Colon cancer: Combining molecular diagnostics and the

art of medicine in the long term management of advanced colon cancer

J. Randolph Hecht, MD

Professor of Clinical Medicine

Director, UCLA GI Oncology Program

David Geffen School of Medicine at UCLA

Median Overall Survival in First-Line MCRC: The Golden Age

BSC

0 6 12 18 24Median OS (mo)

~4-6 mo

12-14 mo

~ 15-16 mo

20.3 mo

?

19-20 mo

5-FU/LV

FOLFOX4 or CAPEOX

IFL + bevacizumab

IFL or FOLFIRI

21.5 moFOLFOX6

FOLFIRI + bevacizumab

BSC = best supportive care.*FOLFOX6 followed by FOLFIRI.

24 mo

BSC 5-FU IFL FOLFOX/IRI

BSC 5-FU IFL FOLFOX/IRI

Modern Chemotherapy for Unresectable Metastatic Disease: 50 Years of Work

• Infusional 5-FU is better than bolus (? Capecitabine)

• Irinotecan and Oxaliplatin: ? Equivalent

• 3 drug hypothesis (Grothey)

• Almost all the improvement in mCRC survival is due to better cytotoxic therapies, not biologic therapies

1st Line Metastatic Colorectal Cancer

• Irinotecan• IFL > 5-FU

• Oxaliplatin• FOLFOX > 5-FU• FOLFOX > IFL

• FOLFOX = FOLFIRI

Treatment: Chemotherapy

• 1st line therapy: CPT-11+5FU/LV (Saltz)– Median survival 14.8 vs. 12.6 mo.– Similar to Douillard, Lancet 2000

NEJM, 2000

1st Line Metastatic Colorectal Cancer

• Irinotecan• IFL > 5-FU

• Oxaliplatin• FOLFOX > 5-FU• FOLFOX > IFL

• FOLFOX = FOLFIRI

0

10

20

30

40

50

60

70

80

90

100

0 1 2Years

% A

live

IFL (med 15.0 mo)

FOLFOX4 (med 19.5 mo)

IROX (med 17.4 mo)

FOLFOX4 vs IFL (P=.0001; HR=0.66) IROX vs IFL (P=.04)

N9741: Overall Survival

Goldberg et al. J Clin Oncol. 2004;22:23.

1st Line Metastatic Colorectal Cancer

• Irinotecan• IFL > 5-FU

• Oxaliplatin• FOLFOX > 5-FU• FOLFOX > IFL

• FOLFOX = FOLFIRI

Colucci, G. et al., J Clin Oncol; 23:4866-4875 2005.

FOLFOX n = 172, 34% RRFOLFIRI n = 164, 31% RRP = 0.60

Copyright © American Society of Clinical Oncology

FOLFOX vs. FOLFIRIin First-Line Metastatic CRC:

Overall Survival

Access to Chemotherapy Improves Survival

Grothey J Clin Oncol 2005;23:9441–9442

Capecitabine

• Converted to systemic 5-FU

• Single agent trials comparable to 5-FU

• CapeOx = FOLFOX (Cassidy)

• ? CapeIRI– Some trials with excessive toxicity– ? Reduced efficacy BICC-C (Fuchs)

Modern Synthesis of Chemotherapy for mCRC 2012

• Combination chemotherapy if possible

• “Continuum of Care”

• Chose for toxicity, not efficacy

• 2nd Line ChemotherapyWhatever they didn’t get 1st line

Molecular Markers

• Colorectal cancers are molecularly heterogeneous– MSI, KRAS, CIMP

– We already do this in other cancers

– Cytotoxics have targets too!

– And yet we treat them all the same!

– Still no validated markers for efficacy or toxicity (sorry Response Genetics!)

Eng at al. BMC Cancer 2010

Advanced Disease: “Standard” Biological Therapies

• Angiogenesis inhibitors– Cancers need new vasculature to grow beyond a certain size

(Folkman)– Multiple angiogenic factors– Hypoxia

• Epidermal growth factor receptor (EGFR) antagonists– Member of HER (ErbB) family of tyrosine kinases– Multiple ligands:

TGF-, EGF, amphiregulin, betacellulin, HB-EGF, and epiregulin

– Undergoes hetero and homodimerization– Activation of multiple downstream pathways including Ras, ERK1/2,

PI3K/AKT, and STAT pathways– Leads to proliferation, survival, angiogenesis, and metastasis

The VEGF and VEGF-Receptor Family

• VEGF regulates angiogenesis via interaction with receptor tyrosine kinases – VEGFR-2/KDR and VEGFR-1/Flt-1

VEGFR-1

(Flt-1)

VEGF-A

Receptorisoforms

Ligandisoforms

VEGFR-2

(KDR)

VEGF-B

VEGFR-1s

Angiogenesis

VEGF-E VEGF-C VEGF-D

VEGFR-3

(Flt-4)

Lymph angiogenesis

tumor metastases

Extracellular

Intracellular

VEGF-A 165

NRP-1

PlGF

Agents Targeting the Vascular Endothelial Growth Factor (VEGF)

Pathway

VEGFR-2VEGFR-1P

PPPP

PPP

Endothelial cellSmall-molecule

VEGFR inhibitors (regorafenib, PTK787,

sunitinib)

Anti-VEGFR antibodies(IMC-1121b)

Soluble VEGF

receptors(aflibercept)

VEGFAnti-VEGF antibodies

(bevacizumab)

First-Line Irinotecan/5-FU/LV + Bevacizumab

Hurwitz H et al. N Engl J Med. 2004;350:2335-2342.

HR = 0.66, P <.001

Per

cen

t S

urv

ivin

g

Duration of Survival (months)

1.0

0.8

0.6

0.4

0.2

0.0

0 10 20 30 40

IFL/bevacizumab IFL/placebo 20.315.6

10.6

100

80

60

40

20

0

0 10 20 30

Pro

gre

ssio

n-f

ree

Su

rviv

al (

%)

Progression-Free Survival (months)

6.2

(n = 402)

(n = 411)

HR = 0.54, P <.001

How was this information processed by the oncology community?

• FOLFOX/bevacizumab became the standard of care– FOLFOX > IFL– IFL+bev > IFL– Ergo, FOLFOX+bev must be > FOLFOX alone, right?

• What was the FOLFOX/ bevacizumab data?– Giantonio E3200 second line– TREE phase II trials– NO16966

PFS chemotherapy + bevacizumab superiority: primary objective met

0 5 10 15 20 25

Months

PF

S e

stim

ate

HR = 0.83 [97.5% CI 0.72–0.95] (ITT)p = 0.0023

9.48.0

1.0

0.8

0.6

0.4

0.2

0

FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

Second Line Bevacizumab: E3200

FOLFOX4 +Bevacizumab

(10 mg/kg, q 2 weeks)

FOLFOX4

Bevacizumab (10mg/kg, q 2 wks)

Previously treated metastatic CRC

PD

PD

PD

• Stratification factors:– ECOG PS: 0 vs 1, 2

– Prior XRT

Giantonio PASCO 2005

E3200: Overall SurvivalP

r o

b a

b i

l i

t y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (months)

0 3 6 9 12 15 18 21 24 27 30 33 36

ALIVEALIVEDEADDEAD MEDIANMEDIANTOTALTOTAL

A:FOLFOX4 + bevacizumabA:FOLFOX4 + bevacizumab 289289 246246 4343 12.912.9B:FOLFOX4B:FOLFOX4 290290 257257 3333 10.810.8C:bevacizumabC:bevacizumab 243243 216216 2727 10.210.2

HR = 0.76

A vs B: p = 0.0018

B vs C: p = 0.95

Giantonio BJ, et al. ASCO 2005

Bevacizumab Beyond Progression

• Bevacizumab Approved• “in combination with intravenous 5-fluorouracil–

based chemotherapy, is indicated for first- OR second-line treatment of patients with metastatic carcinoma of the colon or rectum.” (PI)

• What is the data supporting second-line bevacizumab in bevacizumab failures?• BRITE Registry: Nonrandomized!• ML 18147/AIO Trial FOLFIRI +bev > FOLFIRI OS PR 1/26/12

Aflibercept (VEGF-TRAP)• Fully human fusion protein and

soluble recombinant decoy VEGF receptor composed of Domain 2 of VEGFR1 and Domain 3 of VEGFR2 fused to the Fc of IgG1

• Higher affinity for VEGF-A than bevacizumab and also blocks PlGF; T1/2 17 days

• Where has it been?

EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-

VEGF-TRAP (Aflibercept)

Stratification factors:Prior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)

1:1

mCRC afterfailure of an oxaliplatin

based regimenR

600 ptsAflibercept 4 mg/kg

IV+ FOLFIRI q 2 weeks

600 pts Placebo + FOLFIRIq 2 weeks

26

30% of patients had prior BEVPI: Allegra

N=1226

VELOUR: Results

Van Cutsem, et al. WCGC 2011

VELOUR Discussion

• 30% had received bev, reportedly similar results

• How does this compare to bev 2nd line?• What about EGFR Ab in KRAS WT:

SPIRITT?• Does bev treatment change the tumor?

Regorafenib: What A Difference a F Makes!

Regorafenib:• Small molecule inhibitor of VEGFR and FGFR-1

• CORRECT Trial Grothey et al. 760 pts 2:1

• Chemorefractory mCRC vs BSC, interim analysis

• PFS: 1.9 v 1.7m (HR=0.493) p<0.000001

• OS: 6.4 v 5.0m (HR=0.773) p=0.0051

• Statistically positive but is it clinically significant?

Overall survival (primary endpoint)

Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)

1.00

0.50

0.25

0

0.75

200100500 150 300250 400350 450

Days from randomization

Sur

viva

l dis

trib

utio

n fu

nctio

n

Placebo N=255Regorafenib N=505

Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8

Hazard ratio: 0.77 (95% CI: 0.64–0.94)

1-sided p-value: 0.0052

Regorafenib Placebo

Why these results?

• Possibly benefit from long term anti-VEGF inhibition (BRITE)

• Can anti-VEGF therapy worsen post-therapy outcome? (Bevacizumab Addiction)

– Bevacizumab only leads to modest improvement in OS– VEGF inhibition may up-regulate other parts of pathway and other pathways– Preclinical models of increased metastasis with VEGFR-2 inhibition (Rip-

TAG Paez-Ribes, 2009 and sunitinib conditioning Ebos, 2009)– Differences between PFS and OS with PTK/ZK (Hecht ECCO 2007)

Yarden & Sliwkowski Nat Rev Mol Cell Biol 2001

BOND Trial: Randomized Phase II Study With Cetuximab and Irinotecan

% RR for cetuximab alone (n)

% RR for cetuximab + irinotecan (n) P-value

All patients 11 (111) 23 (218) 0.007

Irinotecan-oxaliplatin

failure11 (44) 24 (80) 0.09

Irinotecan refractory

15 (69) 26 (132 0.07

Cetuximab PI. February 2004

What About Earlier in Treatment?

• 1st Line– High RR in phase II trials– CRYSTAL: FOLFIRI +/- cetuximab

• 2nd Line– EPIC: irinotecan +/- cetuximab PFS not OS

• But– Clearly, only some helped – Significant toxicities, particularly with long-term use in most

Why Do We Try to Predict Response?

• Modestly effective drugs that help a subset

• Toxicity

• Expense

Predictors of Response

Predictors of Response

• NSCLC CancerEGFR mutation, K-ras wt correlate with response

• CRCMutations rare

EGFR staining not helpful (Hecht, 2010)

EGFR copy # (Moroni, 2005)

Ligands: amphiregulin, epiregulin (Ford 2007)

K-ras (Lievre, 2006; DiFiore 2007)

Extracellular

Intracellular

Ligand

EGFR

PI3K

Akt

Ras

Raf

MEK

MAPK

Cell motility

MetastasisAngiogenesis

Proliferation

Cell survivalDNA

PTEN

KRAS as a Biomarker for Panitumumab Response in Metastatic CRC

• PFS log HR significantly different depending on KRAS status (p < .0001)• Percentage decrease in target lesion greater in patients with wild-type KRAS receiving

panitumumab• Approved in EU in KRAS WT

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.

EGFR Abs Earlier in Treatment in the Era of KRAS

• CRYSTAL positive, but others (COIN, NORDIC VII) negative

• Second line trials (EPIC, 181) negative for OS

• SPIRITT: FOLFIRI+bev vs FOLFIRI+Pmab 2012

• Role in second line remains unclear

Other Biomarkers For Anti-EGFR Abs?

BRAF

KRAS G13D

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

Does BRAF Mutation Identify Nonresponders?

Extracellular

Intracellular

Ligand

EGFR

PI3K

Akt

Ras

Raf

MEK

MAPK

Cell motility

MetastasisAngiogenesis

Proliferation

Cell survivalDNA

PTEN

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

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

Van Cutsem GI ASCO 2010

KRAS G13D mutations: Effect on outcome in pts with mCRC treated with First Line Chemotherapy +/- cetuximab

Tejpar et al . Abs 3511 ASCO 2011.

Once Again Larger Numbers Needed: Peeters GI ASCO 2012

• Analysis of PRIME, 181, 408 data sets: 2606 pts!

• 40-45% KRAS codon 12 or 13 mutations

• No allele prognostic for PFS or OS

• G13D worse prognosis in PRIME

• Would not treat G13D pts with an anti-EGFR Ab

What is the treatment of mCRC in 2012?

• 1st Line– FP/Ox +bevacizumab (timing of reintroduction?)– FOLFIRI+ bevacizumab

• 2nd Line– If FP/OX+bevacizumab 1st line

• FOLFIRI+bevacizumab• ? FOLFIRI+aflibercept• (FP)+IRI+panitumumab or cetuximab (KRAS WT)

– IF FOLFIRI+bevacizumab 1st line• FP/Ox+bevacizumab• (FP)+IRI+panitumumab or cetuximab (KRAS WT)

• 3rd Line (KRAS WT)– Whatever wasn’t used

• Salvage– ? Regorafenib