Panitumumab en el tratamiento del CCRm RAS WT · FOLFIRI+ anti-EGFR Douillard10, 2013 FOLFOX/FOLFIRI + anti-EGFR 30 Van Cutsem11, 2015 28.4* Heinemann7, 2014 FOLFOX+ anti-EGFR 25.8*

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?




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


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)

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000741/WC500187313.pdf

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)


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)


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


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


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




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


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

Documents

Panitumumab en el tratamiento del CCRm RAS WT · FOLFIRI+ anti-EGFR Douillard10, 2013 FOLFOX/FOLFIRI + anti-EGFR 30 Van Cutsem11, 2015 28.4* Heinemann7, 2014 FOLFOX+ anti-EGFR 25.8*