Chemotherapyand targeted agentsin 1st line · Metastatic Palliation Acute 5-FU BSC Palliation...

Chemotherapy and targetedagents in 1st line

Presenter

Ramon Salazar

Head of Medical Oncology Dpt.

Catalan Institute of Oncology. Barcelona. Spain

DisclosuresR. Salazar has served in a consultant or advisory role for Amgen, Merck

Serono, Roche Dx and enjoyed research funding for Roche Dx, Roche Pharma and Merck Serono

Metastatic

Palliation Acute

5-FU

BSC

Palliation Chronic

Multidisciplinary

Multi ‘optional’

Curative

6 months

> 5 years

mCRC (R)Evolution

• Slide courtesy of M Peeters.

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h1 I dont like this slide, please deleteh501wrss, 26/05/2015

Oral/IV fluoropyrimidines

Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Regorafenib

Aflibercept

An

gio

gen

esis

Gro

wth TAS-102†

Ramucirumab

Chemo Backbone:

• Slide courtesy of M Peeters.Fluorouracil (25 mg/mL injection) Summary of Product Characteristics, Hospira; Capecitabine (XELODA®), Summary of Product Characteristics, Roche; Raltitrexed (Tomudex®) Summary of Product Characteristics, Hospira; Irinotecan (Campto®) Summary of Product Characteristics, Pfizer; Oxaliplatin (Eloxatin®) Summary of Product Characteristics, Sanofi; Bevacizumab (Avastin®) Summary of Product Characteristics, Roche; Aflibercept (Zaltrap®) Summary of Product Characteristics, Sanofi; Regorafenib (Stivarga®) Summary of Product Characteristics, Bayer; Cetuximab (Erbitux®) Summary of Product Characteristics, Merck Serono; Panitumumab (Vectibix®) Summary of Product Characteristics, Amgen; PR Newswire 02-03-15. Available at: http://www.prnewswire.co.uk/news-releases/taiho-submits-tas-102-marketing-authorisation-application-to-the-european-medicines-agency-for-the-treatment-of-refractory-metastatic-colorectal-cancer-294606511.html. Accessed 21-04-15.

†Marketing Authorisation Applicationsubmitted to the to the European Medicines

Agency in March 2015 for TAS-102for use in the treatment of refractory mCRC.

h4

h4 TAS 102 is not antiangiogenic, is a fluoromirimidin like citotoxic, so I change its location in the graph accordinglyh501wrss, 26/05/2015

OxaliplatinEFC 4584: time to tumour progresssion

Rothenberg M, et al. Proc Am Soc Clin Oncol 2003;22:252 (abst 1011)

Rothenberg ML, et al. J Clin Oncol 2003;11:2059–69

Pro

ba

bil

ity

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20Months

FOLFOX4 vs LV5FU2: p<0.0001

LV5FU2 vs Eloxatin®: p<0.008

5.62.6

1.9

FOLFOX4

Eloxatin®

LV5FU2

Regimen N RR PFS OSAuthor

Douillard/AIO 338 23% 4.4 14.1Douillard

+ Irinotecan 35% 6.7 17.4 Lancet

2000

FL (Saltz) 440 21% 4.3 12.6 Saltz

+ Irinotecan 39% 7.0 14.8 NEJM

2000

AIO 430 32% 6.4 16.9 Köhne

AIO+Irinotecan 54% 8.5 20.1

2003

Irinotecan

Intergroup study N9741: efficacy results

Goldberg RM, et al. J Clin Oncol 2004;22:23–30

IFL FOLFOX

Overall survival (months)

15 19.5 p=0.002

Time to progression (months)

6.9 8.7 p=0.0009

Response rate (%) 31 45 p=0.03

IFL = irinotecan, 5-FU/LV

FOLFOX = 5-FU/LV + oxaliplatin

FOLFOX also outperformed IROX

FOLFIRI followed by FOLFOX6 or the reverse sequence in

advanced colorectal cancer: a randomized GERCOR study

FOLFIRIFOLFIRI FOLFOX6FOLFOX6

OXL100 mg/m2

R

FOLFOX6FOLFOX6 FOLFIRIFOLFIRI

Prog

Prog

Prog

Prog

Tournigand C, André T, Achille E et al.J.

Clin Oncol 2004, 22 (2)

CPT11 180 mg/m2N=226

Logrank

p = 0.26

Pro

ba

bilid

ad

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 16 20 24 28 32

Median (months)

Folfiri 8.5

Folfox 8.0

Months

Pro

ba

bilid

ad

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18

Months

Median (months)

Folfiri 2.5

Folfox 4.2

Logrank

p = 0.003

EFFICACY VARIABLES

TIME TO 1ST LINE PROG TIME TO 2ND LINE PROG

Tournigand C, André T, Achille E et al.J. Clin Oncol 2004, 22 (2)

Chemo Backbone 1st line

Cancer Invest. 2016;34(2):94-104. doi: 10.3109/07357907.2015.1104689. Epub 2016 Feb 11.XELOX vs. FOLFOX in metastatic colorectal cancer: An updated meta-analysis.

Guo Y1, Xiong BH2, Zhang T3, Cheng Y1, Ma L4.

• Folfiri-Folfox are the preferred options

• Simillar PFS and OS

• Sequence does not influence outcome (Tournigand)

• Xelox not inferior than Folfox

• But Folfox has prevailed probably because of differential toxicity profiles

• Pooled analysis revealed that there were no statistical differences between both arms in OS, and ORR. XELOX arm had a higher incidence of thrombocytopenia, hand-foot syndrome, and diarrhea, whereas neutropenia had a higher incidence in the FOLFOX group. For mCRC, the effect of XELOX is similar to FOLFOX.

Small molecule TKI

VEGFR-2

PP

PP

Lymphangiogenic factors

VEGF-DVEGF-C

Regorafinib†

Bevacizumab1

Anti-VEGF-A antibody

VEGF-A

Aflibercept1

VEGF-BPIGF

Fusion protein/VEGF Trap

mCRC Targeted Therapy: Anti-angiogenics

• Adapted from 1. Fakih M. Expert Rev Anticancer Ther 2013;13:427–38;Ciombor KK, et al. Pharmgenomics Pers Med 2014;7:137–44.

• †Additional targets include: PDGFR-β, FGFR1, TIE2, KIT, RET, and BRAF.PIGF, placental growth factor; TK(I), tyrosine kinase (inhibitor);VEGF(R), vascular endothelial growth factor (receptor).

No (clinical) predictive biomarker

h2

h2 add ramucirumab as an anti VEGFR2h501wrss, 26/05/2015

Metastatic

CRC (1rst line)

ECOG 0-1

R

IFL +

bevacizumab 5mg/kg(Q2W)

(n = 403)

IFL + placebo(Q2W)

(n = 411)Endpoints: OS; PFS, ORR, QoL,

duration of response

IFL + placebo IFL + bevacizumab p-value

1-year survival rate (%) 63.4 74.3 < 0.001

ORR (%) 34.8 44.8 0.004

Median duration of response (mo) 7.1 10.4 0.001

Xelox + placebo Xelox +

bevacizumab

FOLFOX-4 +

placebo

FOLFOX-4 +

bevacizumab

PFS HR = 0.77; 97.5 CI, 0.63 – 0.94 HR = 0.89; 97.5 CI, 0.73 – 1.08

PFS (on-treatment) HR = 0.61; 97.5 CI, 0.48 – 0.78 HR = 0.65; 97.5 CI, 0.50 – 0.84

Metastatic

CRC (1rst line)

ECOG 0-2

> 70y old

capecitabine +

bevacizumab 5mg/kg

(n = 140)

capecitabine

(n = 140)

R

Anti-EGFR mAbs Inhibit EGFR Dimerisationand Subsequent Downstream Signalling

• Berg M, Soreide K. Discov Med 2012;14:207–14;Freeman D, et al. J Clin Oncol 2008;26(Suppl 15):abstract 14536 (and poster). • ©2007 Amgen Inc. All rights reserved

EGFREGFR homodimer

RAS

GTP RAS

GDPRAF

MEK

ERK

ElkMyc

JNK

Jun

JNKK

PAK

Nck

Rac

PLCγ

PKC

PTEN

PI3K

S6K

AKT

mTOR

Proliferation

Anti-apoptosis

Survival

Angiogenesis

Metastasis

Fos

EGF

TGF-α

EGFR

Anti-EGFR mAb

(panitumumab/cetuximab)

Ligand

EGFR

Grb2

Sos Ras

BRAF

MEK

ERK

Specific mutations result in a constitutively active RAS protein

RAS

Inactive

GDP

Active

RAS

GTP

Schubbert S, et al. Nat Rev Cancer 2007;7:295−308.

Specific mutations result in a constitutively active RAS

protein

Normal:− Growth

− Proliferation

− Differentiation

RAS

Inactive

GDP

Active

RAS

GTP

Wild-type RAS

Abnormal: − Growth

− Proliferation

− Differentiation

Mutant RAS

PRIME study RAS analysis KRAS, NRAS and BRAF mutation hotspots

Based on Douillard JY, et al. N Engl J Med 2013; 369:1023-34;Oliner KS, et al. EJC 2013; 49 (suppl 3):abstract 2275 (and poster). Percentages have been rounded; 7 patients harboured either KRAS or NRAS codon 59 mutations

EXON 2 EXON 3 EXON 4EXON 1

12 13 61 117 146

EXON 2 EXON 3 EXON 4EXON 1

12 13 61 117 146

EXON 15 EXON 16EXON 1

600

40% 5% 6%

4% 4% 0%

59

59

9%

Among WT KRAS exon 2 patients, an additional 17% of tumours

with RAS mutations were found

12 13 61 117 14659

12 13 61 117 14659

600

Overall RAS

ascertainment rate: 90%

NRAS

BRAF

KRAS

Prevalence of extended RAS mutations across studies

Extended RAS

total

KRAS

Exon 3

KRAS

Exon 4

NRAS

Exon 2

NRAS

Exon 3

NRAS

Exon 4

59 61 117 146 12 13 59 61 117 146

OPUS1 26.3% 5.9% 9.3% 6.8% 5.1% 0.8%

PICCOLO1 9.8% NR 3.7% 6.3% NR NE

200204081 17.6% 4.8% 5.0% 4.2% 3.0% 1.1%

200501811 20.5% 4.6% 7.9% 2.3% 5.8% 0

PRIME1 17.4% 3.7% 5.6% 3.4% 4.1% 0

FIRE-31 16.0% 4.3% 4.9% 3.8% 2.0% 0

PEAK1 20.1% 4.1% 7.7% 5.4% 5.9% 0

COIN1 8.4% 2.1% NE 0.9% 3.0% NE

CRYSTAL1 14.7% 3.3% 5.6% 3.5% 2.8% 0.9%

SUMMARY1 19.9%

(16.7%,

23.4%)

4.3%

(3.3%, 5.5%)

6.7%

(5.7%, 7.9%)

3.8%

(3.0%, 4.8%)

4.8%

(3.4%, 6.8%)

0.5%

(0.2%, 1.2%)

CALGB1 15.3% 1.8% 5.9% 2.3% 4.2% 0

1. Sorich MJ, et al. Ann Oncol 2015;26:13–21; 2. Lenz H, et al. Ann Oncol 2014;25(suppl 4):abstract 5010 (and oral presentation)

pamitumumab

cetuximab

1st Line

Trials:

Improved outcome with better patient selectionHazard ratios KRAS exon 2 WT All RAS WT Any RAS MT

CRYSTAL1,2

PFS (p-value)

OS (p-value)

n=666

0.70 (0.0012)

0.80 (0.0093)

n=367

0.56 (0.0002)

0.69 (0.0034)

n=460

1.10 (NS)

1.05 (NS)

OPUS3,4

PFS (p-value)

OS (p-value)

n=179

0.57 (0.0064)

0.86 (0.39)

n=87

0.53 (0.063)

0.94 (0.80)

n=167

1.29 (0.013)

1.54 (0.157)

PRIME5

PFS (p-value)

OS (p-value)

n=656

0.80 (0.02)

0.83 (0.07)

n=512

0.72 (0.004)

0.78 (0.04)

n=548

1.31 (0.008)

1.25 (0.03)

PEAK6

PFS (p-value)

OS (p-value)

n=285

0.87 (0.353)

0.62 (0.009)

n=170

0.65 (0.029)

0.63 (0.058)

NA

FIRE-37

PFS (p-value)

OS (p-value)

n=592

1.06 (0.55)

0.77 (0.0017)

n=342

0.93 (0.54)

0.70 (0.011)

n=178

1.31 (0.085)

1.09 (0.60)

CALGB 804058

PFS (p-value)

OS (p-value)

n=1,137

1.04 (NS)

0.93 (NS)

n=526

1.1 (NS)

0.9 (NS)

NA

For information only. No formal statistical comparison was made. 1. Van Cutsem E, et al. 2011; 2. Ciardiello F, et al. 2014; 3.

Bokemeyer C, et al. 2011; 4. Tejpar S, et al. 2014; 5. Douillard JY, et al. 2013; 6. Schwartzberg LS, et al. 2014; 7. Stintzing S, et al.

2014; 8. Lenz H, et al. 2014.

pamitumumab

cetuximab

1st Line

Trials:

Click icon to add picture

Study design

21

Randomized Phase III trials of 1st line Erbitux + FOLFIRI1,2

1. Van Cutsem E, et al. N Engl J Med 2009;360:1408–1417;

2. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075;

3. Tejpar S, et al. JAMA 2016; epub 10 Oct 2016;

4. Heinemann V, et al. Oral presentation at ESMO 2016;

5. Van Cutsem E, et al. Oral presentation at ESMO 2016

CRYSTAL and FIRE-3

*Investigator‘s choice

• Primary endpoint: PFS

Retrospective analyses of outcome by primary tumor location

were conducted for the RAS wt populations3–5

Tumor location analyses

CRYSTAL1 FIRE-32

Previously untreated EGFR-expressing

mCRC

Previously untreated KRAS (exon 2) wt

mCRC

Erbitux + FOLFIRI (n=599)

FOLFIRI alone (n=599)


Bevacizumab + FOLFIRI (n=295)

R R

• Primary endpoint: Investigator-assessed ORR


Study design

22

Open-label, randomized Phase III study: 1st line FOLFOX4 ± Erbitux in RAS wt mCRC1

FOLFOX4: Oxaliplatin 85 mg/m2, d1, q2w; LV 200 mg/m2 days 1 and 2, q2w; 5-FU 400 mg/m2 bolus, then 22h continuous infusion 600 mg/m2, days 1 and 2, q2w; Erbitux 400 mg/m2 day 1, then 250 mg/m2

qw

Previously untreated RAS wt

mCRC

No requirement for detectable tumor

EGFR expression

(n=393)

R

Endpoints:

• Primary: PFS

• Secondary: ORR, OS, safety

1. Qin S, et al. WCGC 2016 (Abstract No. O-025);

2. Qin S, et al. ESMO 2016 (Abstract No. 527P)

Prospectively planned subgroup analysis conducted to evaluate

the impact of EGFR expression on outcomes2

Erbitux + FOLFOX4

(n=193)

FOLFOX4 alone

(n=200)

Treatment until PD or unacceptable toxicity

TAILOREGFR expression


Key

data

23

Similar outcomes with 1st line Erbitux + FOLFOX4 irrespective of EGFR expression*

(RAS wt)1

*Erbitux is indicated for treatment of patients with EGFR-expressing, RAS wt

mCRC5

†Analyzed by immunohistochemistry; 354/393 paQents (90%) were evaluable;

‡Erbitux + FOLFOX4 vs FOLFOX4 alone

1. Qin S, et al. ESMO 2016 (Abstract No. 527P);

2. Qin S, et al. WCGC 2016 (Abstract No. O-025);

3. Van Cutsem E, et al. J Clin Oncol 2015;33:692–700;


5. Erbitux SmPC, June/2014

% EGFR-

positive

cells†

No.

paPents‡

PFS‡ ORR‡

Medians, months HR (95% CI) % OR (95% CI)

0 85 vs 77 9.2 vs 7.9 0.62 (0.41–0.92) 67.1 vs 35.1 3.77 (1.97–7.23)

>0–10 35 vs 48 11.3 vs 7.4 0.62 (0.35–1.11) 71.4 vs 41.7 3.50 (1.38–8.88)

>10–20 15 vs 14 9.3 vs 8.1 0.45 (0.15–1.39) 73.3 vs 42.9 3.67 (0.77–17.4)

>20–35 9 vs 14 7.5 vs 9.2 1.34 (0.47–3.86) 44.4 vs 64.3 0.44 (0.08–2.46)

>35 29 vs 28 7.0 vs 5.2 0.73 (0.40–1.35) 44.8 vs 35.7 1.46 (0.50–4.24)

TAILOREGFR expression

PFS and ORR benefit with Erbitux + FOLFOX4 vs FOLFOX4 alone was

independent of EGFR expression level

Outcomes with Erbitux + CT in the subgroup without detectable EGFR expression were

comparable with those in:

(1) 1. The overall TAILOR population2

(2) 2. The RAS wt subgroup of CRYSTAL,3 which enrolled only patients with EGFR-expressing tumors4

Panitumumab randomized 1st Line TrialsTowards 40 month median OS

1. Boeckx N, et al. Ann Oncol 2016;27(Suppl 6):abstract 89P (and poster);2. Douillard JY, et al. N Engl J Med 2013;369:1023‒34;3. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240‒7;4. Peeters M, et al. Clin Cancer Res 2015;21:5469‒79.

Phase 3

1st-line mCRC

Panituumab + FOLFOX4

PEAK3

(NCT00819780)

PRIME2

(NCT00364013)FOLFOX4

Panitumumab + mFOLFOX6

Bevacizumab + mFOLFOX6

Phase 2

1st-line mCRC

R

R

WT RAS

Panitumumab +

FOLFOX4

(n = 259)

FOLFOX4

(n = 253)

Median PFS, mo†2 10.1 7.9

HR

(95% CI)

P-value

0.72

(0.58–0.90)P = 0.004

Median OS, mo†2 26.0 20.2

HR

(95% CI)

P-value

0.78

(0.62–0.99)

P = 0.04

ORR, n (%)†‡3

(95% CI)

149 (59)

(52–65)

114 (46)

(40–53)

Adjusted OR

P-value

1.63

P = 0.009

AE, %2

Grade 3/4

Grade 5

(n = 256)

84.8

5.5

(n = 250)

70.0

6.4

Phase 2 PEAK study overviewmFOLFOX6 + panitumumab or bevacizumab in1st-line treatment of mCRC

1. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7;2. Rivera F, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2014 (and poster).www.amgentrials.com Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780.

†Final analysis.WT RAS = WT KRAS and NRAS exons 2, 3, 4.

• Primary endpoint: PFS1

• No planned formalhypothesis testing

• Prespecified extendedRAS analysis1,2

• RAS ascertainment rate: 82%

WT RAS

Panitumumab

+ mFOLFOX6

(n = 88)

Bevacizumab

+ mFOLFOX6

(n = 82)

Median PFS, mo†2 12.8 10.1

HR

(95% CI)

P-value

0.68(0.48–0.96) P = 0.029

Median OS, mo†2 36.9 28.9

HR

(95% CI)

P-value

0.76

(0.53–1.11)

P = 0.15

ORR, %†2 (n = 88)

65

(n = 81)

60

OR

(95% CI)

P-value

1.12

(0.56‒2.22)

P = 0.86

AEs, %1

Grade 3/4

Grade 5

(n = 86)

89.5

4.7

(n = 80)

72.5

8.8

mCRC

WT KRAS1

(N = 285)

R

Panitumumab 6 mg/kg

(Q2W) +

mFOLFOX6 (Q2W)

Bevacizumab 5 mg/kg

(Q2W) +

mFOLFOX6 (Q2W)

Cytoreduction (shrinkage)

MOLECULAR PROFILE

Treatment of metastatic diseaseEMSO 2016 mCRC Zurich treatment algorithm

*Note: There was an error in Figure 4 of the original Epub ahead of print manuscript(version mdw235v1); the molecular profiles indicated were incorrectly labelled ‘WT’.Correction made at the final manuscript: Van Cutsem E, et al. Ann Oncol 2016; 27:1386-22

†Patients assessed as ‘fit’ or ‘unfit’ according to medical condition,not due to malignant disease; ‡Separate algorithm.

OMD, oligometastatic disease.

Assessment of clinical condition of the patient

Unfit (but may be suitable)†Fit†Unfit†

BSCGOAL

MT BRAF*MT RAS*WT RAS

Patients

with clearly

resectable

metastases

Surgery alone;

surgery with

perioperative/

postoperative

CT

Re-evaluation/assessment of response Q2M

GOAL

Cytoreduction (shrinkage)

Continue

Progressivedisease

Disease control

Continue;

maintenance;

or pause

Second-line

Surgery

Disease control (control progression)

MOLECULAR PROFILE

MT BRAF*MT RAS*WT RAS

Re-evaluaQon/assessment of response Q2−3M

Continue;

maintenance;

or pause

Progressivedisease Second-line

FP + bevacizumab;

reduced dose doublet;

anti-EGFR

OMD†

CT +

bevacizumab

Combination CT +

bevacizumab

CT doublet +

anti-EGFR

CT triplet ±

bevacizumab

CT doublet +

bevacizumab

CT doublet +

biological

Right colon

• +++ MSI-high1,2

• +++ CIMP-high1,2

• +++ CMS13

• +++ Serrated pathway2†

Molecular pathways/tumour classification modelsCIMP-high, MSI-high and CMS distribution varies between colorectal locations

1. Yamauchi M, et al. Gut 2012;61:847–54;2. Missiaglia E, et al. Ann Oncol 2014;25:1995‒2001;3. Guinney J, et al. Nat Med 2015;21:1350‒6 (and Supplementary Figure 10).

+++ denotes that a molecular or morphological subtype ismore prevalent compared with other colorectal segments.

†CIN expression and serrated pathway data are not available for rectal tumours.CIMP, CpG island methylator phenotype; CIN, chromosomal instability;

CMS, Consensus Molecular Subtypes; MSI, microsatellite instability.

Left colorectum

Colon

• +++ CIN+2†

• +++ CMS23

• +++ EREG expression2‡

• MT KRAS1

• EGFR expression1

• Molecular heterogeneity may be captured by the anatomical location of

the tumour

Right colon

• +++ MT BRAF1,2

• MT KRAS1

• EGFR expression1


Study design

28

Randomized Phase III trials of 1st line Erbitux + FOLFIRI1,2


2. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075;

3. Tejpar S, et al. JAMA 2016; epub 10 Oct 2016;

4. Heinemann V, et al. Oral presentation at ESMO 2016;


CRYSTAL and FIRE-3


• Primary endpoint: PFS

Retrospective analyses of outcome by primary tumor location

were conducted for the RAS wt populations3–5

Tumor location analyses

CRYSTAL1 FIRE-32

Previously untreated EGFR-expressing

mCRC

Previously untreated KRAS (exon 2) wt

mCRC


FOLFIRI alone (n=599)


Bevacizumab + FOLFIRI (n=295)

R R

• Primary endpoint: Investigator-assessed ORR

29


Key

data

Unprecedented OS benefit with Erbitux + CT vs CT alone in left-sided RAS wt mCRC1,2

CRYSTAL

Tumor location analysis

RAS wt

Left-sided Right-sided

Erb + CT

(n=142)

CT alone

(n=138)

Erb + CT

(n=33)

CT alone

(n=51)

ORR

% 72.5 40.6 42.4 33.3

OR (95% CI) 3.99 (2.40–6.62) 1.45 (0.58–3.64)

p-value <0.001 0.43

PFS

Median, months 12.0 8.9 8.1 7.1

HR (95% CI) 0.50 (0.34–0.72) 0.87 (0.47–1.62)

p-value <0.001 0.66

OS

Median, months 28.7 21.7 18.5 15.0

HR (95% CI) 0.65 (0.50–0.86) 1.08 (0.65–1.81)

p-value 0.002 0.76

CT = FOLFIRI; Erb, Erbitux

Clear poor prognostic effect of right-

sided tumor location in both arms

Unprecedented OS benefit in left-

sided mCRC with Erbitux + CT vs CT

alone

1. Tejpar S, et al. JAMA Oncol 2016; epub 10 Oct 2016;


No difference in outcomes between

arms in right-sided tumors, but

conclusions are limited by small

sample size


Key

data

30

Unprecedented OS benefit with Erbitux + CT vs bevacizumab + CT in left-sided RAS wt

mCRC1,2

FIRE-3Tumor location analysis

1. Tejpar S, et al. JAMA Oncol 2016; epub 10 Oct 2016;

2. Heinemann V, et al. Oral presentation at ESMO 2016

RAS wt

Left-sided (n=306) Right-sided (n=88)

Erb + CT

(n=157)

Bev + CT

(n=149)

Erb + CT

(n=38)

Bev + CT

(n=50)

ORR

% 68.8 61.7 52.6 50.0

OR (95% CI) 1.37 (0.85–2.19) 1.11 (0.48–2.59)

p-value 0.23 0.83

PFS

Median, months 10.7 10.7 7.6 9.0

HR (95% CI) 0.90 (0.71–1.14) 1.44 (0.92–2.26)

p-value 0.38 0.11

OS

Median, months 38.3 28.0 18.3 23.0

HR (95% CI) 0.63 (0.48–0.85) 1.31 (0.81–2.11)

p-value 0.002 0.28

CT = FOLFIRI; Erb, Erbitux; bev, bevacizumab

Clear poor prognostic effect of right-

sided tumor location in both arms

Unprecedented OS benefit in left-

sided mCRC with Erbitux + CT, with

pronounced increase in median OS

(>10 months)

No difference in outcomes between

arms in right-sided tumors, but


sample size


Key

data

31

Unprecedented OS benefit with Erbitux + CT vs bevacizumab + CT in left-sided

RAS/BRAF wt mCRC1

FIRE-3Tumor location analysis

1. Heinemann V, et al. Oral presentation at ESMO 2016

RAS/BRAF wt


Erb + CT

(n=143)

Bev + CT

(n=139)

Erb + CT

(n=28)

Bev + CT

(n=37)

ORR

% 67.8 62.6 47.4 42.0

OR 1.26 1.37

p-value 0.38 0.61

PFS

Median, months 11.1 11.1 8.0 10.5

HR 0.89 1.70

p-value 0.37 0.046

OS

Median, months 38.7 28.6 18.9 23.6

HR 0.62 1.31

p-value 0.002 0.34

CT = FOLFIRI; Erb, Erbitux; bev, bevacizumab

Data consistent w RAS wt

subgroup analysis

Borderline-significant increase in PFS

with bevacizumab, but no significant

difference in OS or ORR. However,


sample size



Key

data

32

Venook AP, et al. Oral presentation at ESMO 2016

CT = Investigator’s choice of FOLFIRI or mFOLFOX6

*Adjusted for biologic, protocol CT, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases

CALGB/SWOG 80405 trial

RAS wt


Erb + CT

(n=173)

Bev + CT

(n=152)

Erb + CT

(n=71)

Bev + CT

(n=78)

PFS

HR (95% CI) 0.84 (0.66–1.06) 1.64 (1.15–2.36)

p-value 0.15 0.006

Treatment × tumor location

interaction (p-value)*0.001

OS

Median, months 39.3 32.6 13.7 29.2

HR (95% CI) 0.77 (0.59–0.99) 1.36 (0.93–1.99)

p-value 0.04 0.10

Treatment × tumor location

interaction (p-value)*0.009

Longer PFS with bevacizumab vs

Erbitux, but no difference in OS

between arms, in right-sided

tumors; conclusions are limited

by small sample size

Unprecedented, significant OS benefit with Erbitux + CT vs bevacizumab

+ CT in left-sided RAS wt mCRCSignificant treatment × tumor location interaction for

PFS and OS

Clear poor prognostic effect of

right-sided tumor location on

OS in both arms

Unprecedented efficacy of Erbitux + CT vs bevacizumab + CT in left-sided RAS wt mCRC

Panitumumab outcome by tumour location analysisBackground

1. Boeckx N, et al. Ann Oncol 2016;27(Suppl 6):abstract 89P (and poster);2. Douillard JY, et al. N Engl J Med 2013;369:1023‒34;3. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240‒7;

• Retrospective, exploratory analysis of outcomes by primary tumour location for patients with WT RAS and WT RAS/WT BRAF mCRC participating in:1

Phase 3

1st-line mCRC

Panituumab + FOLFOX4

PEAK3

(NCT00819780)

PRIME2

(NCT00364013)FOLFOX4

Panitumumab + mFOLFOX6

Bevacizumab + mFOLFOX6

Phase 2

1st-line mCRC

R

R


Key

data

34

Trend for greater efficacy of 1st line panitumumab + FOLFOX vs FOLFOX in left- vs

right-sided tumors (RAS wt)1,2

Panitumumab trialsTumor location analyses

Trial

(line)Treatments

Tumor

locationPatients, n ORR, %

PFS OS

Median, monthsHR

(95% CI)*Median, months

HR

(95% CI)*

Phase III

PRIME

(1st line)

Pani + FOLFOX4

vs FOLFOX4

Left 169 vs 159 68 vs 53 12.9 vs 9.20.72

(0.57–0.90)30.3 vs 23.6

0.73

(0.57–0.93)

Right 39 vs 49 42 vs 35 7.5 vs 7.00.80

(0.50–1.26)11.1 vs 15.4

0.87

(0.55–1.37)

Phase II PEAK

(1st line)

Pani +

mFOLFOX6 vs

bev +

mFOLFOX6

Left 53 vs 54 64 vs 57 14.6 vs 11.50.65

(0.21–2.00)43.4 vs 32.0

0.84

(0.22–3.27)

Right 22 vs 14 63 vs 50 8.7 vs 12.6 0.84

(0.18–3.79)17.5 vs 21.0

0.45

(0.08–2.49)

1. Peeters M, et al. Oral presentation at ESMO 2016;

2. Boeckx C, et al. ESMO 2016 (Abstract No. 89P);

3. Rivera F, et al. ECC 2015 (Abstract No. 2014);

4. Peeters M, et al. Clin Cancer Res 2015;21:5469–5479

Bev, bevacizumab; pani, panitumumab; *Adjusted for

BRAF status, prior adjuvant CT and ECOG PS

Significant increase in OS and PFS only in the left-sided

subgroup of PRIME


Key

data

35

Trend for greater efficacy of 1st line panitumumab + FOLFOX vs FOLFOX in left- vs

right-sided tumors (RAS/BRAF wt)1,2

Panitumumab trialsTumor location analyses

Trial

(line)Treatments

Tumor

locationPatients, n ORR, %

PFS OS

Median, monthsHR

(95% CI)Median, months

HR

(95% CI)

Phase III

PRIME

(1st line)

Pani + FOLFOX4

vs FOLFOX4

Left 156 vs 148 70.3 vs 54.8 12.9 vs 9.30.69

(0.54–0.88)32.5 vs 23.6

0.67

(0.56–0.86)

Right 26 vs 32 52.0 vs 41.2 8.9 vs 7.30.71

(0.40–1.27)22.5 vs 21.5

0.94

(0.53–1.67)

Phase II PEAK

(1st line)

Pani +

mFOLFOX6 vs

bev +

mFOLFOX6

Left 52 vs 53 63.5 vs 58.5 14.6 vs 11.50.67

(0.44–1.02)43.4 vs 32.0

0.77

(0.46–1.28)

Right 13 vs 13 69.2 vs 46.2 10.3 vs 12.60.88

(0.39–2.02)22.5 vs 23.3

0.63

(0.26–1.54)

1. Peeters M, et al. Oral presentation at ESMO 2016;

2. Boeckx C, et al. ESMO 2016 (Abstract No. 89P);

3. Rivera F, et al. ECC 2015 (Abstract No. 2014);

4. Peeters M, et al. Clin Cancer Res 2015;21:5469–5479

Data consistent with RAS wt

subgroup analysis1,2

Summary: A review of the clinical evidence

• Left versus Right

• Subgroup of Subgrup Analysis Evidence

• Anti-EGFR superior in all endpoints in the left tumors (except PFS in Fire 3)

• Right side sobgroup analysis flawed with small numbers

• CALGB and Fire 3 clearly favour Bev vs cetuximab

• (recent NCCN guidelines have deleted anti EGFR option in the right)

• PEAK phase 2 trial not clear

• Anti EGFR still increase RR on the right

• In practice, mutational status of KRAS/NRAS should be obtained upfront for mCRC to decide on the best therapeutic option

• Simillar results in RAS wt than in RAS/BRAF wt

• BRAF mutants do poorly unmet medical need

• can be treated with the same standards but clinical trials warranted

• Sequence of chemo-biological combos has not been tested

• Low use biologicals 2nd line impact OS

1. Douillard JY, et al. N Engl J Med 2013; 369:1023-342. Peeters M, et al J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).3. Patterson SD, et al. J Clin Oncol 2013; 31 (suppl):abstract 3617 (and poster).

• Population: Left colon or rectum unresectable metastatic (M1) adenocarcinoma

• Primary endpoint: OS

• Hypothesis Arm A pmab � bmab: 40 months

• Hypothesis Arm B bmab � pmab: 30 months

Phase III CR SEQUENCE conceptPlanned study designTTD-Intergroup studyPI R Salazar/A Carrato

PD, progressive disease.

Cooperative groups (CG)

Country N. Coordinator Group CountriesSites

estimated

Feasibilities II

received

Patients

per year

SpainRamón Salazar

Alfredo CarratoTTD 1 57 57 320

Portugal Helder Mansinho GICD 1 18 13 90

GreeceDemetris

PapamichaelEORTC 1* 1 20

Italy Stefano Cascinu AIOM 1 UNK 0 UNK

Germany Michel Geissler EORTC 1 15 0 90

Austria

Gerald Prager CECOG

1 4 3 20

Hungary 1 1 1 15

Bosnia

Herzegovina? 1* 1 12

Chez republic 1 1 1 12

Romania 2 1 34

Serbia 1 1 20

Slovakia ? 1 1 10

Latvia 2* 2 12

Belgium Marc Peeters BGDO 1 15 1 75

France Julien Taieb AGEO 1 11 2 36

TOTALS 8 130 85 766

* Sites without any mark under country field require study drug provision

[email protected] you

Grupo de Tratamiento delos Tumores Digestivos

FIS 12/01589

Acknowledgements

http://ico.gencat.cat

@ICOnoticies

www.facebook.com/ICOnoticies

Institut Català d’Oncologia

ICO l’HospitaletHospital Duran i Reynals

Av. Granvia de L’Hospitalet, 199-20308908 L’Hospitalet de Llobregat

ICO BadalonaHospital Germans Trias i Pujol

Ctra. del Canyet s/n08916 Badalona

ICO GironaHospital Doctor Trueta

Av. França s/n17007 Girona

ICO Camp de Tarragona i Terres de l’EbreHospital Joan XXIIIC. Dr. Mallafrè Guasch, 4 43005 TarragonaHospital Verge de la Cinta

C. de les Esplanetes, 14 43500 Tortosa

BACK UP SLIDES

Therapeutic Progress in Advanced CRC and Improvements in OS Over Time

• Adapted from Vickers M. Oncol Exch 2013;12;30–3. • Bev, bevacizumab; BSC, best supportive care; C’mab, cetuximab; FU, fluorouracil; P’mab, panitumumab.

30

25

20

15

10

5

Ove

rall

su

rviv

al (m

onth

s)

1970 1980 1990 1995 2000 2005 2010 2013BSC

5-FUIrinotecanOxaliplatinCapcitabine Bev P’mab

C’mab Aflibercept TAS-102Regorafenib

0

Assaigs clínics: Bevacizumab

ESTUDI de Hurwitz et al. (Fase III):

Bevacizumab+IFL (irinotecan/5FU/leucovorin) vs Placebo+IFL

Resultats:

Variable principal: SG

Mediana de SG: 20,3 mesos per a bevacizumab+IFL vs 15,6 mesos per a

placebo+IFL (HR=0,66; p<0,001).

Variable secundària: SLP, taxa de resposta

Mediana de SLP: 10,6 mesos per bevacizumab+IFL vs 6,2 mesos per

placebo+IFL (HR: 0,54; p<0,001).

Taxa de resposta: 44,8% per a bevacizumab+IFL i de 34,8% per a

placebo+IFL (p=0,004).

Assaigs clínics: BevacizumabESTUDI de Saltz et al. (Fase III):

Bevacizumab+FOLFOX-4/XELOX vs FOLFOX-4/XELOX+placebo

Resultats:

Variable principal: SLP

Mediana de SLP: 9,4 mesos per a bevacizumab + XELOX/FOLFOX-4 vs 8,0 mesos

per a XELOX/FOLFOX-4 + placebo (HR: 0,83; IC 97,5%: 0,72-0,95; p=0,0023).

Variable secundària: SG, taxa de resposta

Mediana de SG: 21,3 mesos per a bevacizumab associat a XELOX/FOLFOX-4 vs

19,9 mesos per a XELOX/FOLFOX-4 (HR: 0,89; IC 97,5%: 0,76-1,03; p=0,077).

Taxa de resposta (segons un comité independent): 38% en ambdós grups de

tractament (OR: 1,0; IC97,5%:0,78-1,28; p=0,99).

Bevacizumab

• L’estudi AVEX té com a població diana pacients d’edat avançada amb CCRM

• Es va emprar capecitabina com a comparador en incloure pacients que no esconsideraven candidats a tractament amb oxaliplatí o irinotecà.

• Resultats:

SLP: capecitabina+BVZ 9,1 mesos vs capecitabina 5,1 mesos;

HR 0,53 (0,41-0,69); p<0,0001

SG: capecitabina+BVZ 20,7 mesos vs capecitabina 16,8 mesos;

HR 0,79 (0,57-1,09); p=0,18

Summary: A review of the clinical evidence

• The anti-EGFR MoAb panitumumab has (Level 1 evidence) activity in all lines of mCRC treatment:

• In 1st line in combination with FOLFOX1

• In 2nd line in combination with FOLFIRI2

• In 3rd line as single agent3

• In all lines, refinement of patient selection by expanded search for KRAS/NRAS mutations improves the risk-benefit ratio of panitumumab

• In practice, mutational status of KRAS/NRAS should be obtained upfront for mCRC to decide on the best therapeutic option

• Panitumumab is safe and increases ETS, DpR, RR in combination withchemo 1st line

• correlate both with PFS, OS and Resection Rates

• LLD: panitumumab in combination with chemotherapy is of choice

1. Douillard JY, et al. N Engl J Med 2013; 369:1023-342. Peeters M, et al J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).3. Patterson SD, et al. J Clin Oncol 2013; 31 (suppl):abstract 3617 (and poster).

Panitumumab outcome by tumour location analysisMethods (1 of 2)

Boeckx N, et al. Ann Oncol 2016;27(Suppl 6):abstract 89P (and poster). ECOG, Eastern Cooperative Oncology Group.

• Primary tumour side was ascertained either by description of:

• The primary tumour surgery in the patient case report form or

• The operative resection specimen on the pathology report

• Ascertainment of tumour side was blinded to treatment allocationand clinical outcome

• Primary tumour side categorisation:

• Right-sided: tumours located in the caecum to transverse colon (inclusive)

• Left-sided: tumours located in the splenic flexure to rectum (inclusive)

• HRs for OS and PFS were adjusted for BRAF status, adjuvant chemotherapy and ECOG performance status

PRIME study post-hoc analysis (ETS and response)

PFS and OS by ETS (30% cut-off) at Week 8(updated analysis)

Douillard JY, et al. Eur J Cancer 2015;51:1231−42.

†Includes patients with baseline and Week 8 tumour shrinkage data only;‡Assessing the overall relationship between Week 8 tumour shrinkage and PFS at 6 months;

§Assessing the overall relationship between Week 8 tumour shrinkage and OS at 2 years.

Panitumumab + FOLFOX4 FOLFOX4

ETS < 30% ≥ 30% < 30% ≥ 30%

n (%)† 89 (41) 130 (59) 138 (62) 83 (38)

Median PFS, months

(95% CI)

9.3

(6.7–10.7)

14.9

(12.8–18.6)

7.0

(5.7–7.8)

10.9

(9.3–11.7)

HR

(95% CI)

P-value

0.56

(0.42–0.76)

0.0001

0.62

(0.47–0.83)

0.0014

Phi coefficient‡ 0.30

Median OS, months

(95% CI)

18.2

(14.2–22.5)

34.5

(29.8–40.7)

16.0

(14.2–18.8)

30.7

(23.6–36.2)

HR

(95% CI)

P-value

0.52

(0.38–0.70)

< 0.0001

0.46

(0.34–0.63)

< 0.0001

Phi coefficient§ 0.33

WT RAS

Panitumumab outcome by tumour location analysisSummary of results

Boeckx N, et al. Ann Oncol 2016;27(Suppl 6):abstract 89P (and poster).

WT RAS

N pts

(left/right)

OS, months PFS, months CR + PR, %

Left Right Left Right Left Right

PRIME (Phase 3, 1st line)

Pmab + FOLFOX 169/39 30.3 11.1 12.9 7.5 68 42

FOLFOX 159/49 23.6 15.4 9.2 7.0 53 35

HR

(95% CI)

--

0.73(0.57‒0.93)

0.87(0.55‒1.37)

0.72(0.57‒0.90)

0.80(0.50‒1.26)

--

--

PEAK (Phase 2, 1st line)

Pmab + FOLFOX 53/22 43.4 17.5 14.6 8.7 64 64

Bev + FOLFOX 54/14 32.0 21.0 11.5 12.6 57 50

HR(95% CI)

--

0.84(0.22‒3.27)

0.45(0.08‒2.49)

0.65(0.21‒2.00)

0.84(0.18‒3.79)

--

--

181 (Phase 3, 2nd line)

Pmab + FOLFIRI 150/31 20.1 10.3 8.0 4.8 50 13

FOLFIRI 148/39 16.6 8.1 5.8 2.4 13 3

HR(95% CI)

--

0.96(0.74‒1.23)

1.14(0.68‒1.89)

0.88(0.69‒1.12)

0.75(0.45‒1.27)

--

--

Panitumumab outcome by tumour location analysisEfficacy outcomes by tumour location in patients with WT RAS/WT BRAF disease

Boeckx N, et al. Ann Oncol 2016;27(Suppl 6):abstract 89P (and poster).

WT RAS/

WT BRAF

PRIME PEAK Study 181

Pmab +

FOLFOX FOLFOX

Pmab +

FOLFOX Bev + FOLFOX

Pmab +

FOLFIRI FOLFIRI

Pts, n (left/right) 156/26 148/32 52/13 53/13 143/22 144/26

Median OS, months

Left 32.5 23.6 43.4 32.0 20.1 16.9

HR (95% CI) 0.67 (0.56‒0.86) 0.77 (0.46‒1.28) 0.97 (0.76‒1.26)

Right 22.5 21.5 22.5 23.3 11.9 10.9

HR (95% CI) 0.94 (0.53‒1.67) 0.63 (0.26‒1.54) 0.84 (0.46‒1.54)

Median PFS, months

Left 12.9 9.3 14.6 11.5 8.0 6.6

HR (95% CI) 0.69 (0.54‒0.88) 0.67 (0.44‒1.02) 0.89 (0.70‒1.14)

Right 8.9 7.3 10.3 12.6 6.8 3.7

HR (95% CI) 0.71 (0.4‒1.27) 0.88 (0.39‒2.02) 0.62 (0.34‒1.13)

CR + PR, %

Left 70.3 54.8 63.5 58.5 50.7 13.5

Right 52.0 41.4 69.2 46.2 19.0 3.8


Study

design

51

US randomized Phase III trial of 1st line Erbitux + CT vs bevacizumab + CT in KRAS (exon 2) wt mCRC1,2

1. Venook AP, et al. ASCO 2014 (Abstract No. LBA3);

2. Lenz HJ, et al. ESMO 2014 (Abstract No. 501O);

3. Venook AP, et al. Oral presentation at ESMO 2016

CALGB/SWOG 80405 trial


Endpoints:

• Primary: OS

• Secondary: ORR, PFS, TTF, DoR, eligibility for surgery, safety

Previously untreated KRAS (exon

2) wt mCRC

(n=1137)

Erbitux +

FOLFIRI or mFOLFOX6*

(n=578; RAS wt, n=270)

Bevacizumab +

FOLFIRI or mFOLFOX6*

(n=559; RAS wt, n=256)

R

Retrospective analysis of outcome by primary tumor location

was conducted for the RAS wt population3


PEAK study RAS analysis Subsequent therapy (longer follow-up analysis)

Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7.

†Time to subsequent therapy is time interval from random assignment date to time of subsequent therapy; WT RAS = WT KRAS and NRAS exons 2/3/4.

Therapy received after the protocol treatment phase

Panitumumab+ mFOLFOX6

(n = 88)

Bevacizumab+ mFOLFOX6

(n = 82)

Anti-EGFR mAb

n (%) 19 (22) 30 (37)

Median time to subsequent therapy (months)† 14.7 15.4

Anti-VEGF

n (%) 35 (40) 27 (33)


Irinotecan-, oxaliplatin-, or fluoropyrimidine-containing chemotherapy

n (%) 53 (60) 50 (61)


WT RAS

PRIME study KRAS exon 2 analysis Grade 3/4 AEs of interest (primary analysis)

Douillard JY, et al. J Clin Oncol 2010;28:4697−705.AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities.

WT KRAS = WT KRAS in codons 12/13.

AE1 by MedDRA, %

WT KRAS exon 2 MT KRAS exon 2

Panitumumab+ FOLFOX4

(n = 322)FOLFOX4(n = 327)

Panitumumab+ FOLFOX4

(n = 217)FOLFOX4(n = 218)

Patients with any event 84 69 80 73

Neutropenia 42 41 37 47

Skin toxicity 36 2 30 1

Diarrhoea 18 9 20 10

Neurological toxicities 16 16 17 17

Hypokalaemia 10 5 9 4

Fatigue 9 3 7 5

Mucositis2,3 9 < 1 6 3

Hypomagnesaemia 6 < 1 6 < 1

Paronychia3 3 0 2 0

Pulmonary embolism 3 2 3 4

Febrile neutropenia4 2 2 3 3

Infusion-related reaction (panitumumab)3 < 1 - 0 -

Fatal AEs5, % 5 6 8 31Included all events regardless of relation to therapy; 2Results are based on the following pre-specified list of preferred terms: stomatitis,

mucosal inflammation, aphthous stomatitis, mouth ulceration, mucosal dryness, and mucosal ulceration; 3No grade 4; 4There was 1 Grade 5 febrile neutropenia in the panitumumab arm (MT KRAS exon 2 group); 5Includes cases in which primary cause of death was reported to be

disease progression; 2 were reported to be related to panitumumab (pneumonia and pneumonitis), both in the WT KRAS subgroup..

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