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Panitumumab en el tratamiento del CCRm RAS WT
Dra E. González Flores Hospital Virgen de las Nieves
Granada
Ganando tiempo al tiempo en CCRm…
1. N Engl J Med 2000; 343:905-14; 2. Lancet 2000; 355:1041-7; 3. J Clin Oncol
2004; 22:23-30; 4. J Clin Oncol 2007;25:1670-6; 5. N Engl J Med 2004;
350:2335-42; 6. J Clin Oncol 2008; 26:2013-9; 7. Lancet Oncol. 2014;15:1065-
75; 8. JAMA 2017;317:2392:401; 9. Ann. Oncol. 25 (5s Suppl.), LBA3 (2014);
10.N Eng J Med 2013;369:1023-34; 11. J Clin Oncol 2015; 33:692-70; 12. Int J
Colorectal Dis. 2017;32:1179-90
Informal comparison as these are not head-to-head clinical trials
*RAS WT population; #phase 2 (WT in KRAS and NRAS exons 2, 3, and 4)
0 5 10 15 20 25
12.6Saltz1, 2000 5-FU/LV bolus
14.1Douillard2, 2000 5-FU/LV infusion
14.8Saltz1, 2000 IFL
17.4Douillard2, 2000 FOLFIRI (de Gramont or AIO)
19.5Goldberg3, 2004 FOLFOX
22.6Falcone4, 2007 FOLFOXIRI
Overall survival (months)
21.3Saltz6, 2008 FOLFOX /XELOX+ anti-VEGF
33.1*
20.3Hurwitz5, 2004 IFL + anti-VEGF
32.0*
FOLFIRI+ anti-EGFR
Douillard10, 2013
FOLFOX/FOLFIRI + anti-EGFR
30
Van Cutsem11, 2015 28.4*
Heinemann7, 2014
FOLFOX+ anti-EGFR 25.8*
25.6*FOLFIRI+ anti-VEGF
31.2*FOLFOX/FOLFIRI + anti-VEGF
FOLFIRI + anti-EGFR
Venook8, 2017; Lenz9 2014
Venook8, 2017; Lenz9, 2014
Heinemann7, 2014
36.9*#FOLFOX + anti-EGFR Rivera12, 2017
35
Chemotherapy + anti-VEGF (bevacizumab)
Chemotherapy
Chemotherapy + anti-EGFR (panitumumab or cetuximab)
DETRÁS DE CADA HITO HAY UNA GRAN HISTORIA QUE NOS DEJA HUELLA….
• MUJER 35 AÑOS
• PROFESORA
• AMANTE DEL MAR Y LA MONTAÑA
• DOS HIJOS DE 8 Y 6 AÑOS
• SIN ANTECEDENTES FAMILIARES ONCOLÓGICOS
• HISTORIA ONCOLÓGICA: JUNIO 2015
❑ Debut de clinica:
❑ DISTENSIÓN ABDOMINAL
❑ CUADRO CONSTITUCIONAL
❑ DOLOR ABDOMINAL INTENSO ( TTO MÓRFICOS)
❑ INGRESA PARA estudio en Digestivo
❑ ECO ABDOMEN: LOES HEPATICAS BILOBARES
❑ ANALITICA: ❑ GOT 354
❑ GPT 245
❑ LDH 1863
❑ CEA 2045
❑ COLONOSCOPIA: o A 35 CM de margen anal se aprecia masa mamelonada, irregular, de crecimiento exofítico, ulcerado con áreas de necrosis en superficia, queocupa el 60% de la circunferencia permitiendo el paso del endoscopio.
DIAGNÓSTICO ANATOMOPATOLÓGICO:BIOPSIA INCISIONAL ENDOSCÓPICA :• ADENOMA TUBULAR CON DISPLASIA DE ALTO GRADO
ESTUDIO DE EXTENSIÓN PET-TAC
Comité multidisciplinar
• CA COLON IZQUIERDO• MET HEPÁTICAS IRRESECABLES• SE SOLICITA BAG HEPÁTICA
CON ESTUDIO MUTACIONAL DE RAS Y MSI
• SE TRASLADA A PLANTA DE ONCOLOGÍA MÉDICA
Biomarcadores
1. http://ec.europa.eu/health/documents/community-register/html/h423.htm (accessed 08-03-18);2. http://ec.europa.eu/health/documents/community-register/html/h281.htm (accessed 08-03-18).
*This slide shows selected label updates, focusing on changes relating to the patient population eligible for anti-EGFR therapy. Therapeutic indications have been abbreviated; please see product labels for full details; †and intolerant to irinotecan; ‡for patients who have received 1st-line fluoropyrimidine-based chemotherapy (excluding irinotecan).CTx, chemotherapy; CTxR, chemotherapy refractory; IRI, irinotecan.
20072004
Cetuximab2
EU
la
be
l va
ria
tio
ns
*
Combination: IRI (CTxR)
Monotherapy (CTxR)(WT KRAS)
Combination:FOLFOX or FOLFIRI (1st
line);FOLFIRI (2nd line‡);
monotherapy (CTxR) (WT RAS)
Combination: CTx; Monotherapy (CTxR†)
(WT KRAS)
Label variation(WT RAS)
Combination: FOLFOX (1st line); FOLFIRI (2nd line);
monotherapy (CTxR)(WT KRAS)
2008 2009 2010 2011 2012 2013 2014 2015
Unselected WT KRAS exon 2 WT RAS
All KRAS RAS
Labelvariation(WT RAS)
PASADO PRESENTE FUTURO
Panitumumab1
Phase 4 PERSEIDA study Determination of the mutational status of RAS in liquid biopsies of
subjects with 1st line RAS WT metastatic colorectal cancer: An observational, prospective, multicentre study in Spain
Before starting 1st-line
treatment
Plasma samples from 1st-line mCRC patients
with wild-type RAS(tumour tissue biopsy)
Liq
uid
bio
psie
s
20 ± 2 weeks
At disease
progression
Valladares et al. SEOM congress 2018; Abstract O-39 (and oral presentation)
García-Alfonso et al. ESMO congress 2018; Abstract 3887 (and poster discussion)
LB: BEAMing
Tasa de RG en pacientes tratados con panitumumab
• ORR in the panitumumab subgroup according to RAS mutation
status at baseline (analyzed using cfDNA from a liquid biopsy):
ORR (not confirmed)
% (95% CI)
Odds ratio (95% CI)
P-value (Fisher’s
exact test)MAF, cut-off (n) RAS wild-type RAS mutated
≥ 1% (90 wild-type
/ 3 mutated)
78.9
(69.0 – 86.8)
33.3
(0.8 – 90.6)
7.5 (0.6 – 86.9)
0.129
≥ 0.1% (88 wild-
type / 5 mutated)
78.4
(68.4 – 86.5)
60.0
(14.7 - 94.7)
2.4 (0.4 – 15.6)
0.315
≥ 0.02% (80 wild-
type / 13 mutated)
80.0
(69.6 – 88.1)
61.5
(31.6 – 86.2)
2.5 (0.7 – 8.7)
0.160
García-Alfonso et al. ESMO congress 2018; Abstract 3887 (and poster discussion)
Preliminary Results
FUTURO: INVESTIGAR EL PUNTO DE CORTE ÓPTIMO DE MAFPAPEL DE LA BIOPSIA LIQUIDA EN LA PREDICCIÓN PRECOZ DE RESPUESTA Y DE RESISTENCIA AL TRATAMIENTO
Cytoreduction (shrinkage)
MOLECULAR PROFILE
Adaptado de Van Cutsem. ESMO guideline. Annals of Oncology 0: 1–37, 2016.
CLINICAL CONDITION OF THE PATIENT
Unfit (but may be suitable)Fit Unfit
FP ± bevacizumab;
reduced dose doublet;
anti-EGFR
BSCGOAL
MT BRAFMT RASWT RAS
Triplet +
bevacizumab
Combination +
bevacizumab
Doublet +
anti-EGFR
NED
Clearly
resectable
metastases
Surgery alone;
surgery with
perioperative/
postoperative
CTRe-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 BRAFMT RASWT RAS
Unusual,
see text
CT +
bevacizumab
CT + biological
agent
Re-evaluation/assessment of response Q2−3M
Continue;
maintenance;
or pause
Progressivedisease
Second-line
LOCALIZACIÓN
Selección de tratamiento en CCRm
SECUENCIA TERAPÉUTICA
En Oncología Médica ….• BAG HEPÁTICA
– Adenocarcinoma de origen intestinal – RAS NATIVO– BRAF NO MUTADO– AUSENCIA DE INESTABILIDAD
SELECCIÓN DE TRATAMIENTOPACIENTE FIT
CITORREDUCCIÓNLOCALIZACION IZQUIERDA
SECUENCIA?
1.N Eng J Med 2013;369:1023-34; 2. Ann Oncol 2017;28:1862-8. 3.Eur J Cancer 2013;49:S18; 4. Eur
J Cancer 2015;51:1231–42. 5. Int J Colorectal Dis. 2017;32:1179-90; 6.J Clin Oncol 2014; 32:5s (suppl):abstract 3629 (and poster); 7. Eur J Cancer 2017; 81:191–202 8;
FOLFOX + PANITUMUMAB
Evolución de la supervivencia global en CCRm ¿Qué ha aportado panitumumab?
1.N Eng J Med 2013;369:1023-34; 2. Ann Oncol 2017;28:1862-8. 3.Eur J Cancer 2013;49:S18; 4. Eur
J Cancer 2015;51:1231–42. 5. Int J Colorectal Dis. 2017;32:1179-90; 6.J Clin Oncol 2014; 32:5s (suppl):abstract 3629 (and poster); 7. Eur J Cancer 2017; 81:191–202 8;
Informal comparison as these are not head-to-head clinical trials
FOLFOX6 + panitumumab (WT-RAS and left-sided tumour) (n=53)
36.9
28.3Douillard1, 2013 FOLFOX+ panitumumab (WT-RAS WT-BRAF) (n=228)
Peeters3, 2013 FOLFOX + panitumumab (WT-RAS receiving anti-VEGF after progression) (n=55) 40.0
26.0Douillard1, 2013 FOLFOX + panitumumab (WT-RAS) (n=259)
30.3Boeckx2, 2017 FOLFOX+ panitumumab (WT-RAS left-sided tumour) (n=168)
Carrato7, 2017 FOLFIRI + panitumumab (WT-RAS and LLD) (n=26)
39.0
43.4
0 5 10 15 20 25
Overall survival (months)
30 35 40
FOLFOX + panitumumab (WT-RAS and LLD) (n=48) 40.7
FOLFOX + panitumumab (WT-RAS and WT-BRAF left-sided tumour) (n=156) 32.5Boeckx2, 2017
Douillard4 2015
FOLFOX6 + panitumumab (WT-RAS WT-BRAF) (n=48)
Carrato7, 2017 FOLFOX4 + panitumumab (WT-RAS and LLD) (n=27)
FOLFOX6 + panitumumab (WT-RAS) (n=57)
43.4
41.3
FOLFOX6 + panitumumab (WT-RAS WT-BRAF and left-sided tumour) (n=52)
49.0
PEAK-Ph2:Pmab+FOLFOX vs Bmab+FOLFOX
PRIME-Ph3: Pmab +FOLFOX vs FOLFOX
PLANET-Ph2: Pmab+FOLFOX vs Pmab+FOLFIRI
Boeckx2, 2017
Boeckx2, 2017
Rivera5, 2017
Rivera5, 2017
FOLFOX6 + panitumumab (WT-RAS receiving anti-VEGF after progression) (n=35)Rivera6, 2014 41.3
FOLFIRI/FOLFOX4 + panitumumab (WT-RAS and LLD and resected patients) (n=28) 52.0Carrato7, 2017
RAS WT:CITORREDUCCIÓN
LOCALIZACION IZQUIERDA DEL TUMOR PRIMARIOSECUENCIA DE TRATAMIENTO
Panitumumab en primera linea:Evidencia en combinación con
FOLFOX / FOLFIRI
EPAR Vectibix http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000741/WC500187313.pdf(accessed 23-04-18)
CI: confidence Interval; NA: Not applicable; NE: Not estimable; ORR: Overall response rate; PFS: progression-free survival; OS: Overall survival
2006314 PLANET 20050203
Pmab+FOLFIRI Pmab+FOLFIRI Pmab+FOLFOX Pmab+FOLFOX
Total number of subjects enrolled per treatment arm
154 39 38 593
Overall RAS ascertainment rate 93% 83% 90%
Number of subjects with wild-type RAS status
69 26 27 259
ORR, % 58.8 73.1 77.8 58.7
PFS
Median months (95% CI)11.2
(7.6, 14.8)14.8
(7.1, 18.7)12.8
(6.2, 22.0)10.1
(9.3, 12.0)
Hazard ratio vs. control arm (95% CI) NA0.86
(0.47, 1.56)0.72
(0.58, 0.90)
OS
Median OS, months (95% CI) NE45.8
(32.8, 51.5)39.0
(26.5, NE)26.0
(21.7, 30.4)
Hazard ratio vs. control arm (95% CI) NA0.97
(0.41, 2.28)0.78
(0.62, 0.99)
Meta-analysis: Impacto de ETS en Resección
Taieb J, et al. J Cancer Res Clin Oncol 2018;144:321-35
Meta-analysis of overall resection data also favoured ETS ≥ 20% vs ETS < 20% (odds
ratio = 0.36; 95% CI, 0.21‒0.63). Weight is relative weight (%) from the fixed-effects
models. logOR, log odds ratio; logSE, standard error of logOR.
FavoursETS ≥ 30%
FavoursETS < 30%
Heterogeneity: Chi2 = 1.27, df = 2, (P = 0.53), I2 = 0%, Tau2 = 0
PEAK
PLANET
PRIME
Total(Fixed)
Odds ratio (95% CI)logOR logSE Weight
Total (Random)
0.37 (0.21‒0.66)
0.59 (0.24‒1.50)
0.25 (0.070‒0.91)
0.40 (0.25‒0.63)
0.40 (0.25‒0.63)
‒0.990
‒0.522
‒1.39
0.2945
0.4715
0.6571
62.9
24.5
12.6
100.0
0.1 1 10
Meta-analysis of overall resection data favoured Week 8 ETS ≥ 30% vs < 30%
WT RAS
Evidencia en primera línea frente a Antiangiogénico: Estudio PEAK
Rivera F, et al. Int J Colorectal Dis 2017;32:1179−90.
*From stratified Cox model; †As assessed by RECIST (for ORR n = 81
for the WT RAS bevacizumab group); ‡Defined as the odds of having an
objective response in the panitumumab + mFOLFOX6 arm relative to the
odds in the bevacizumab + mFOLFOX6 arm; ¥Stratified exact test.
WT RAS
Panitumumab+ mFOLFOX6
(n = 88)
Bevacizumab+ mFOLFOX6
(n = 82)
Median PFS, months (95% CI)
12.8(10.7‒15.1)
10.1(9.0‒12.7)
Hazard ratio (95% CI) 0.68 (0.48‒0.96)
P-value* 0.029
Median OS, months (95% CI)
36.9(27.9‒46.1)
28.9(23.3‒32.0)
Hazard ratio (95% CI) 0.76 (0.53‒1.11)
P-value* 0.15
ORR,† %(95% CI)
65(54‒75)
60(49‒71)
Odds ratio‡ (95% CI) 1.12 (0.56‒2.22)
P-value¥ 0.86
LOCALIZACIÓN:
ESMO primary tumour location pooled analysisPredictive analysis of tumour location (right vs left) in
trials comparing CTx + anti-EGFR with CTx ± bevacizumab*
Arnold D, et al. Ann Oncol 2017;28(8):1713-29
HR < 1 favours CTx + anti-EGFR; HR > 1 favours CTx ± bevacizumab;
OR > 1 favours CTx + anti-EGFR; OR < 1 favours CTx ± bevacizumab.
No significant inter-study heterogeneity for any of the three endpoints.†Test comparing HRLeft and HRRight/ORLeft and ORRight.
WT RAS (pooled) Total LEFT Total RIGHT
OS
HR (95% CI), right vs left
P-value
0.75 (0.67‒0.84)
< 0.001Favours CTx + anti-EGFR
1.12 (0.87‒1.45)
0.381Favours CTx ± bevacizumab
HRInteraction (95% CI)
P-value HRInteraction†
1.50 (1.19‒1.88)
P < 0.001
PFS
HR (95% CI), right vs left
P-value
0.78 (0.70‒0.87)
< 0.001Favours CTx + anti-EGFR
1.12 (0.87‒1.44)
0.365Favours CTx ± bevacizumab
HRInteraction (95% CI)
P-value HRInteraction†
1.43 (1.14‒1.80)
P = 0.002
ORR
OR (95% CI), right vs left
P-value
2.12 (1.77‒2.55)
< 0.001Favours CTx + anti-EGFR
1.47 (0.94‒2.29)
0.089Favours CTx + anti-EGFR
ORInteraction (95% CI)
P-value ORInteraction†
0.69 (0.46‒1.04)
P = 0.07
*PRIME, Phase 2 PEAK, 181, FIRE-3, CRYSTAL, CALGB 80405
Panitumumab y localizacion tumoral
WT RAS/WT BRAF
PRIME PEAK
Pmab +
FOLFOX FOLFOX
Pmab +
FOLFOX Bev + FOLFOX
Left, n
Right, n
156
26
148
32
52
13
53
13
Median OS, months
Left 32.5 23.6 43.4 32.0
Adjusted HR† (95% CI)
P-value
0.68 (0.52‒0.87)
0.0027
0.76 (0.45‒1.27)
0.2945
Right 22.5 21.5 22.5 23.3
Adjusted HR† (95% CI)
P-value
0.97 (0.55‒1.74)
0.9295
0.64 (0.26‒1.58)
0.3326
Median PFS, months
Left 12.9 9.3 14.6 11.5
Adjusted HR† (95% CI)P-value
0.69 (0.54‒0.88)
0.0028
0.65 (0.43‒1.00)
0.0514
Right 8.9 7.3 10.3 12.6
Adjusted HR† (95% CI)
P-value
0.75 (0.42‒1.33)
0.3260
0.90 (0.39‒2.07)
0.8092
Boeckx N, et al. Ann Oncol 2017;28:1862-8.
†For PRIME, adjusted treatment HR was calculated from a model with factors for region and
baseline ECOG PS; for PEAK, adjusted treatment HR was calculated from a model with factors for
prior adjuvant oxaliplatin therapy.
A HR < 1 favours the panitumumab treatment arm.
all
Van Cutsem. ESMO guideline. Annals of Oncology 2016; 0: 1–38.
¿ CÓMO PODEMOS MEJORAR LOS RESULTADOS CON PANITUMUMAB?
PANITUMUMAB + FOLFIRINOX
Tripletes
1. CRC treatment continuum representation based on: Van Cutsem E, et al. Ann Oncol 2016;27:1386‒422. 2. Study sponsor: AIO-Studien-gGmbH.ClinicalTrials.gov identifier:
NCT01328171 (accessed 8-03-2018); Geissler M, et al. Ann Oncol 2017;28(Suppl 5):abstract 475O (and oral presentation). 3. Study sponsor: UNICANCER. ClinicalTrials.gov
identifier: NCT02980510 (accessed 8-03-2018. 4. Study sponsor: Gruppo Oncologico del Nord-Ovest (GONO). Clinicaltrials.gov identifier NCT03231722 (accessed 8-03-2018).
VOLFI: NCT013281712
PANIRINOX: NCT029805104
TRIPLETE: NCT032317223
mCRC UnresectableWT RAS(n = 96)
R
Treatment until PD, resectable status or to maximum 12 cycles
mFOLFOXIRI† Q2W +panitumumab 6 mg/kg
Q2W (n = 63)
FOLFOXIRI‡ Q2W(n = 33)
2:1
If resectable:Surgery then protocol
treatment (max 12 cycles)
If CR/PR/SD after 12 cycles:re-induction with
same combinationrecommended on PD
Unresectable mCRCWT RAS/WT BRAF
(N ~ 432)
mFOLFOXIRI† Q2W+ panitumumab
6 mg/kg Q2W
mFOLFOX6 Q2W +panitumumab6 mg/kg Q2W
R
Treatment to maximum 12 cycles
If no PD: patients will receive maintenance 5FU/LV + panitumumab‡
until PD, unacceptable toxicity or patient’s refusal
Unresectable Mcrc WT RAS/WT BRAF(N = 209)
FOLFIRINOX† + panitumumab Q2W
mFOLFOX6 + panitumumab Q2W
R
ccfDNA analysis
RESECCIONES: 33 VS 12%
TOXICIDAD GRADO 3-5: 81% VS 66%NO DIFERENCIAS EN CALIDAD DE VIDA
EVOLUCIÓN TRAS PRIMERA LÍNEA CON FOLFOX + PANITUMUMAB
❑ TRAS PRIMER CICLO MEJORIA SUBJETIVA MUY IMPORTANTE ( NO REQUIERE ANALGESIA)
❑ GANANCIA DE PESO
❑ ALTA DOMICILIARIA
❑ RECIBE 4 CICLOS CON REEVALUACIÓN CLÍNICA Y RADIOLÓGICA
Evolución analítica
1873 U/L 271 U/L2093ng/ml 23,7mg/ml
Evolución radiológica
Evolución SEPTIEMBRE 2015
• Asintomática • ECOG: 0• Toxicidad cutánea grado
1-2• Excelente calidad de
vida
Evolución global de la paciente
• En CMT se descarta resecabilidad por enfermedad bilobar múltiple aunque con RP importante
• Continúa 8 ciclos de FOLFOX+ PANI
• Por Neurotoxicidad y deseo de la paciente ( Calidad de vida) suspende Oxaliplatino y mantiene 5FU+ Panihasta diciembre 2016 manteniendo RP
1. Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and methodologic considerations. J Vasc Interv Radiol 2006;17:1251–78. 2. Benson AB, Geschwind JF, Mulcahy MF, et al. Radioembolisation for liver metastases: results from a prospective 151 patient multi-institutional phase II study. Eur J Cancer 2013;49(15):3122–30. 3. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival. Radiology 2008;247(2):507–15. 4. Lewandowski RJ, Memon K, Mulcahy MF, et al. Twelve-year experience of radioembolization for colorectal hepatic metastases in 214 patients: survival by era and chemotherapy. Eur J Nucl Med Mol Imaging 2014;41(10):1861–9.
MANTENIMIENTOSECUENCIARETRATAMIENTO
Mantenimiento
1. CRC treatment continuum representation based on: Van Cutsem E, et al. Ann Oncol 2016;27:1386‒422; 2. ClinicalTrials.gov identifier: NCT01991873 (accessed 08-03-
18); 3. ClinicalTrials.gov identifier: NCT01384994 (accessed 08-03-18); 4. ClinicalTrials.gov identifier: NCT02476045 (accessed 08-03-18); 5. Nakamura M et al. GICS 2018.
Abstract 729 & poster
Valentino: NCT024760454 SAPPHIRE5
PanaMa: NCT019918732
mCRCWT RAS(N ~ 380)
Panitumumab6 mg/kg Q2W+ mFOLFOX6 Q2W
CR/PRor SD at12 weeks
R
5-FU/FA† Q2W
Panitumumab 6 mg/kg Q2W+ 5-FU/FA† Q2W Panitumumab
6 mg/kg Q2W+ mFOLFOX6Q2W
Induction Maintenance Re-inductionon progression
Panitumumab
6 mg/kg Q2W+ FOLFOX4
Q2WR
Induction Maintenance
1st-linemCRCWT RAS(N ~ 224)
Advanced/ recurrent CRCWT RAS †
(N ~ 164)
Panitumumab6 mg/kg ++ mFOLFOX6 Q2Wx 6 cycles
CR/PRor SD
R
Panitumumab 6 mg/kg + 5-FU/LV Q2W
Panitumumab 6 mg/kg + mFOLFOX6Q2W
Induction Maintenance
Panitumumab
6 mg/kg Q2W+ 5-FU/LV Q2W
Panitumumab
6 mg/kg Q2W
Panitumumab
6 mg/kg Q2W+ FOLFOX4
Q2W
Dis
eas
e p
rogr
essi
on
/un
acce
pta
ble
to
xici
ty/c
on
sen
t w
ith
dra
wal
Treatment up to 8 cycles
Slide 11
Presented By Filippo Pietrantonio at 2018 ASCO Annual Meeting
VALENTINO
SAPPHIRE
▪ Primary Endpoint: PFS rate at 9 months after randomization
PFS after radomization OS after radomization
Group A and Group B both met the primary endpoint with a PFS rate 9 months significantly above the 30% threshold.
The median period of treatment from randomization was 14.5 months in Group A and 13.8 months in Group B.
Nakamura M et al. WGICC 2018. Abstract PD-011
PN-related AEs* after enrollment
SECUENCIA: Análisis exploratorio de tres
estudios de Panitumumab en primera línea
Peeters M et al. ESMO Open 2018;3:e000297 DOI: 10.1136/esmoopen-2017-000297
2nd-line
FOLFIRI
2nd-line
Panitumumab
+FOLFIRI
(N=29)
1st-line
panitumumab
+FOLFOX4
PRIME
R
PEAK
R
181
1st-line
+FOLFOX4
1st-line
panitumumab
+mFOLFOX6
1st-line
bevacizumab
+mFOLFOX6
2nd-line
VEGFI ±Chemotherapy
(N=35)
2nd-line
VEGFI ±Chemotherapy
(N=31)
vs.
vs.
OS OS
Pooled
2nd-line
EGFRI ±Chemotherapy
(N=9)
OS
1st-line
VEGFI
± oxaliplatin
R
OS
Pooled
vs.
Pmab→VEGFi(n=58)
VEGFi→Pmab(n=35)
OS median (95%CI) months
41.3(31.6-46.1)
28.9(24.2-39.2)
HR (95%CI) 0.58 (0.36-0.95)
P-value 0.03
Pmab→VEGFi(n=66)
VEGFi→Pmab(n=38)
OS median (95%CI) months
36.8(30.3-43.8)
27.8(24.2-35.6)
HR (95%CI) 0.65 (0.42-1.03)
P-value 0.06
SG según la secuencia de tratamiento
RAS WT
RAS WT BRAF WT
Peeters M et al. ESMO Open 2018;3:e000297 DOI: 10.1136/esmoopen-2017-000297
SECUENCIA
Evolución global de la paciente
• PRO hepática en noviembre 2017: SIRT + segunda línea con FOLFIRI+ AFLIBERCEPT
• EE hepática y mantiene tratamiento en el momento actual
SLP a Folfox+ Pani:28 mesesSG actual: 45meses
CONTINUA VIVA
1. Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and methodologic considerations. J Vasc Interv Radiol 2006;17:1251–78. 2. Benson AB, Geschwind JF, Mulcahy MF, et al. Radioembolisation for liver metastases: results from a prospective 151 patient multi-institutional phase II study. Eur J Cancer 2013;49(15):3122–30. 3. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival. Radiology 2008;247(2):507–15. 4. Lewandowski RJ, Memon K, Mulcahy MF, et al. Twelve-year experience of radioembolization for colorectal hepatic metastases in 214 patients: survival by era and chemotherapy. Eur J Nucl Med Mol Imaging 2014;41(10):1861–9.
Panitumumab….colaborando al aumento de la SG del CCRm
1.N Eng J Med 2013;369:1023-34; 2. Ann Oncol 2017;28:1862-8. 3.Eur J Cancer 2013;49:S18; 4. Eur
J Cancer 2015;51:1231–42. 5. Int J Colorectal Dis. 2017;32:1179-90; 6.J Clin Oncol 2014; 32:5s (suppl):abstract 3629 (and poster); 7. Eur J Cancer 2017; 81:191–202 8;
Informal comparison as these are not head-to-head clinical trials
FOLFOX6 + panitumumab (WT-RAS and left-sided tumour) (n=53)
36.9
28.3Douillard1, 2013 FOLFOX+ panitumumab (WT-RAS WT-BRAF) (n=228)
Peeters3, 2013 FOLFOX + panitumumab (WT-RAS receiving anti-VEGF after progression) (n=55) 40.0
26.0Douillard1, 2013 FOLFOX + panitumumab (WT-RAS) (n=259)
30.3Boeckx2, 2017 FOLFOX+ panitumumab (WT-RAS left-sided tumour) (n=168)
Carrato7, 2017 FOLFIRI + panitumumab (WT-RAS and LLD) (n=26)
39.0
43.4
0 5 10 15 20 25
Overall survival (months)
30 35 40
FOLFOX + panitumumab (WT-RAS and LLD) (n=48) 40.7
FOLFOX + panitumumab (WT-RAS and WT-BRAF left-sided tumour) (n=156) 32.5Boeckx2, 2017
Douillard4 2015
FOLFOX6 + panitumumab (WT-RAS WT-BRAF) (n=48)
Carrato7, 2017 FOLFOX4 + panitumumab (WT-RAS and LLD) (n=27)
FOLFOX6 + panitumumab (WT-RAS) (n=57)
43.4
41.3
FOLFOX6 + panitumumab (WT-RAS WT-BRAF and left-sided tumour) (n=52)
49.0
PEAK-Ph2:Pmab+FOLFOX vs Bmab+FOLFOX
PRIME-Ph3: Pmab +FOLFOX vs FOLFOX
PLANET-Ph2: Pmab+FOLFOX vs Pmab+FOLFIRI
Boeckx2, 2017
Boeckx2, 2017
Rivera5, 2017
Rivera5, 2017
FOLFOX6 + panitumumab (WT-RAS receiving anti-VEGF after progression) (n=35)Rivera6, 2014 41.3
FOLFIRI/FOLFOX4 + panitumumab (WT-RAS and LLD and resected patients) (n=28) 52.0Carrato7, 2017
CONCLUSIONES
◆ Mutaciones de RAS( KRAS, NRAS Y BRAF) deben estardisponibles al diagnóstico en todos los pacientes con CCRm
◆ Biopsia liquida representa el futuro inmediato para laselección de pacientes , respuesta precoz y retratamiento
◆ Panitumumab ha demostrado benefico en
◆ Primera línea en combinación con FOLFOX/FOLFIRI
◆ Segunda línea en combinación con FOLFIRI
◆ En pacientes pretratados en monoterapia
◆ Aumenta de forma importante la SG en población Ras WT:
◆ Citorreducción
◆ En localización izquierda del tumor primario
◆ Podemos mejorar los resultados con tripletes +Panitumumab?
◆ Panitumumab + 5Fu se presenta como una adecuadaopción de mantenimiento tras primera línea.
◆ Aumentamos la evidencia de la secuencia antiEGFR-Antiangiogénico en RAS WT
◆ Pendiente de estudios que avalen el RETRATAMIENTO conantiEGFR
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