anti-efgr: ¿qué aporta en la secuenciación y el ... · derangère v, et al. oncotarget...
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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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