Anti-EFGR: ¿qué aporta en la secuenciacióny el Rechallenge?

Ramon SalazarHospital Duran i Reynals.

Institut Català d´Oncologia

Financial disclosures

Advisory boards: Amgen, VCN-BCN, Agendia, Guardant Health, Roche, Ferrer, Pfizer,

Novartis, Ipsen, Merck, Lilly, MSD

Speaker: Amgen, Pfizer, Novartis, Merck, MSD, AZD, Celgene, Sace Medhealth

Consulting company: Sace Medhealth

OPINIONS ARE MINE

PRIME/PEAK/181 (exploratory analysis)OS in patients receiving panitumumab → anti-VEGF vs bevacizumab → anti-EGFR

•Sobrero A, et al. Ann Oncol 2016;27(Suppl 3):abstract P-145 (and poster).

WT RAS

62605856545250484644424038363432302826242220181614121086420 64

100

90

80

70

60

50

40

30

20

10

0

Pro

po

rtio

n a

live

(%

)

Panitumumab → anti-VEGF (n = 66)

median OS; 36.8 m

Bevacizumab → anti-EGFR (n = 38)

median OS: 27.8 m

HR 0.65 p 0.06

Censor indicated by vertical bar.

Months

• Patient-level data were pooled for all WT RAS patients who received:

– 1st-line panitumumab (PEAK and PRIME) followed by 2nd-line anti-VEGF

– 1st-line bevacizumab (PEAK and 181) followed by 2nd-line anti-EGFR

Meta-analysis PEAK / FIRE-3 / CALGB (Before Sideness)

Heinemann V, Rivera F et al. EJC, 2016

1.096 pts RAS wt: 170 p + 400 p + 526 pStudy level data

1º end point: OS

Meta-analysis PEAK / FIRE-3 / CALGB (Before Sideness)

Heinemann V, Rivera F et al. EJC, 2016

PFS

1.096 pts RAS wt: 170 p + 400 p + 526 pStudy level data

Meta-analysis PEAK / FIRE-3 / CALGB (Before Sideness)

Heinemann V, Rivera F et al. EJC, 2016

PFS

1.096 pts RAS wt: 170 p + 400 p + 526 pStudy level data

Meta-analysis PEAK / FIRE-3 / CALGB (Before Sideness)

Heinemann V, Rivera F et al. EJC, 2016

1º end point: PFS

Putative mechanisms of decreased anti-EGFR mAb efficacy after anti-VEGF

Putative effect of VEGF pathway inhibition:

• Hypoxia-induced EGFR-independentRAS signal activation1

• Hypoxia-induced EMT transition2

– sensitivity to EGFR inhibition

– Aggressive/invasive cell characteristics

• VEGF-A → VEGF-A-inducedresistance to anti-EGFR3 in WT KRAS/NRAS colon cancer cell lines

– VEGFR2/Stat-3-dependent

Adapted from Zaniboni A, Formica V. Cancer Chemother Pharmacol 2016 [Epub ahead of print].

1. Zang M, et al. PLoS One 2010;5:e10966; 2. Zhou J, et al. Oncotarget 2015;6:44332‒45;

3. Derangère V, et al. Oncotarget 2016;7:9309‒21.

EMT, epithelial-mesenchymal transition;

A431: cells sensitive to cetuximab

S1, S2, S3: A431 with overexpressionof VEGF. mVEGF164 (mVEGF164 isoform) protein produced by clones S1 to S3. The human A431P cells do not express the mouse protein, as expected

Viloria-Petit A, et al. Cancer Res 2001;61:5090‒101.

Antiangiogenic treatment elevates VEGF levels

that produce resistance to anti-EGFR

-20

40

80

120

160

180

140

100

60

0

Time (days)

0 5 10 15 20 25 30

Tu

mo

ur

siz

e (

% o

f D

ay 1

)

20

A431P

mVEGF.S1

mVEGF.S2

mVEGF.S3

Vector

• Derangère V, et al. Oncotarget 2016;7:9309‒21.

Sensitivity to 2nd-line therapyPrevious anti-VEGF exposure may decrease efficacy of anti-EGFR

mAb therapy

Clinical data:†

• Prior bevacizumab therapy was associated with significantly reduced PFS†

• Bevacizumab therapy was associated with increased VEGF-A in patients’ serum‡

Derangère V, et al. Oncotarget 2016;7:9309‒21.

†Retrospective analysis of a patient cohort treated at a centre in France;‡Independent cohort of 26 mCRC patients treated with FOLFOX/bevacizumab compared with 12 digestive

cancer patients treated with CTx alone. VEGF-A, vascular endothelial growth factor-A.

PFS in WT RAS mCRC patients treated

with 2nd- or 3rd-line anti-EGFR mAb ± CTx

0

20

40

60

80

100

Su

rviv

al p

rob

ab

ility

(%

)

Months

0 142 4 6 128 10

No previous bevacizumab (n = 52)

Previous bevacizumab (n = 76)

Median 4.0 vs 2.8 months

P = 0.003

PRODIGE 18: BEVA vs. CETU + QT después de progresión a BEVA + QT en ptes RAS WT.

BEV, bevacizumab; CET, cetuximab. Annals of Oncology, Volume 28, Issue suppl_5, 1 September 2017, mdx393.004,

Bevacizumab + CT (n=65) Cetuximab + CT (n=65)

4-month PFS, % (95% CI) 80 (71.8, 91.2) 66.7 (56.0, 79.4)

ORR, % (95% CI) 24.6 (13.9, 35.4) 32.3 (20.2, 44.2)

OS

PFS

p=0.0714

BEV+CT CET+CT

mPFS, months (95% CI)

7.1 (5.8, 8.5)

5.6(4.4, 7.1)

BEV+CT CET+CT

mOS, months (95% CI)

15.8 (12.0,

23.5)

10.4(7.7, 16.8)

p=0.0709

Surv

ival

, pro

po

rtio

n

1.00

0.75

0.50

0.25

0.00

Time (months)

0 3 6 9 12 15 18 21 24

BEV+CTCET+CT

Surv

ival

, pro

po

rtio

n

1.00

0.75

0.50

0.25

0.00

Time (months)0 3 6 9 12 15 18 21 24

BEV+CTCET+CT

Fase II, Objetivo PFS a 4 meses, N=133

Meta-analysis PEAK / FIRE-3 / CALGB (Before Sideness)

Heinemann V, Rivera F et al. EJC, 2016

1º end point: PFS

Ciardiello F, et al. Clin Cancer Res 2004;10:784‒93;Lee et al. ASCO GI 2004; Viloria-Petit A, et al. Cancer Res 2001;61:5090‒101; Bianco R, et al. Clin Cancer Res 2008;14:5069‒80.

C225 = cetuximab ZD6474 = vandetanib.

3. After anti-EGFR → high sensitivity to

antiangiogenics in preclinical models

0.0

1.5

2.5

3.0

2.0

0.5

Time (days)0 20 40 60 80 100 120

Tu

mo

ur

vo

lum

e (

cm

3)

1.0

140

Control

C225

C225 → ZD6474

C225 treatment ZD6474 or C225 treatment

800 p RAS wt

mCRC 1st line

FOLFOX-Panitumumab

FOLFOX-Bevacizumab

P III PARADIGM (Japan)

1º endpoint: OS

Pani vs Beva in 1st line mCRCOngoing Randomized trials

OSCAR: NCT02885753

Study sponsor: Federation Francophone de

Cancerologie Digestive

Liver-limited mCRC(N ~ 268‡)

Panitumumab 6 mg/kg (WT RAS) or bevacizumab 5 mg/kg (MT RAS) +

oxaliplatin 85 mg/m2 intra-arterial

+ LV5FU2† Q2W

R

Panitumumab 6 mg/kg (WT RAS) or bevacizumab 5 mg/kg (MT RAS) +

oxaliplatin 85 mg/m2 intravenous

+ LV5FU2† Q2W

Treatment until PD or toxicity

Baseline ctDNA

Early response (Day 28) evaluation by ctDNA

15

Meta-analyses support the preferential use of anti-EGFR + CT over bevacizumab + CT for LS tumors

1. Holch JW, et al. Eur J Cancer 2017;70:87–98;2. Arnold D, et al. Ann Oncol 2017; epub Apr 12. doi: 10.1093/annonc/mdx175;

3. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075;4. Stintzing S, et al. Lancet Oncol 2016;17:1426–1434;

5. Venook A, et al. JAMA. 2017;317:2392-2401.

Arnold meta-analysis of OS2Holch meta-analysis of OS1

1st line CT + anti-EGFR vs CT + bevacizumab in patients with LS tumors*

1st/2nd line CT + anti-EGFR vs CT ± bevacizumab in patients with LS tumors*

FE, fixed-effects model; RE, random-effects model*FIRE-3 did not meet its primary endpoint of significantly improving ORR in patients with KRAS (exon 2) wt mCRC based on investigators’ read;3 the OS benefit of cetuximab plus chemotherapy vs bevacizumab plus chemotherapy demonstrated for patients with RAS wt mCRC in the FIRE-3 study4 could not be confirmed in the CALGB/SWOG 80405 study5

86% of LS anti-EGFR + CT-treated patients in the head-to-head trials vs bevacizumab + CT received cetuximab + CT

LEFT Meta-analysis OS

16

Meta-analyses support the preferential use of bevacizumab + CT over anti-EGFR + CT for RS tumors

1. Holch JW, et al. Eur J Cancer 2017;70:87–98;2. Arnold D, et al. Ann Oncol 2017; epub Apr 12. doi: 10.1093/annonc/mdx175;

3. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075;4. Stintzing S, et al. Lancet Oncol 2016;17:1426–1434;

5. Venook A, et al. JAMA. 2017;317:2392-2401.

FE, fixed-effects model; RE, random-effects model*FIRE-3 did not meet its primary endpoint of significantly improving ORR in patients with KRAS (exon 2) wt mCRC based on investigators’ read;3 the OS benefit of cetuximab plus chemotherapy vs bevacizumab plus chemotherapy demonstrated for patients with RAS wt mCRC in the FIRE-3 study4 could not be confirmed in the CALGB/SWOG 80405 study5

86% of LS anti-EGFR + CT-treated patients in the head-to-head trials vs bevacizumab + CT received cetuximab + CT

RIGHT Meta-analysis PFS

Arnold meta-analysis of PFS2Holch meta-analysis of PFS1

1st line CT + anti-EGFR vs CT + bevacizumab in patients with RS tumors*

1st/2nd line CT + anti-EGFR vs CT ± bevacizumab in patients with RS tumors*

CAIRO5: NCT021625631

Study sponsor: Dutch Colorectal Cancer Group (DCCG).

Liver-limited mCRC

Unresectable†

(N ~ 640)

RWT RAS/

BRAF andleft-sidedprimary

MT RAS/BRAFand/or

right-sidedprimary

R

Panitumumab 6 mg/kg+ FOLFOX or FOLFIRI

Q2W

Bevacizumab 5 mg/kg+ FOLFOX or FOLFIRI

Q2W

Bevacizumab 5 mg/kg+ FOLFOX or FOLFIRI

Q2W

Bevacizumab 5 mg/kg+ FOLFOXIRI‡

Q2W

Stratification factors include:

Resectability of liver metastases

(potentially resectable vs

permanently unresectable)

1. Huiskens J, et al. BMC Cancer 2015;15:365; ClinicalTrials.gov identifier: NCT02162563 (accessed 08-03-18)

Pani vs Beva in 1st line mCRCOngoing Randomized trials

Phase III Co-operative Group CR-SEQUENCE studyPanitumumab + CTx → bevacizumab + CTx vs the reverse sequence in WT RAS mCRC

Countries: Spain & Portugal (Sponsor: TTD, Spain)

Unresectable

mCRC

WT RAS

Left-sided

primary tumour

(N = 370)

FOLFOX +

panitumumab

FOLFIRI +

bevacizumab

FOLFIRI +

panitumumab

FOLFOX +

bevacizumab

PD

PD

Investigator

choice:

1st-line

reintroduction

Or

regorafenib Or

other

Treatment until PD, toxicity

or conversion surgery

Treatment until

PD or toxicity

R

Primary endpoint: PFS rate at 35 months

Study sponsor: Grupo de Tratamiento de los Tumores Digestivos (TTD)

Eudra CT 2018-000347-60. https://eudract.ema.europa.eu/results-web/ (Accessed June 2018)

Pani vs Beva in 1st line mCRCOngoing Randomized trials

“Under Pressure” Clonal Selection vs. Evolution

Vilar E & Tabernero J. Nature. 2012;486:482-3.

Mutations in RAS emerge during anti-EGFR treatment

and decline when treatment is suspendend

RAS

RAS

wt

Response to treatment Progression to treatment

wtRAS wt

Off treatment ????

Basal RAS wt tumor

rechallenge

Siravegna et al. Nat Med 2015

Rechallenge with anti-EGFR

Siravegna et al. Nat Med 2015

Overall Survival from 1st Line Treatment Baseline in Patients who Underwent Epidermal Growth Factor Receptor Inhibitor Rechallenge in the PRIME and PEAK

Studies (Pooled Data)

Siena S, et al. Rechallenge with EGFR Inhibitors in Patients with mCRC: Effect on Outcomes.

CI, confidence interval; OS, overall survival; PFS, progression-free survival.

Rechallenge of anti-EGFR mAb in mCRC

Santini D, et al (Ann Oncol 2012)

- 39 pts with KRAS WT mCRC

irinotecan based CT + cetuximab• > 6m disease control

• Prog under cetuximab

Treatment without antiEGFR

(median 6 m)Irinotecan-

cetuximab

PFS

mCRC ptsRAS and BRAF wt

Study Design

FOLFIRI/FOLFOXIRI

+ Cetuximab

FOLFOX/XELOX/FOLFOXIRI

+ Bevacizumab

Irinotecan+ Cetuximab

Target accrual: 27 pts

PD PD

Phase II, non comparative, study

• At least a RECIST 1.1 partial response

• 1st-line PFS ≥6 months• PD to 1st-line cetuximab within

4 weeks after the last cetuximab administration

• Time between the end of 1st-line therapy and the start of3rd-line ≥4 months

Study treatment:Irinotecan 180 mg/sqm ivCetuximab 500 mg/sqm iv

*RAS reassessment not planned at enrolment; **Prior 1st line irinotecan-based and cetuximab-containing regimen with at least RECIST partial response lasting at least 6 months, and progression within 4 weeks after the last administration of cetuximab; prior 2nd line oxaliplatin-based and bevacizumab-containing treatment; FP, fluoropyrimidine

Bevacizumab+ FOLFOX/

FOLFOXIRI/XELOX

Cetuximab + FOLFIRI/

FOLFOXIRI

CCRm RAS/

BRAF wt* n=27

Cetuximab + irinotecan**

REC

LUTA

MIE

NTO

CCRm RAS/BRAF wt(n=26; evaluables para respuesta)

Cetuximab + irinotecan

Tasa de respuesta, % 23

Respuesta parcial, % 23

Enfermedad estable, %

31

Progresión, % 46

Tasa control enfermedad, %

54

Objetivo primario: ORR (RECIST)

Estudio fase II de un solo brazo

Tasa de respuestas similar a la observada previamente en pacientes

naïve a anti-EGFR que recibieron Cetuximab en ≥ 2ª L

Rossini et al WCGC 2017 (Abstract no. 591)

CRICKET

ctDNA: Progression-Free Survival and Overall Survival

RAS Wild-Type ctDNA: 4.0 monthsRAS Mutated ctDNA: 1.9 monthsp=0.026HR 0.44 [95%CI 0.18-0.98]

RAS Wild-Type ctDNA: 12.5 monthsRAS Mutated ctDNA: 5.2 monthsp=0.24HR 0.58 [95%CI 0.22-1.52]

Rechallenge Cetuximab

P III FIRE-4 (NCT02934529)

N = 550 pts

Primary endpoint : OS after Rand 2

Liquid biopsy to track/identify

resistance

RAS wt

mCRC

Centuximab +

FOLFIRIRegorafenib

3rd line2nd line1st line

Pani-Panitumumab Irino-Irinotecan

Centuximab +

Irinotecan/FOLFIRICentuximab +

FOLFIRI

Bevacizumab +

FP maintenance

Bevacizumab +

FOLFIRI/XELOXR R

N = 35 pts

Primary endpoint : 3m PFS CT+Pan

i

> 6m

DC

2nd line without

EGFR

Pani-

lrino

3rd line

FIRE 4= ONLY RANDOMIZED TRIAL

Rechallenge Cetuximab

Phase II A-REPEAT study (HECOG, Greece)

Study sponsor: Hellenic Cooperative Oncology Group

Clinicaltrials.gov identifier NCT03311750 (accessed Nov. 2018).

• Primary endpoint: ORR

• Secondary endpoints: ORR by RAS status, PFS, OS, safety, biomarkers and ctDNA

Anti-EGFR re-challenge and plasma genotyping of patients with WT RAS

mCRC

CapIri, capecitabine + irinotecan; CapOx, capecitabine + oxaliplatin;

Pre-trial phase

1st line 2nd line 3rd line

mCRCWT RAS

FOLFIRI or CapIrior capecitabine

or irinotecan± anti-VEGF

FOLFOXor CapOx

or capecitabine± anti-VEGF

Enro

lmen

t

FOLFOX +panitumumab

FOLFIRI oririnotecan +

panitumumab

FOLFOX +anti-EGFR

FOLFIRI +anti-EGFR

(N = 33)

Trial phase

Liquid biopsy

Rechallenge Panitumumab

Rechallenge Panitumumab

1.Clinicaltrials.gov identifier NCT03227926 (accessed 11-09-17).

2.Clinicaltrials.gov identifier NCT03259009 (accessed 11-09-17);

CHRONOS: NCT03227926 (Phase II)1

Study sponsor: Fondazione del Piemonte per l'Oncologia

RASINTRO: NCT032590092

Study sponsor: Association des Gastroentérologues Oncologues

mCRC

WT RAS/

WT BRAF

CTx + anti-EGFR mAbAnti-EGFR mAb-free

CTx

Pre-trial phase/molecular screening Trial phase

Baseline mutational load

Intermediate mutational

load

Rechallenge mutational

load

PD PD

Q2W blood sampling

Panitumumab

rechallenge

(N = 73)

ctDNA C3C1 C2

Interval chemotherapy

(≥ 1 line)Anti-EGFR mAb‡mCRC

WT RASPD PD PD

Clinical benefit† on anti-EGFR

mAb + CTx

(any line)

Pre-trial phase Trial phase

Liquid biopsy

‡Panitumumab is recommended

Liquid biopsy in

PD

RAS WT

mCRC

FOLFIRI +

panitumumabScreening

Treatment until PD,

unacceptable toxicity

or consent withdrawal

Study sponsor: Grupo Gallego de Investigación en Tumores Digestivos (GITuD)

Eudra CT number 2017-003242-25 https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003242-25/ES Accessed 14-03-18

Phase II CONVERTIX study:Pmab + FOLFIRI in 2nd-line treatment of WT RAS converted subjects with mCRC treated in 1st line

with FOLFOX + bevacizumab

Conversion

Liquid biopsy

(Biocartis' Idylla)

mCRC

MUT RAS

FOLFOX +

bevacizumab

1st-line

Pre-trial phase

WT RAS

PD

Beyond progression

Study sponsor: Grupo Español Multidisciplinario del Cáncer Digestivo (GEMCAD)

Eudra CT number 2017-004519-38. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004519-38/ES Accessed 14-03-18.

Phase II BEYOND study

Second-line FOLFIRI + Pmab in subjects who have received FOLFOX +

Pmab in first-line

Liquid biopsy

(Biocartis' Idylla)

Screening

(N = 85*)

Treatment until PD,

unacceptable toxicity

or consent withdrawal

FOLFIRI +

panitumumab

FOLFIRI

R

3:2

WT RAS

Inclu

sio

n†

mCRC

WT RAS

FOLFOX +

panitumumab

1st-line

PD

Pre-trial phase

Summary• Sequence and sideness

• Rechallenge

• Conversion

• Beyond progression

Descubre los avances

en cáncer

más destacados

del año

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