.2 m 8.4 m 10.6 m

Monoclonal EGFR Inhibitor History for CRC at ASCO

2007 – Abstract 4000 (Van Cutsem) – CRYSTAL

FOLFIRI FOLFIRI + Cetuximab

N 599 599Response rate 39% 47%Median PFS 8.0 8.9 p = 0.047

Van Cutsem et al JCO, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4000

Monoclonal EGFR Inhibitor History for CRC at ASCO 2008 – Abstract 237 @ GI ASCO (Hecht) - PACCE

Bevacizumab +

Ox-CT(n = 410)

Pmab+ Bevacizumab +

Ox-CT(n = 413)

Bevacizumab +

Iri-CT(n = 115)

Pmab+ Bevacizumab +

Iri-CT(n = 115)

Best ORR 46 % 45 % 37 % 40 %

Median PFS 11 m 9.5 m 10.7 m 10.6 m

Hecht GI ASCO, abstract 273

Conclusions regarding efficacy til ASCO 2008

Single agent cetuximab or panitumumab – about 10% response rate, 30% stable disease rate – benefit often short lived, some long

Cetuximab + irinotecan active in 2nd and 3rd line

Cetuximab + combination cytotoxics active in first line therapy Maybe not as initially reported (not 70% RR) Interaction with oxali regimens in PFS? Activity comparable to bevacizumab + combination cytotoxics

in first line

Where do 4 anti-EGFR abstracts from today’s colorectal cancer poster discussion session fit?

3 trials regarding safety and efficacy of first-line cetuximab/panitumumab German AIO CRC Study Group led by Heinemann:

XELOX + Cetuximab v XELIRI + Cetuximab (4033) CECOG led by Ciuleanu: FOLFOX + Cetuximab v

FOLFIRI + Cetuximab (4032) PRIME led by Siena: FOLFOX +/- Panitumumab (4034)

Meta-analysis of small K-ras studies Di Fiore and colleagues combined data from 7 studies

(4035)

Heinemann et al Cetuximab plus XELIRI or XELOX

Randomized multi-center trial – 35 centers

185 previously untreated met CRC

Primary objective: Response Rate

Secondary objectives: TTP, Disease control, Tolerability

Heinemann et al Cetuximab plus XELIRI or XELOX Day: 1 8 15 21

Arm A: (*)Irinotecan200mg/m², 30min i.v.Cetuximab (**)250mg/m², 60min i.v. Capecitabine800mg/m² p.o., twice daily

Arm B:Oxaliplatin130mg/m², 120min i.v.Cetuximab (**)250mg/m², 60min i.v.Capecitabine1000mg/m² p.o., twice daily

(*): 20% dose reduction for patients > 65 years, arm A(**): Cetuximab initial dose: 400mg/m², 120min

q 3 weeks

Day: 1 8 15 21

Arm A: (*)Irinotecan200mg/m², 30min i.v.Cetuximab (**)250mg/m², 60min i.v. Capecitabine800mg/m² p.o., twice daily

Arm B:Oxaliplatin130mg/m², 120min i.v.Cetuximab (**)250mg/m², 60min i.v.Capecitabine1000mg/m² p.o., twice daily

(*): 20% dose reduction for patients > 65 years, arm A(**): Cetuximab initial dose: 400mg/m², 120min

q 3 weeks(*): 20% dose reduction for patients > 65 years, arm A(**): Cetuximab initial dose: 400mg/m², 120min

Heinemann et al Cetuximab plus XELIRI or XELOX

XELIRI + Cetuximab XELOX + Cetuximab

Response rate 47% 48%Median TTP 6.7 m 7.9 mMedian TTF 4.7 5.1 m Higher rates of grade III+ toxicity

Neutropenia/Anemia Neuropathy

Dose reductions 34 % 44 %Dose delay 17 % 17 %

Heinemann et al Cetuximab plus XELIRI or XELOX

What did we learn? XELIRI + Cetuximab and XELOX + Cetuximab can be given

in first line with good responses but lower TTP than usually seen with combination cytotoxics + biologic in this trial

Though not statistically different, skin changes meaningful

XELIRI + Cetuximab XELOX + Cetuximab

Grade 3 + Exanthema / desquamation

14 % 6 %

Grade 3+ Skin (other) 5 % 21 %

Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX

Randomized multi-center trial

151 previously untreated met CRC

Primary objective: 9 months PFS rate

Secondary objectives: PFS at 3,6,12 months, OS, RR, safety

Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX

RANDOMI

Z E

Arm A: Cetuximab + FOLFOX 6Arm A: Cetuximab + FOLFOX 6Cetuximab 400 mg/m2 day 1 then 250Cetuximab 400 mg/m2 day 1 then 250 mg/m2 weeklymg/m2 weeklyOxaliplatin 100 mg/m2 day 1Oxaliplatin 100 mg/m2 day 15-FU bolus 400 mg/m2 day 15-FU bolus 400 mg/m2 day 1Leucovorin day 1 every 2 wksLeucovorin day 1 every 2 wks5-FU CI 2400 mg/m2 over 46 hours5-FU CI 2400 mg/m2 over 46 hours

Arm B: Cetuximab + FOLFIRIArm B: Cetuximab + FOLFIRICetuximab 400 mg/m2 day 1 then 250Cetuximab 400 mg/m2 day 1 then 250 mg/m2 weeklymg/m2 weeklyIrinotecan 180 mg/m2 day 1Irinotecan 180 mg/m2 day 15-FU bolus 400 mg/m2 day 15-FU bolus 400 mg/m2 day 1Leucovorin day 1 every 2 wksLeucovorin day 1 every 2 wks5-FU CI 2400 mg/m2 over 46 hours5-FU CI 2400 mg/m2 over 46 hours

Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX

FOLFIRI + Cetuximab

FOLFOX + Cetuximab

PFS @ 9 months 34 % 45 %Median PFS 8.3 m 8.6 mResponse rate 45 % 43 %

Higher rates of grade III+ toxicity

-- ANC / Platelets

Dose reductions 30 % 45 %Dose delay > 14 days

20 % 32 %

Ciuleanu et al Cetuximab plus FOLFIRI or FOLFOX

What did we learn?

1st line FOLFIRI + Cetuximab and FOLFOX + Cetuximab similar efficacy and tolerability

Results similar-ish to first line bevacizumab trials 9.4 m PFS N016966 (FOLFOX + Bevacizumab) 11.2 m PFS BICC-C (FOLFIRI + Bevacizumab)

Differential interaction with cytotoxic backbone not answered

Siena et al FOLFOX +/- Panitumumab

Randomized multi-center trial

1183 previously untreated met CRC

Primary objective: PFS

Secondary objectives: OS, RR, duration of response, TTP, safety, tolerability

Siena et al FOLFOX +/- Panitumumab

RANDOMI

Z E

Arm A: Panitumumab + FOLFOX 4Arm A: Panitumumab + FOLFOX 4Panitumumab 6 mg/kg Panitumumab 6 mg/kg FOLFOX – 4FOLFOX – 4Every 2 weeksEvery 2 weeks

Arm B: FOLFOX 4Arm B: FOLFOX 4FOLFOX – 4FOLFOX – 4Every 2 weeksEvery 2 weeks

Siena et al FOLFOX +/- Panitumumab

Safety analysis

The safety interim analyses were prospectively planned for enrollment milestones: 25, 100, 300, 600, and 900 patients

The analysis set presented here is for the 900 patient cutoff

Siena et al FOLFOX +/- Panitumumab

No red flags in safety

Safety data not broken down by treatment arm

Investigators promise in the future… Further safety – presumably by treatment arm Efficacy for all patients and for K-ras wildtype

Blocks required for enrollment but not prospectively tested

K-ras story

Khambata-Ford et al Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3230-3237

K-ras story

Lievre, A. et al. Cancer Res 2006;66:3992-3995

30 pts MCRC

Most with prior irinotecan exposure

97% irinotecan + cetuximab regimen

K-ras story

Khambata-Ford et al Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3230-3237

Single agent cetuximab therapy

K-ras storyK-ras Mutation Wild-Type K-ras

Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.

Panitumumab registration trial

Di Fiore et al K-ras meta-analysis

281 irinotecan-refractory patients treated with cetuximab plus irinotecan based-chemotherapy from 7 studies ranging in size 27-113 patients

Patients received a mean of 2.4 ± 1.0 chemotherapy lines before cetuximab

35% had KRAS mutation

Di Fiore et al K-ras meta-analysis K-ras

Wildtype2 %

41 %36 %21 %

5.4 m13.2 m

Response to cetuximab-Irinotecan (n,%)Complete response 3 1.1%Partial response 74 26.3%Stable disease 107 38.1%Progressive disease 97 34.5%Survival Times in months (median, IC95)Progression-free Survival (PFS)

4.5 3.8-5.1

Overall Survival (OS) 10 8.7-11.2

K-ras mutation

0 %0 %

41 %58 %

2.7 m8 m

Di Fiore et al K-ras meta-analysis

6

Di Fiore et al K-ras meta-analysis

Di Fiore et al K-ras meta-analysis

What did we learn? Another confirmation that in 2nd line and beyond use of

cetuximab (and p-mab), K-ras is predictive of response rate, progression-free survival and likely overall survival

Should we start testing?

Should we stopping using cetuximab and panitumumab in patients with K-ras mutations?

Do THESE data move monoclonal EGFR inhibitors to first-line?

YES

PROBABLY YES

NO

K-ras storyAt ASCO 2008 Clinical Science Symposium Saturday 1:15 pm OPUS Trial

RANDOMIZ E

FOLFOX

FOLFOX + Cetuximab

n = 110

n = 113

Response Rate PFS Response Rate PFS

Wild-type K-ras (n = 134) 37% 7.2 m 61% 7.7 m

Mutant K-ras (n = 99) 49% 8.6 m 33% 5.5 m

Bokemeyer ASCO 2008; JCO 28: May 20 suppl; abstr 4000.

FOLFOX FOLFOX + Cetuximab

K-ras storyAt ASCO 2008 Oral Colorectal Session Saturday 3 pm CAIRO-2 Trial

RANDOMIZ E

CAPEOX + Bevacizumab

CAPEOX + Bevacizumab + Cetuximab

All patientsCAPEOX + Bevacizumab 10.7 m CAPEOX + Bevacizumab + Cetuximab 9.6 mP value 0.02

Punt ASCO 2008; JCO 28: May 20 suppl; abstr 4011

K-ras wildtype K-ras mutant10.7 m 12.5 m10.5 m 8.6 m

0.1 0.04

K-ras storyAt ASCO 2008 Plenary Session TODAY 1 pm CRYSTAL Trial

RANDOMIZ E

FOLFIRI

FOLFIRI + Cetuximab

n = 599

n = 599

Van Cutsem ASCO 2008; JCO 28: May 20 suppl; abstr 2.

K-ras subset analysis to be presented

ConclusionsMonoclonal antibodies against EGFR continue to prove to be active in metastatic colorectal cancer

Role in first-line setting has more questions than answers Equivalence to bevacizumab – unknown Differential interaction with oxaliplatin and irinotecan?

K-ras story our first step to tailoring therapy to the patient We avoid toxicity to 30-40% of patients We lost an option for 30-40% of patients

Current and future trials will need to incorporate K-ras data