anti-egfr antibodies in metastatic colorectal cancer: which patients, when, and how? j. randolph...

Anti-EGFR Antibodies in Metastatic Colorectal Cancer:

Which Patients, When, and How?

J. Randolph Hecht, MD

David Geffen School of Medicine at UCLA

Disclosures

• Research Funding

Amgen

Novartis

GSK

Pfizer

ImClone

Genvec

Roche

Anti-EGFR Ab: Clinical Development

• Single Agent Phase II, Salvage– Saltz, JCO, 2004– Hecht, Cancer, 2007

• Single Agent Randomized Trials, Salvage– 408 Van Cutsem, JCO 2007 – CO.17 Jonker, NEJM, 2008

• Modest RR ~10%

• Modest improvement in PFS, OS

CO.17

Jonker, NEJM, 2007

Combination Trials• Cetuximab

– Saltz (Salvage) Cetuximab+ Irinotecan– Cunningham (2nd line, Salvage) Cetuximab+Irinotecan– EPIC (2nd line) Sobrero PhIII Irinotecan +/- cetuximab– 80203 (1st line) Venook rPhII FOLFOX/FOLFIRI +/- cetuximab– OPUS (1st line) Bokemeyer rPhII FOLFOX +/- cetuximab– CRYSTAL (1st line) Van Cutsem PhIII FOLFIRI +/- cetuximab– COIN (1st line) Maughan PhIII FOLFOX/XELOX +/- cetuximab– CAIRO2 (1st line) Tol CapeOx/bev +/- cetuximab

• Panitumumab– Berlin (1st line) PhII 5-FU/Irinotecan + panitumumab– PRECEPT (2nd line) PhII Cohn FOLFIRI + panitumumab– STEPP (2nd line) PhII Mitchell FOLFIRI + panitumumab– PACCE (1st line with bev) Hecht PhIII FOLFOX/IRI + bev +/- panitumumab

Progression-free survival time (months)

PF

S e

stim

ate

1.0

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 10 12 14 16 18 20

HR = 0.851; 95% CI = [0.726-0.998]

Stratified log-rank p-value = 0.0479

8.9 mo

8.0 mo

FOLFIRI, n=599

Cetuximab + FOLFIRI, n=599

1-year PFS rate23% vs 34%

Subjects at risk

FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI

599 499 392 298 196 103 58 29 12 5 1

CRYSTAL Trial: PFS

Van Cutsem ASCO 2007

Bokemeyer, JCO, 2009

OPUS

Standard Therapy of Metastatic CRC: US 2007

1st Line: FP/oxaliplatin (usually) + bevacizumab

2nd Line: – FOLFIRI + bevacizumab– Irinotecan + cetuximab

3rd Line: – Irinotecan + cetuximab– Single agent cetuximab or panitumumab

Questions Regarding EGFR Abs:

• Clearly only a subset of patients benefit from EGFR antibody therapy, yet almost all patients get some toxicity

• How do we determine which patients will benefit from such therapy?

• Should anti-EGFR Mabs be used earlier in treatment?

EGFR Signaling Pathway

Extracellular

Intracellular

Ligand

EGFR

PI3K

Akt

Ras

Raf

MEK

MAPK

Cell motility

MetastasisAngiogenesis

Proliferation

Cell survivalDNA

PTEN

KRAS

GTPase downstream from numerous receptors

Mutations (codons 12, 13, 61) activating and found in ~40% of CRC regardless of stage

Smaller retrospective trials indicated lack of response with EGFR antibodies (Lievre, De Roock, Khambata-Ford, etc.)

KRAS as a Biomarker for Panitumumab Response in

Metastatic CRC

Patients With Mutant KRAS

Meanin Wks

Stratified log rank test: P < .0001

115/124 (93)

Patients With Wild-Type KRAS

1.0

0.9

Pro

po

rtio

n W

ith

PF

S

0.8

0.70.60.50.4

0.3

0.20.1

00 2 4 6 8 10

Events/N (%)Medianin Wks

Pmab + BSCBSC alone

114/119 (96)

12.37.3

19.09.3

HR: 0.45 (95% CI: 0.34–0.59)

12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52

Weeks

Pro

po

rtio

n W

ith

PF

S

1.0

0.90.8

0.70.60.50.4

0.30.20.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50

Weeks

Pmab + BSCBSC alone Mean

in Wks

76/84 (90)

Events/N (%)Medianin Wks

95/100 (95)

7.47.3

9.910.2

HR: 0.99 (95% CI: 0.73–1.36)

52

Amado et al., JCO 2008.

What About EGFR Ab/Chemotherapy Combinations 1st Line in KRAS WT Pts?

1st Line Chemotherapy/Ab Trials KRAS WT

Maughan ESMO 2009

CRYSTAL PFS 9.9 vs 8.7m HR 0.68 p=0.017

OPUS PFS 7.7 vs 7.2 HR 0.57 p=0.016

COIN PFS 8.6 vs 8.6 m HR 0.96 (0.84-1.09) p=0.60

What About Panitumumab/ Chemotherapy (without Bevacizumab) Combinations

First Line?

Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as first-line

treatment in patients with metastatic colorectal cancer: the PRIME trial

S. Siena,1 J. Cassidy,2 J. Tabernero,3 R. Burkes,4 M.E. Barugel,5

Y. Humblet,6 D. Cunningham,7

F. Xu,8 J. Gansert,8 J.Y. Douillard9 1Ospedale Niguarda Ca’ Granda, Milan, Italy; 2The Beatson West Of Scotland Cancer

Centre, Glasgow, United Kingdom; 3Vall d'Hebron University Hospital, Barcelona, Spain; 4Mount Sinai Hospital, Toronto, Canada; 5Hospital de Gastroenterología,

Buenos Aires, Argentina; 6Centre du Cancer de l'Université Catholique de Louvain, Brussels, Belgium; 7The Royal Marsden NHS Foundation Trust, London, United Kingdom; 8Amgen Inc., Thousand Oaks, California, 9Centre René Gauducheau,

Nantes, France;

Study Schema and Stratification

Treatment Treatment Arm 1:Arm 1:

Panitumumab Panitumumab 6.0 mg/kg Q2W + 6.0 mg/kg Q2W + FOLFOX4 Q2WFOLFOX4 Q2W

EENNRROOLLLLMMEENNTT

EENND D OOF F

TTRREEAATTMMEENNTT

LLOONNGG

TTEERRMM

FFOOLLLLOOWW

UUPP

Disease assessment Disease assessment every 8 weeksevery 8 weeks

Treatment Arm 2:Treatment Arm 2:

FOLFOX4 Q2WFOLFOX4 Q2W

Enrollment Target:Enrollment Target:1150 patients 1150 patients

Randomization stratification:Randomization stratification:• ECOG score: 0-1 vs. 2ECOG score: 0-1 vs. 2• Geographic Region: Western Geographic Region: Western

Europe, Canada, and Australia Europe, Canada, and Australia vs. Rest of the Worldvs. Rest of the World

SSCCRREEEENNIINNGG

PRIME PRIME Study Study CountriesCountries

CanadaCanada

United KingdomUnited KingdomBelgiumBelgiumFranceFranceSpainSpainSwitzerlandSwitzerlandItalyItalyPolandPolandCzech RepublicCzech RepublicHungaryHungaryLatviaLatvia

SouthSouthAfricaAfrica

MexicoMexicoCostaCostaRicaRica

BrazilBrazilChileChileArgentinaArgentina

AustraliaAustralia

Siena Results

• Primary Endpoint (KRAS WT) – PFS: 9.5 vs 8.0m; HR 0.80 (0.66-0.97) p=.02

• Secondary Endpoints (KRAS WT)– OS: 23.9 vs 19.7m; HR 0.83 (0.67-1.02) p=.07– RR: 55 vs 48%

• Increased toxicity: skin, diarrhea, mucositis

• ECOG 2 HR 1.99 (0.96-4.15)

Conclusions• Large, well done randomized trial• KRAS WT data analyzed prospectively• Reached PFS endpoint• Improved OS, but p=0.07• Worse outcome has been seen in ECOG 2 pts in similar

trials• How does this compare to other EGFR Ab 1st line trials?

– Overlapping CI with CRYSTAL and OPUS– Where does COIN fit in?

• Does the chemotherapy backbone matter?• Should panitumumab be approved 1st line?

Conclusions (cont.)• The question is not cetuximab vs panitumumab

but EGFR Ab vs bevacizumab in KRAS WT• Increased RR with EGFR Ab• Increased GI, skin toxicity vs rare ATE, perforation• PEAK (rPhII)

– mFOLFOX6 + panitumumab– mFOLFOX6 + bevacizumab

• CALGB 80405 (PhIII)– FOLFOX/FOLFIRI + cetuximab– FOLFOX/FOLFIRI + bevacizumab– FOLFOX/FOLFIRI + cetuximab + bevacizumab

What About EGFR Ab/Chemotherapy Combinations Second Line?

EPIC (Sobrero)PFS 4.0 vs 2.6m HR 0.78 p=<.0001RR 16.4 vs 4.2%No OS difference (? crossover)

KRASODAC HR 0.70 but <25%of pts

What about panitumumab/chemotherapy combinations second line in KRAS WT patients?

Randomized phase 3 study of panitumumab with Randomized phase 3 study of panitumumab with FOLFIRI vs FOLFIRI alone as 2nd-line treatment in FOLFIRI vs FOLFIRI alone as 2nd-line treatment in patients with metastatic colorectal cancer: Patient patients with metastatic colorectal cancer: Patient

reported outcomes (PRO)reported outcomes (PRO)

M. Peeters,M. Peeters,1 1 T. Price,T. Price,22 Y. Hotko, Y. Hotko,33 A. Cervantes, A. Cervantes,44 M. Ducreux,M. Ducreux,5 5 T. André,T. André,66 A. H. Strickland, A. H. Strickland,77 G. G.

Wilson,Wilson,88 Y. Tian, Y. Tian,99 J. Gansert J. Gansert99

11University Hospital Ghent, Ghent, Belgium; University Hospital Ghent, Ghent, Belgium; 22Queen Elizabeth Hospital, Woodville, Australia; Queen Elizabeth Hospital, Woodville, Australia; 33Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod, Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod,

Ukraine; Ukraine; 44Hospital Clínico Universitario de Valencia, Valencia, Spain; Hospital Clínico Universitario de Valencia, Valencia, Spain; 55Institut Gustave Institut Gustave Roussy, Villejuif, France; Roussy, Villejuif, France; 66Pitié-Salpétrière HospitalPitié-Salpétrière Hospital, Paris, France; , Paris, France; 77Monash Medical Center, Monash Medical Center,

East Bentleigh, AustraliaEast Bentleigh, Australia; ; 88Christie Hospital, Manchester, United KingdomChristie Hospital, Manchester, United Kingdom ; ; 99Amgen Inc., Amgen Inc., Thousand Oaks, CaliforniaThousand Oaks, California

Peeters Results

• Primary Endpoints (KRAS WT)– PFS: 5.9 vs 3.9m; HR 0.73 (0.59-0.90) p=.004– OS: 14.5 vs 12.5m; HR 0.85 (0.70-1.04) p=.12

• Secondary Endpoint– RR: 35 vs 10%

• Increased toxicity: skin, diarrhea, mucositis– Improved EQ-5D OHR (VAS) but not HSI (5 EQ-5D OHR (VAS) but not HSI (5

dimensions) in KRAS wtdimensions) in KRAS wt

Conclusions

• Large well done study• First prospective second line in KRAS WT• Expected toxicity, ? significance of PRO• Excellent PFS, OS in both arms• Statistical improvement in PFS, but not OS in a

“good” KRAS wt group but wide Cis• Should panitumumab be approved in 2nd line

combined with irinotecan based therapy?• Is this the new standard in second line KRAS

WT metastatic CRC?

Conclusions (cont)• How does this compare with bevacizumab

containing regimens?– ECOG 3200 (Giantonio, JCO 2007)– BRITE “study” (Grothey, JCO, 2008)

• Randomized Trials (KRAS WT)– ML18147/AIO0504 (PhIII)

• FP/Ox vs FP/Ox + bevacizumab• FP/Iri vs FP/Iri + bevacizumab

– SPIRITT (rPhII)• FOLFIRI + panitumumab• FOLFIRI + bevacizumab

– S0600 (PhIII)• FOLFIRI/Iri + cetuximab• FOLFIRI/Iri + bevacizumab

Does BRAF Mutation Identify Nonresponders?

Extracellular

Intracellular

Ligand

EGFR

PI3K

Akt

Ras

Raf

MEK

MAPK

Cell motility

MetastasisAngiogenesis

Proliferation

Cell survivalDNA

PTEN

BRAF Background

• BRAF is a serine/threonine kinase downstream of KRAS

• V600E mutation is found in 5-10% of CRCs• Mutation mutually exclusive with KRAS mut• Correlatated with poor prognosis

– Ogino, Gut, 2009– Tol, NEJM, 2009 (letter)

• Retrospective studies correlated with lack of response– Di Nicolantonio, JCO, 2008

Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer: the influence of KRAS and

BRAF biomarkers on outcome: updated data from the CRYSTAL trial

Eric Van Cutsem*, I Lang, G. Folprecht, M.P. Nowacki,

S. Cascinu, I. Shchepotin, J. Maurel,

D. Cunningham, Ph Rougier,

I. Celik, C.H. Köhne

*University Hospital Gasthuisberg,

Leuven, Belgium

Updated CRYSTAL Results KRAS WT (From Paper and ASCO)

• More pts analyzed, longer follow-up, retrospective analysis

• PFS– 9.9 vs 8.4m HR 0.70 p=.0012

• OS– 23.5 vs 20.0m HR 0.80 p=.0093

• PS 2 ? less benefit (small numbers)• Yes, OS is now statistically significant, but

does this change anything?

Clinical efficacy in KRAS wild-type tumors by BRAF mutation status

KRAS wt/BRAF wt (n=566)

KRAS wt/BRAF mt (n=59)

FOLFIRI 

(n= 289)

Cetuximab +FOLFIRI (n= 277)

FOLFIRI 

(n=33)

Cetuximab +FOLFIRI

(n=26)

Median OS mo[95% CI]

21.6[20.0–24.9]

25.1[22.5–28.7]

10.3[8.4–14.9]

14.1[8.5–18.5]

HR [95% CI]p-valuea

0.830 [0.687–1.004]0.0549

0.908 [0.507–1.624]0.7440

Median PFS mo[95% CI]

8.8[7.6–9.4]

10.9[9.4–11.8]

5.6[3.5–8.1]

8.0[3.6–9.1]

HR [95% CI]p-valuea

0.679 [0.533–0.864]0.0016

0.934 [0.425–2.056]0.8656

OR rate (%)[95% CI]

42.6[36.8–48.5]

61.0[55.0–66.8]

15.2[5.1–31.9]

19.2[6.6–39.4]

p-valueb <0.0001 0.9136

CI, confidence interval; OR, best overall response; OS, overall survival; PFS, progression-free survival; mo, months; mt, mutant; wt, wild-type

aStratified log-rank test; bCochran-Mantel-Haenszel test

Conclusions• BRAF confirmed as marker of poor prognosis

• Not so fast on excluding people from EGFR treatment (NCCN guidelines), but small numbers

• Need to look at randomized studies to validate predictive markers

• Possible target for therapy (PLX4032 in melanoma)

Standard Therapy of Metastatic CRC: US 2010

KRAS WT1st Line:

FP/oxaliplatin or Iri + bevacizumabFP/Ox or Iri + cetuximab*FP/Ox + panitumumab*

2nd Line: FP/oxaliplatin or Iri + bevacizumabIrinotecan + cetuximab (if EGFR Ab not used 1st line)FOLFIRI + panitumumab* (if EGFR Ab not used 1st line)

3rd Line: Irinotecan + cetuximab (if EGFR Ab not used earlier)Single agent cetuximab or panitumumab (if not used earlier)

Standard Therapy of Metastatic CRC: US 2010

KRAS Mut1st Line:

FP/oxaliplatin or Iri + bevacizumab

2nd Line: FOLFIRI or FP/ox + bevacizumab

3rd Line: Clinical trialBSC