Personalized Therapy in Colorectal Cancers

J. Randolph Hecht, MDProfessor of Clinical Medicine

Director, UCLA GI Oncology ProgramDavid Geffen School of Medicine at UCLA

What Does Personalized Therapy Mean?

• Right Treatment

• Right Patients

Biomarker• NIH Definition: a characteristic that is objectively

measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

• Predictive: (Ex: HER-2, BRAF, cytogentic abnormalities)

• Prognostic: (Ex: HER-2, KRAS)

Biomarkers

Evaluating Predictive Biomarkers: Trial Design

Patient Population R

Biomarkerpositive

Biomarkernegative

Receive treatment

Do not receive treatment

Receive treatment

Do not receive treatment

Biology of Colorectal Cancers

• Subgroup Analysis– Breast cancer does it, is it time for CRC?

• CIN vs MSI vs CIMP+– CIN: Majority of tumors MSS, APC mutation– MSI: Abnormal DNA mismatch repair

• ~15%• Most Sporadic (BRAF mut); others HNPCC

• Molecular Subgroup Analysis

Tabernero, ASCO GI 2013

Uronis, ASCO GI 2013

Cancer Genome Atlas Network, Nature 2012

Biomarkers• Histology: TNM

Dukes, J Path Bacteriol, 1932

Survival Rates of by Stage of Adenocarcinoma of the Colon

Edge SB, et al. AJCC cancer staging manual. 2010. Data from the SEER 1973-2005 Public Use File diagnosed in years 1998-2000.

Surv

ival

Rat

e

0

20

0

40

60

80

100

1 2 3 4 5

30

50

70

90

10

100100100100100100100100

IIIAIIBIICIIIAIIIBIIIC

IV

91.489.985.466.098.383.471.939.9

87.083.477.852.588.070.850.319.7

82.677.869.145.383.659.339.011.3

78.272.062.941.579.151.732.97.6

74.066.558.637.373.146.328.05.7

Yrs From Diagnosis

Other Putative Biomarkers:

• Molecular pathology• CTCs• Molecular abnormalities

– Mutations– microRNAs

• Gene expression profiles

Where Would Biomarkers Be Most Useful?

• Adjuvant– Treat those who would benefit– Don’t treat those that won’t

• Metastatic Disease– We have multiple agents. How can we

choose for safety and efficacy?

Stage II Colon Cancer

• Which stage II colon cancer patients should be treated with adjuvant chemotherapy?– 75% to 80% cured with surgery alone– Benefit of chemotherapy is small and no

consensus on whom to treat or on how to identify whom to treat

• Decision to give chemotherapy based on– Clinical/pathologic markers of risk– Molecular biomarkers – Not informative for majority of patients

1.0

0.8

0.6

0.4

0.2

0

Stage II Stage III

Follow-up (Yrs)

Surgery alone: 66.8%Surgery + FU-based chemotherapy: 72.2%

Surgery alone: 42.7%Surgery + FU-based chemotherapy: 53.0%

0 1 2 3 4 5 6 7 8

1.0

0.8

0.6

0.4

0.2

0

Sargent D, et al. J Clin Oncol. 2009;27:872-877.

∆ = 5.4%P = .026

0 1 2 3 4 5 6 7 8

∆ = 10.3%P < .0001

Adjuvant Therapy Increases OS:ACCENT Database of 20,898 Patients

Prob

abili

ty o

f Sur

viva

l

Prob

abili

ty o

f Sur

viva

l

Determining Who Benefits From Adjuvant Therapy in CRC

• Risk assessment in stage II (III) CRC: prognostic factor(s) of recurrence of disease and predictive factor(s) to the treatment.– High-risk prognostic factors[1]

• Stage II: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion, or < 10 examined nodes

• Stage III: age, lymph node involvement, T stage, tumor obstruction, differentiation

– Defective mismatch repair and microsatellite instability[2-5]

1. André T, et al. J Clin Oncol. 2009;27:3109-3116. 2. Hutchins G, et al. J Clin Oncol. 2011;29:1261-1270. 3. Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226. 4. Sinicrope FA, et al. J Natl Cancer Inst. 2011;103:863-875. 5. Ribic CM, et al. N Engl J Med. 2003;349:247-257.

MOSAIC: Exploratory Analysis of DFS and OS in “High-Risk” Stage II CRC

André T, et al. J Clin Oncol. 2009;27:3109-3116.

0.4 0.6 0.8 1.0 1.2 1.4 1.6

Stage II

High-risk stage II

Stage III

Stage II

High-risk stage II

Stage III

OS at 6 Yrs

DFS at 5 Yrs

HR

Favors FOLFOX4 Favors LV5FU2

Missed Micrometastases

IHC+

H&E

LN “N0”

RT-PCR+

MMR-D (MSI) Is a Favorable Prognostic Marker in Stage II (and III) Colon Cancer

Study StageTreatment

EndpointMMR-D vs MMR-P

HR (95% CI; P Value)

Ribic et al[1] II/IIISurgery alone OS 0.31 (0.14-0.72; .004)

Roth et al(PETACC-3)[2]

II5-FU/LV ± irinotecan

Relapse-free survival

OS

0.27 (0.10-0.72; .0094)0.14 (0.03-0.64; .011)

Sargent et al[3] II/IIISurgery alone

DFSOS

0.46 (0.22-0.95; .03*)0.51 (0.24-1.10; .06*)

Gray et al(QUASAR)[4]

IISurgery alone

Recurrence-free interval 0.31 (0.15-0.63; < .001)

1. Ribic CM, et al. N Engl J Med. 2003;349:247-257. 2. Roth AD, et al. J Clin Oncol. 2010;28:466-474. 3. Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226. 4. Gray R, et al. J Clin Oncol. 2011;29:4611-4619.

5-FU Not Beneficial and Survival Longer in Stage II Patients With MMR Deficiency

Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226.

No Adjuvant 5-FU Chemotherapy

Adjuvant 5-FU Chemotherapy

HR for OS: 0.47 (95% CI: 0.26-0.83;

P = .004)

HR for OS: 0.78 (95% CI: 0.49-1.24;

P = .28)

Perc

ent A

live

and

Prog

ress

ion

Free

Yrs0 21 3 4 5

0

20

40

60

80

100

MMR-d (n = 86)MMR-p (n = 426)

HR: 0.79 (95% CI:0.49-1.25; P = .30)

Perc

ent A

live

and

Prog

ress

ion

Free

Yrs0 21 3 4 5

0

20

40

60

80

100

MMR-d (n = 79)MMR-p (n = 436)

HR: 0.51 (95% CI:0.29-0.89; P = .009)

• Gene signatures provide prognostic, not predictive, information• 12-gene recurrence score assay validated for recurrence risk in

stage II patients

– QUASAR: 12% (low risk) vs 22% (high risk) 3-yr recurrence risk[1]

– CALGB 9581: 13% (low risk) vs 21% (high risk) 5-yr recurrence in T3, MMR proficient disease[2]

1. Gray RG, et al. J Clin Oncol. 2011;29:4611-4619. 2. Venook AP, et al. ASCO 2011. Abstract 3518.

Genomic Tests for CRC Risk Stratification

Ris

k of

Rec

urre

nce

at 5

Yrs

(%)

Colon Cancer Recurrence Score0 2010 30 40 50 60

0

5

10

15

20

25

30

35

70

Risk95% CI

Ris

k of

Rec

urre

nce

at 3

Yrs

(%)

Recurrence Score0 2010 30 40 50 60

0

5

10

15

20

25

30

35

70

P = .004

Personalized Therapy For Metastatic Disease

• Cytotoxics

• Anti-EGFR Antibodies

• Anti-VEGF Pathway Agents

Cytotoxic Agents

• Fluoropyrimidines– TS: A target. No clear evidence for choosing therapy– DPD: Dihydropyrimidine dehydrogenase deficiency

associated with severe FP toxicity• Testing only in patients with toxicity

• Irinotecan– UGT1A1*28 (10% of North Americans)

• Originally associated with diarrhea but later studies with neutropenia instead

• In package insert, but not used– Topo 1: Conflicting data

• Oxaliplatin– ERCC1: Unproven for efficacy

Anti-EGFR Agents

EGFR Signaling Pathway

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

1.00.9

Prop

ortio

n W

ith P

FS

0.80.70.60.50.40.30.20.1

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

Prop

ortio

n W

ith P

FS

1.00.90.80.70.60.50.40.30.20.1

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.

Tejpar et al., ASCO 2011

What About G13D (~20% mutations)

No Effect Of G13D in Larger Sample

Peeters ASCO GI 2012

EGFR Signaling Pathway

Extracellular

Intracellular

Ligand

EGFR

PI3K

Akt

Ras

Raf

MEK

MAPK

Cell motility

MetastasisAngiogenesis

Proliferation

Cell survivalDNA

PTEN

BRAF– V600E mutation relatively common in CRC (5-15%)

– Poor prognostic factor (Van Cutsem ASCO GI, 2010)• FOLFIRI+cetuximab PFS: 25.1 vs 14.1 months

– Inhibitors: sorafenib, PLX4032 (vemurafenib)

– PLX4032: 70% RR in V600E melanoma, but 5% in CRC

CI, confidence interval; CT, chemotherapy; HR, hazard ratio; mt, mutant; OS, overall survival; wt, wild-type

32 25 16 12 8 5 2 2 2 038 24 14 6 6 3 3 1 0 0

00CT

CT + cetuximab

Pro

babi

lity

of o

vera

ll su

rviv

al

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

180 6 12 24 6030 36 42 48 54Time (months)Number of patients

349 317 268 225 163 120 80 63 19 4381 350 283 212 149 107 63 46 17 2

00CT

CT + cetuximab

KRAS wt/BRAF wtHR [95% CI]: 0.840 [0.710–0.993]p=0.041 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 24.8 months FOLFIRI / FOLFOX4: (n=381) median 21.1 monthsKRAS wt/BRAF mtHR [95% CI]: 0.633 [0.378–1.060]p=0.079 FOLFIRI / FOLFOX4 + cetuximab: (n=32) median 14.1 months FOLFIRI / FOLFOX4: (n=38) median 9.9 months

Bokemeyer

Pooled analysis of OS in patients with KRAS wt/BRAF mt tumors

Other Markers (Unknown Benefit)

• Rare KRAS mutations• NRAS• Ligands (amphiregulin, epiregulin)• Copy Number

Anti-VEGF Pathway Drugs

None!

Molecular Profiling

• Multiple Targets (Caris, Foundation Medicine)• Sequencing• Explants

• No Evidence of Clinical Benefit• Hours of Physician Time

We are on the verge of truly personalized therapy for colorectal cancer

• We need to be able to identify subgroups by genetic alterations and activated pathways

• We need to validate molecular tests before selling them to the public

• We need to identify new targets for new drugs• We may have to find ways to do trials in small

subsets

BONUS

New indications for anti-VEGF pathway agents!!

Agents Targeting the Vascular Endothelial Growth Factor (VEGF) Pathway

VEGFR-2VEGFR-1PPP

PPPP

P

Endothelial cell Small-moleculeVEGFR inhibitors

(PTK787, sunitinib, sorafenib, regorafenib, axitinib)

Anti-VEGFR antibodies(IMC-1121b)

Soluble VEGF

receptors(VEGF-TRAP/ aflibercept)

VEGFAnti-VEGF antibodies

(bevacizumab)

Golden Age of CRC Therapeutics: Bevacizumab

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

HR = 0.66, P <.001

Perc

ent S

urvi

ving

Duration of Survival (months)

1.0

0.8

0.6

0.4

0.2

0.00 10 20 30 40

IFL/bevacizumab IFL/placebo

20.315.6

10.6

100

80

60

40

20

00 10 20 30

Prog

ress

ion-

free

Sur

viva

l (%

)

Progression-Free Survival (months)

6.2

(n = 402)

(n = 411)

HR = 0.54, P <.001

What About Angiogenesis Inhibition After First Line Therapy?

• Bevacizumab• Aflibercept• Regorafenib

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

ALIVEDEAD MEDIANTOTALA:FOLFOX4 + bevacizumab 289 246 43 12.9B:FOLFOX4 290 257 33 10.8C:bevacizumab 243 216 27 10.2

HR = 0.76A vs B: p = 0.0018B vs C: p = 0.95

Giantonio BJ, et al. ASCO 2005

No first line bev!

BEV + standard first-line CT (either

oxaliplatin oririnotecan-based)

(n=820)

Randomise 1:1

Standard second-line CT (oxaliplatin or irinotecan-

based) until PD

BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-

based) until PD

PD

ML18147 (TML) study design

CT switch:Oxaliplatin → IrinotecanIrinotecan → Oxaliplatin

Study conducted in 220 centres in Europe and Saudi Arabia

Primary endpoint • Overall survival (OS) from randomisation

Secondary endpoints included

•Progression-free survival (PFS)•Best overall response rate•Safety

Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)• First-line PFS (≤9 months, >9 months)• Time from last BEV dose (≤42 days, >42 days)• ECOG PS at baseline (0/1, 2)

Arnold 2012

OS: ITT populationO

S es

timat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48

No. at riskCT 410 293 162 51 24 7 3 2

0BEV + CT 409 328 188 64 29 13 4 1

0

CT (n=410)BEV + CT (n=409)

9.8 mo 11.2 mo

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)p=0.0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)p=0.0211 (log-rank test)

aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

PFS: ITT populationPF

S es

timat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

No. at riskCT 410 119 20 6 4 0 0 0BEV + CT 409 189 45 12 5 2 2 0

CT (n=410)BEV + CT (n=409)

4.1 mo 5.7 mo

Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test)

Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)p<0.0001 (log-rank test)

aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

What else does TML teach us?

• Affirms the limited utility of Registry studies regarding interventions and outcomes:– BRITE: 9.5 v. 19.2 OS beyond PD– TML: 9.8 v. 11.2

BRiTE findings not replicated; the publication* could be cited as an example of the pitfalls of Registry data

* Grothey et al, JCO, 2008 Venook 2012

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

• EFC10262 (VELOUR )– Phase III Trial 2nd Line

FOLFIRI +/- VEGF-TRAP (Aflibercept)

• Where has it been?

VELOUR Study Design

Primary endpoint: overall survival

Sample size: HR=0.8, 90% power, 2-sided type I error 0.05

Final analysis of OS: analyzed at 863rd death event using a 2-sided nominal significance level of 0.0466 (α spending function)

Metastatic Colorectal Cancer

RANDOMIZE

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks

Placebo IV, day 1+ FOLFIRIq2 weeks

1:1 Disease Progression Death

600

600Stratification factors:• ECOG PS (0 vs 1 vs 2)• Prior bevacizumab (Y/N)

VELOUR: Results

Van Cutsem, et al. WCGC 2011

VELOUR Study• Overall results

– Adding aflibercept to FOLFIRI in mCRC patients previously treated with an oxaliplatin-based regimen resulted in significant OS and PFS benefits

Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

OS PFS

Overall Survival: Stratified by Prior Bevacizumab – ITT Population

Allegra 2012

Progression-Free Survival: Stratified by Prior Bevacizumab – ITT Population

Allegra 2012

TML/VELOUR

• Is aflibercept better than bevacizumab second-line?

• ? Differences in toxicity than bevacizumab

• What about anti-EGFR Ab? SPIRITT trial (KRAS WT) pending

Small Molecule TKIs

• Both Abs and TKIs may inhibit the “classic” VEGF-A/VEGFR-2 pathway

• Inhibition of multiple VEGF receptors may be important

• Inhibition of other receptors (Clean vs. Dirty)• c-kit, PDGF-R, RET, FGF-R

MAb

TKI

Godzilla vs. Mothra 1964

CRC: Graveyard of VEGFR TKIs

Negative Randomized Trials: 6365+ pts

SU5416 719CONFIRM 1 1168CONFIRM 2 855HORIZON II/III 1050/1614SUN1122 768SUN1104 191

TKI

TKI

TKI

TKITKI

VEGFR TKIs: Take 2

• Negative in combination with chemotherapy

• New studies with chemo free regimens

• Front-line vs salvage

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• 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

tribu

tion

func

tion

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

Grothey 2012

1.00

0.50

0.25

0

0.75

200100500 150 300250 350

Days from randomization

Sur

viva

l dis

tribu

tion

func

tion

Placebo N=255Regorafenib N=505

Regorafenib Placebo

Median 1.9 mos 1.7 mos95% CI 1.9–2.1 1.7–1.7

Hazard ratio: 0.49 (95% CI: 0.42–0.58) 1-sided p-value: <0.000001

Progression-free survival (secondary endpoint)

Grothey 2012

Overall response and disease control rates(secondary endpoints)

*DCR = PR + SD; p<0.000001

Grothey 2012

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 JCO 2010)