secuenciación terapéutica en cáncer de...

Secuenciacion terapeutica en cancer de pancreas

Andrés J. Muñoz Martín MD PhD

Servicio de Oncología Médica

Hospital General Universitario Gregorio Marañón

My disclosures

• Consultant or advisory role: Celgene

• Speaking: Celgene, Shire

• En los últimos siete años se ha modificado de forma significativa el tratamiento de primera línea de pacientes con cáncer de páncreas con la aparición de dos regímenes de quimioterapia: FFX y G-A

Se ha observado un incremento significativo de la supervivencia

Se han observado “largos supervivientes” (>2-3 años)

Se ha triplicado la tasa de respuestas

• En los últimos dos años se ha consolidado el tratamiento de

segunda línea basado en la combinación de FP y oxaliplatino o naliri y se ha introducido un nuevo concepto terapéutico “secuenciación”

Ensayos aletaorizados fase III en 3ª línea PANCRIT-1 (pacientes están

viviendo más y con buena calidad de vida)

En los últimos siete años en

cáncer de páncreas….

Primary Endpoint (OS) & Response Rate

Conroy T. N Engl J Med 2011;364:1817-25

mOS 11.1m FOLFIRINOX VS. 6.8 m G

mOS 8.7 m NP-G vs. 6.6 m G

Von Hoff DD, N Engl J Med. 2013;369:1691-1703

Diferencias de resultados…

Response rate 23% (29%) vs 31%

¿Son comparables los resultados de los dos estudios?

No

¿Por qué no son comparables? Las poblaciones incluidas son diferentes

¿Se podrían justificar las diferencias observadas?

Se podrían justificar…

¿Podemos esperar una comparación directa de los dos esquemas en un estudio randomizado?

Muy probablemente no…

MPACT vs PRODIGE

Características de las poblaciones

Estudio PRODIGE/ACCORD FOLFIRINOX

MPACT GZT+NBP

Edad (mediana y rango) 61 años (25-76) 63 años (27-86)

Pacientes ancianos >76 años No Si

Pacientes PS0 37% 16%

Pacientes PS2 1% 7%

Mediana de localizaciones metastásicas

2 3

Ca19.9 >59 LAN

(medida indirecta carga tumoral)

++ 42%

+++ 52%

MPACT

• Población con características clínicas más desfavorables en cáncer de páncreas: más jóvenes y más “sanos”

• Mayor número de pacientes recibieron tratamiento de 2ª línea en el estudio de FFX: FFX 47% vs G-NABP 40%, 2ª línea impacta en supervivencia

Tabernero et al. Beaujon Conference 2014

Pacientes ECOG 0-1 MPACT

Mediana de SG: 9,7 meses

Tabernero J et al, The Oncologist 2015;20:1–8

ASCO 2014: US Study Oncology Network, OS comparative study

First line chemo n Median OS

FOLFIRINOX 666 11.2 months

Gem + other drug 1567 7.0 months

Gem + nabpaclitaxel 184 10.2 months

Cartwright TH et al. J Clin Oncol 2014:32(15s):287s (Abs 4132)

YOSEMITE trial PhIIR, ESMO 2017 Related Adverse Events ≥ 15%

Overall Survival

Overall Survival by Region

Progression-Free Survival

There is accumulating evidence that the cell types within tumors are heterogeneous and that a

subset of the cells retain the property to self-renew and give rise to more differentiated progeny.

These cells, called Cancer Stem Cells (CSCs) or tumor initiating cells drive tumor growth and

metastasis and are more resistant to chemotherapy and radiotherapy than the remaining tumor cells.

The ability to characterize the CSCs through surface markers and functional limiting tumor dilution

assays, using minimally passaged human tumors, has enabled the identification of novel agents that

target the CSC population. One pathway which appears critical for the CSCs is the Notch pathway.

The pathway is comprised of 4 Notch receptors (1-4) and 5 ligands, Jagged (1-2) and delta-like

ligand (DLL1, 3 and 4). The DLL4 ligand contributes to CSC self-renewal and vascular

development. Demcizumab (DEM) is a humanized IgG2 antibody that binds to DLL4. In minimally

passaged human tumor xenografts, DEM was observed to have activity against a variety of tumors

including colorectal cancer, breast cancer, lung cancer, pancreatic cancer, melanoma and ovarian

cancer. The impact of treatment on the frequency of tumorigenicity was assessed using a limiting

dilution assay. In several models, using different chemotherapeutic agents, while the chemotherapy

alone decreased tumor volume, the frequency of tumor initiating cells was increased in the residual

tumor. In contrast, DEM alone decreased the frequency of CSCs and the greatest reduction was

observed when DEM was combined with GEM and nab-paclitaxel.

YOSEMITE: A 3 Arm Double-Blind Randomized Phase 2 Study of Gemcitabine, Paclitaxel Protein-Bound Particles for Injectable

Suspension (Abraxane®) and Placebo (GAP) versus Gemcitabine, Abraxane® and either 1 or 2 Truncated Courses of Demcizumab

Subject Disposition Placebo/

Placebo

Demcizumab/

Placebo

Demcizumab/

Demcizumab

Total

Intent to Treat 68 71 65 204

Safety Population 68 71 65 204

Ongoing 16 18 9 43

Discontinued 52 53 56 161

Reason for discontinuation

Progression

Death

AE

Withdraw Consent

Other Cancer Treatment

Investigator Decision

Other

34

5

3

0

0

2

8

28

4

5

4

0

5

7

34

3

5

1

1

2

10

96

12

13

5

1

9

25

RECIST Best Overall Response (n=204) Best Response Placebo/

Placebo

(N = 68)

Demcizumab

(N = 136)

P value

CR 0 1

PR 28 44

SD 20 56

PD 14 19

Response Rate (CR+PR) (95%

CI)

28 (41.2%) 45 (33.1%) 0.2815

Clinical Benefit (CR+PR+SD)

(95% CI)

48 (70.6%) 101 (74.3%) 0.5023

Conclusions •This was a randomized, double blind, 3 arm (1:1:1) study in subjects

with 1st-line metastatic pancreatic ductal adenocarcinoma.

•Two hundred and seven patients were randomized via an IWRS

system and 204 patients were treated.

•Patients were well balanced for the known prognostic factors between

the 3 treatment Arms.

•The efficacy outcomes were similar between Arm 1 vs. Arms 2 and 3

combined:

–Response rate: 41.2% vs 33.1% (p value = 0.2815)

–PFS: 5.49 mos. (95% CI:3.81-7.36) vs.5.52 mos.(95% CI:4.17-7.39) (HR = 0.93)

–OS: NR (95% CI:NR-8.97-NR) vs.13.24 mos.(95% CI: 9.79-16.53) (HR= 1.02)

• The efficacy outcomes were also similar when Arm 1 was compared

separately to Arm 2 and Arm 3.

•The most common AE’s in Arms 1, 2 and 3 respectively were:

–Nausea 61.8%, 53.5% and 63.1%

–Diarrhea 50.0%, 57.7% and 69.2%

–Anemia 39.7%, 60.6% and 53.8%

–Fatigue 50.0%. 43.7% and 56.9%

–Peripheral Edema 42.6% 54.9 and 52.9%

•The incidence of ≥ Grade 3 heart failure and pulmonary hypertension

were low and similar in all 3 treatment Arms. The incidence of ≥ Grade

3 bleeding was higher in the demcizumab arms.

–Heart Failure: 0/68 (0%), 4/71 (5.6%) and 1/65 (1.5%)

–Pulmonary Hypertension: 0/68 (0%), 1/71 (1.4%) and 0/65 (0%)

–Bleeding: 1/68 (1.5%), 7/ 71 (9.8%) and 4/65 (6.2%)

All Adverse Events ≥ 30%

Cancer Characteristics

Placebo/

Placebo

(N= 68)

Demcizumab/

Placebo

(N= 71)

Demcizumab/

Demcizumab

(N= 65)

Total

(N= 204)

ECOG PS

0

1

34

34

33

38

31

34

98

106

Region

US/Canada

Europe/Australia

20

48

23

48

19

46

62

142

CA 19-9

0-ULN

>ULN - < 59 X ULN

> = 59 X ULN

14

27

27

15

28

28

12

26

27

41

81

82

Background

Study Design Demographics

Placebo/

Placebo

(N= 68)

Demcizumab/

Placebo

(N= 71)

Demcizumab/

Demcizumab

(N= 65)

Total

(N= 204)

Age (Median) 62 63 66 63

Sex (M/F) 41/27 40/31 35/30 116/88

Number of Metastatic

Sites

0

1

2

3

> 3

1

27

23

12

5

0

26

24

18

3

1

23

28

8

5

2

76

75

38

13

Hepatic Metastases

Yes

No

72.1%

27.9%

74.6%

25.4%

75.4%

24.6%

74%

26%

NLR (Median) 3.2 3.8 3.4 3.5

Copies of this poster obtained through Quick Response (QR) code are for personal use only

and may not be reproduced without written permission from ASCO and the authors of this poster.

Study Schema

Primary Endpoint Secondary Endpoints Exploratory Endpoints

PFS

Survival Response

Safety

Biomarkers

Randomized: 207 pts Treated: 204 pts Data Cut: Nov 7, 2016

Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Heart Failure

0 - 4 (5.6) 1 (1.5) 5 (2.5)

Pulmonary

Hypertension

0 - 1 (1.4) 0 - 1 (0.5)

Bleeding

1 (1.5) 7 (9.8) 4 (6.2) 12 (5.9)

Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Nausea 42 ( 61.8) 38 ( 53.5) 41 ( 63.1) 121 ( 59.3)

Diarrhea 34 ( 50.0) 41 ( 57.7) 45 ( 69.2) 120 ( 58.8)

Anemia 27 ( 39.7) 43 ( 60.6) 35 ( 53.8) 105 ( 51.5)

Fatigue 34 ( 50.0) 31 ( 43.7) 37 ( 56.9) 102 ( 50.0)

Edema peripheral 29 ( 42.6) 39 ( 54.9) 34 ( 52.3) 102 ( 50.0)

Alopecia 30 ( 44.1) 33 ( 46.5) 28 ( 43.1) 91 ( 44.6)

Vomiting 27 ( 39.7) 32 ( 45.1) 25 ( 38.5) 84 ( 41.2)

Pyrexia 24 ( 35.3) 30 ( 42.3) 23 ( 35.4) 77 ( 37.7)

Decreased appetite

19 ( 27.9) 30 ( 42.3) 27 ( 41.5) 76 ( 37.3)

Neutropenia 21 ( 30.9) 24 ( 33.8) 25 ( 38.5) 70 ( 34.3)

Constipation 20 ( 29.4) 21 ( 29.6) 28 ( 43.1) 69 ( 33.8)

Abdominal pain 24 ( 35.3) 16 ( 22.5) 27 ( 41.5) 67 ( 32.8)

Asthenia 18 ( 26.5) 27 ( 38.0) 20 ( 30.8) 65 ( 31.9)

Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Fatigue 22 ( 32.4) 20 ( 28.2) 27 ( 41.5) 69 ( 33.8)

Nausea 21 ( 30.9) 17 ( 23.9) 19 ( 29.2) 57 ( 27.9)

Anemia 15 ( 22.1) 19 ( 26.8) 17 ( 26.2) 51 ( 25.0)

Diarrhoea 10 ( 14.7) 18 ( 25.4) 22 ( 33.8) 50 ( 24.5)

Alopecia 12 ( 17.6) 16 ( 22.5) 13 ( 20.0) 41 ( 20.1)

Edema

peripheral 14 ( 20.6) 13 ( 18.3) 14 ( 21.5) 41 ( 20.1)

Vomiting 9 ( 13.2) 18 ( 25.4) 7 ( 10.8) 34 ( 16.7)

Asthenia 9 ( 13.2) 13 ( 18.3) 11 ( 16.9) 33 ( 16.2)

Decreased

appetite 5 ( 7.4) 16 ( 22.5) 11 ( 16.9) 32 ( 15.7)

Hypertension 6 ( 8.8) 11 ( 15.5) 12 ( 18.5) 29 ( 14.2)

Cubillo A1, Dean A2, Munoz A3, Hidalgo 1, Pazo Cid R4, Martin M5, Macarulla T6, Lipton L7, Harris M8, Manzano JL9, MaurelJ10, Gullen-Ponce C11, Tebbutt N12, Cooray P13, Sohal D14, Zalupski M15, Kolevska T16, Stagg R17, , Goldstein D18. 1Hospital Universitario HM Sanchinarro –

CIOCC, Madrid, 2St John of God Hospital Subiaco, Perth, 3Hospital General Universitario Gregorio Marañon, Madrid, 4Hospital Universitario Miguel Servet, Zaragoza, 5Hospital de La Santa Creu i Sant Pau, 6Vall d´Hebron University Hospital (HUVH) and Vall d’Hebron Institute of

Oncology (VHIO), Barcelona, 7Sunshine Hospital, Melbourne, 8Monash Medical Centre, Moorabbin Campus, 9Germans Trias i Pujol Hospital, ICO-Badalona, Barcelona, 10Hospital Clinic de Barcelona, Barcelona, 11Hospital Universitario Ramón y Cajal, Madrid, 12Austin Health,

Heidelberg, 13Box Hill Hospital, Melbourne, 14Cleveland Clinic, Cleveleand, OH, 15University of Michigan Cancer Center, Ann Arbor, MI 16Kaiser Permanente, Vallejo, CA, 17OncoMed Pharmaceuticals, Redwood City, CA 18Prince of Wales Hospital, Sydney, Australia.

This was a randomized, double blind, 3 arm (1:1:1) study in subjects with 1st-line metastatic pancreatic ductal

adenocarcinoma. The study was designed to randomize pproximately two hundred and one patients via an

IWRS system. Patients were randomized to one of the following 3 arms:

Arm 1 – Abraxane® and gemcitabine plus placebo (3 cycles), Abraxane® and gemcitabine (3 cycles),

Abraxane® and gemcitabine plus placebo (3 cycles) and then Abraxane® and gemcitabine until disease

progression

Arm 2 - Abraxane® and gemcitabine plus demcizumab (3 cycles), Abraxane® and gemcitabine (3 cycles),


progression


Abraxane® and gemcitabine plus demcizumab (3 cycles) and then Abraxane® and gemcitabine until disease

progression.

The primary efficacy analyses compared Arm 1 to Arms 2 and 3 combined. Efficacy analyses comparing Arm 1

to Arm 2 and Arm 3 separately were also performed. The primary endpoint of the study was a comparison the

Investigator-assessed PFS between Arm 1 and Arms 2 and 3 combined. Secondary endpoints included a

comparison of response, survival, safety, immunogenicity and biomarkers. Gemcitabine was given by IV

infusion at a dose of 1000 mg/m2 on Days 1, 8 and 15 of each 28-day treatment cycle (or until toxicity

necessitated reducing or holding a dose). Abraxane® was administered by IV infusion at a dose of 125 mg/m2

over 30 minutes on Days 1, 8 and 15 of each 28-day treatment cycle. Demcizumab 3.5 mg/kg or placebo was

administered by IV infusion (prior to the administration of Abraxane® and gemcitabine) once every 2 weeks for

either one (1st course through Study Day 70) or two (2nd course begun on Study Day 168 and continued

through Study Day 238) 70 day courses. Patients who had two consecutive B-type natriuretic (BNP) values

>100 pg/mL or one value >200 pg/mL were unblinded by the Investigator through the IWRS system and if they

were receiving demcizumab they were started on an ACE inhibitor or carvedilol. Subjects were assessed for

disease status every 8 weeks and for safety at every visit and through 30 days following the termination visit.

The data cut-off for this analysis was November 7, 2016.

USA/Canada Europe/Australia

≥ Dem (N=94)

≥ Placebo N=48)

Time (months

Pro

bab

ility

(%

)

Time (months

Time (months

≥ Dem (N=136)

≥ Placebo N=68)

≥ Dem (N=136)

≥ Placebo N=68)

Pro

ba

bili

ty (

%)

Pro

bab

ility

(%

)

Dem vs. Placebo

Hazard Ratio: 0.930

95% CI (0.630-1.375)

Log-Rank p-value 0.7158

Kaplan Meier Medians

Demcizumab: 5.52 (4.17-7.39) months

Placebo: 5.49 (3.81-7.36) months

Dem vs. Placebo

Hazard Ratio: 1.018

95% CI (0.616-1.683)




Placebo: NR (8.97-NR) months

Dem vs. Placebo

Hazard Ratio: 0.80

95% CI (0.453-1.416)



Demcizumab: 13.96 (10.3-16.5) mos

Placebo: 9.89 (7.1-NR) mos

0 1

0 2

0 3

0

4

0

50

6

0 7

0 8

0 90

1

00

0 3 6 9 12 15 18 21

0

10

2

0

30

4

0

50

6

0

70

8

0

90

1

00

0

1

0

20

3

0

40

5

0

60

7

0

80

9

0

10

0

0 3 6 9 12 15 18 21

0 3 6 9 12 15 18

Related Adverse Events ≥ 15%

Overall Survival























Placebo

Demcizumab/

Placebo

Demcizumab/

Demcizumab

Total



Ongoing 16 18 9 43



Progression

Death

AE

Withdraw Consent



Other

34

5

3

0

0

2

8

28

4

5

4

0

5

7

34

3

5

1

1

2

10

96

12

13

5

1

9

25


Placebo

(N = 68)

Demcizumab

(N = 136)

P value

CR 0 1

PR 28 44

SD 20 56

PD 14 19


CI)

28 (41.2%) 45 (33.1%) 0.2815


(95% CI)

48 (70.6%) 101 (74.3%) 0.5023








combined:







–Nausea 61.8%, 53.5% and 63.1%

–Diarrhea 50.0%, 57.7% and 69.2%

–Anemia 39.7%, 60.6% and 53.8%

–Fatigue 50.0%. 43.7% and 56.9%







–Bleeding: 1/68 (1.5%), 7/ 71 (9.8%) and 4/65 (6.2%)



Placebo/

Placebo

(N= 68)

Demcizumab/

Placebo

(N= 71)

Demcizumab/

Demcizumab

(N= 65)

Total

(N= 204)

ECOG PS

0

1

34

34

33

38

31

34

98

106

Region

US/Canada

Europe/Australia

20

48

23

48

19

46

62

142

CA 19-9

0-ULN

>ULN - < 59 X ULN

> = 59 X ULN

14

27

27

15

28

28

12

26

27

41

81

82

Background


Placebo/

Placebo

(N= 68)

Demcizumab/

Placebo

(N= 71)

Demcizumab/

Demcizumab

(N= 65)

Total

(N= 204)

Age (Median) 62 63 66 63

Sex (M/F) 41/27 40/31 35/30 116/88


Sites

0

1

2

3

> 3

1

27

23

12

5

0

26

24

18

3

1

23

28

8

5

2

76

75

38

13

Hepatic Metastases

Yes

No

72.1%

27.9%

74.6%

25.4%

75.4%

24.6%

74%

26%

NLR (Median) 3.2 3.8 3.4 3.5



Study Schema


PFS

Survival Response

Safety

Biomarkers


Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Heart Failure

0 - 4 (5.6) 1 (1.5) 5 (2.5)

Pulmonary

Hypertension

0 - 1 (1.4) 0 - 1 (0.5)

Bleeding

1 (1.5) 7 (9.8) 4 (6.2) 12 (5.9)

Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Nausea 42 ( 61.8) 38 ( 53.5) 41 ( 63.1) 121 ( 59.3)

Diarrhea 34 ( 50.0) 41 ( 57.7) 45 ( 69.2) 120 ( 58.8)

Anemia 27 ( 39.7) 43 ( 60.6) 35 ( 53.8) 105 ( 51.5)

Fatigue 34 ( 50.0) 31 ( 43.7) 37 ( 56.9) 102 ( 50.0)


Alopecia 30 ( 44.1) 33 ( 46.5) 28 ( 43.1) 91 ( 44.6)

Vomiting 27 ( 39.7) 32 ( 45.1) 25 ( 38.5) 84 ( 41.2)

Pyrexia 24 ( 35.3) 30 ( 42.3) 23 ( 35.4) 77 ( 37.7)

Decreased appetite

19 ( 27.9) 30 ( 42.3) 27 ( 41.5) 76 ( 37.3)

Neutropenia 21 ( 30.9) 24 ( 33.8) 25 ( 38.5) 70 ( 34.3)

Constipation 20 ( 29.4) 21 ( 29.6) 28 ( 43.1) 69 ( 33.8)

Abdominal pain 24 ( 35.3) 16 ( 22.5) 27 ( 41.5) 67 ( 32.8)

Asthenia 18 ( 26.5) 27 ( 38.0) 20 ( 30.8) 65 ( 31.9)

Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Fatigue 22 ( 32.4) 20 ( 28.2) 27 ( 41.5) 69 ( 33.8)

Nausea 21 ( 30.9) 17 ( 23.9) 19 ( 29.2) 57 ( 27.9)

Anemia 15 ( 22.1) 19 ( 26.8) 17 ( 26.2) 51 ( 25.0)

Diarrhoea 10 ( 14.7) 18 ( 25.4) 22 ( 33.8) 50 ( 24.5)

Alopecia 12 ( 17.6) 16 ( 22.5) 13 ( 20.0) 41 ( 20.1)

Edema

peripheral 14 ( 20.6) 13 ( 18.3) 14 ( 21.5) 41 ( 20.1)

Vomiting 9 ( 13.2) 18 ( 25.4) 7 ( 10.8) 34 ( 16.7)

Asthenia 9 ( 13.2) 13 ( 18.3) 11 ( 16.9) 33 ( 16.2)

Decreased

appetite 5 ( 7.4) 16 ( 22.5) 11 ( 16.9) 32 ( 15.7)

Hypertension 6 ( 8.8) 11 ( 15.5) 12 ( 18.5) 29 ( 14.2)










progression



progression



progression.
















≥ Dem (N=94)

≥ Placebo N=48)

Time (months

Pro

ba

bili

ty (

%)

Time (months

Time (months

≥ Dem (N=136)

≥ Placebo N=68)

≥ Dem (N=136)

≥ Placebo N=68)

Pro

ba

bili

ty (

%)

Pro

bab

ility

(%

)

Dem vs. Placebo

Hazard Ratio: 0.930

95% CI (0.630-1.375)





Dem vs. Placebo

Hazard Ratio: 1.018

95% CI (0.616-1.683)





Dem vs. Placebo

Hazard Ratio: 0.80

95% CI (0.453-1.416)



Demcizumab: 13.96 (10.3-16.5) mos


0 1

0 2

0 3

0

4

0

50

6

0 7

0 8

0 90

1

00

0 3 6 9 12 15 18 21

0

10

2

0

30

4

0

50

6

0

70

8

0

90

1

00

0

1

0

20

3

0

40

5

0

60

7

0

80

9

0

10

0

0 3 6 9 12 15 18 21

0 3 6 9 12 15 18

Related Adverse Events ≥ 15%

Overall Survival























Placebo

Demcizumab/

Placebo

Demcizumab/

Demcizumab

Total



Ongoing 16 18 9 43



Progression

Death

AE

Withdraw Consent



Other

34

5

3

0

0

2

8

28

4

5

4

0

5

7

34

3

5

1

1

2

10

96

12

13

5

1

9

25


Placebo

(N = 68)

Demcizumab

(N = 136)

P value

CR 0 1

PR 28 44

SD 20 56

PD 14 19


CI)

28 (41.2%) 45 (33.1%) 0.2815


(95% CI)

48 (70.6%) 101 (74.3%) 0.5023








combined:







–Nausea 61.8%, 53.5% and 63.1%

–Diarrhea 50.0%, 57.7% and 69.2%

–Anemia 39.7%, 60.6% and 53.8%

–Fatigue 50.0%. 43.7% and 56.9%







–Bleeding: 1/68 (1.5%), 7/ 71 (9.8%) and 4/65 (6.2%)



Placebo/

Placebo

(N= 68)

Demcizumab/

Placebo

(N= 71)

Demcizumab/

Demcizumab

(N= 65)

Total

(N= 204)

ECOG PS

0

1

34

34

33

38

31

34

98

106

Region

US/Canada

Europe/Australia

20

48

23

48

19

46

62

142

CA 19-9

0-ULN

>ULN - < 59 X ULN

> = 59 X ULN

14

27

27

15

28

28

12

26

27

41

81

82

Background


Placebo/

Placebo

(N= 68)

Demcizumab/

Placebo

(N= 71)

Demcizumab/

Demcizumab

(N= 65)

Total

(N= 204)

Age (Median) 62 63 66 63

Sex (M/F) 41/27 40/31 35/30 116/88


Sites

0

1

2

3

> 3

1

27

23

12

5

0

26

24

18

3

1

23

28

8

5

2

76

75

38

13

Hepatic Metastases

Yes

No

72.1%

27.9%

74.6%

25.4%

75.4%

24.6%

74%

26%

NLR (Median) 3.2 3.8 3.4 3.5



Study Schema


PFS

Survival Response

Safety

Biomarkers


Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Heart Failure

0 - 4 (5.6) 1 (1.5) 5 (2.5)

Pulmonary

Hypertension

0 - 1 (1.4) 0 - 1 (0.5)

Bleeding

1 (1.5) 7 (9.8) 4 (6.2) 12 (5.9)

Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Nausea 42 ( 61.8) 38 ( 53.5) 41 ( 63.1) 121 ( 59.3)

Diarrhea 34 ( 50.0) 41 ( 57.7) 45 ( 69.2) 120 ( 58.8)

Anemia 27 ( 39.7) 43 ( 60.6) 35 ( 53.8) 105 ( 51.5)

Fatigue 34 ( 50.0) 31 ( 43.7) 37 ( 56.9) 102 ( 50.0)


Alopecia 30 ( 44.1) 33 ( 46.5) 28 ( 43.1) 91 ( 44.6)

Vomiting 27 ( 39.7) 32 ( 45.1) 25 ( 38.5) 84 ( 41.2)

Pyrexia 24 ( 35.3) 30 ( 42.3) 23 ( 35.4) 77 ( 37.7)

Decreased appetite

19 ( 27.9) 30 ( 42.3) 27 ( 41.5) 76 ( 37.3)

Neutropenia 21 ( 30.9) 24 ( 33.8) 25 ( 38.5) 70 ( 34.3)

Constipation 20 ( 29.4) 21 ( 29.6) 28 ( 43.1) 69 ( 33.8)

Abdominal pain 24 ( 35.3) 16 ( 22.5) 27 ( 41.5) 67 ( 32.8)

Asthenia 18 ( 26.5) 27 ( 38.0) 20 ( 30.8) 65 ( 31.9)

Placebo/

Placebo

(N=68)

Demcizumab/

Placebo

(N=71)

Demcizumab/

Demcizumab

(N=65)

Total

(N=204)

Fatigue 22 ( 32.4) 20 ( 28.2) 27 ( 41.5) 69 ( 33.8)

Nausea 21 ( 30.9) 17 ( 23.9) 19 ( 29.2) 57 ( 27.9)

Anemia 15 ( 22.1) 19 ( 26.8) 17 ( 26.2) 51 ( 25.0)

Diarrhoea 10 ( 14.7) 18 ( 25.4) 22 ( 33.8) 50 ( 24.5)

Alopecia 12 ( 17.6) 16 ( 22.5) 13 ( 20.0) 41 ( 20.1)

Edema

peripheral 14 ( 20.6) 13 ( 18.3) 14 ( 21.5) 41 ( 20.1)

Vomiting 9 ( 13.2) 18 ( 25.4) 7 ( 10.8) 34 ( 16.7)

Asthenia 9 ( 13.2) 13 ( 18.3) 11 ( 16.9) 33 ( 16.2)

Decreased

appetite 5 ( 7.4) 16 ( 22.5) 11 ( 16.9) 32 ( 15.7)

Hypertension 6 ( 8.8) 11 ( 15.5) 12 ( 18.5) 29 ( 14.2)










progression



progression



progression.
















≥ Dem (N=94)

≥ Placebo N=48)

Time (months

Pro

ba

bili

ty (

%)

Time (months

Time (months

≥ Dem (N=136)

≥ Placebo N=68)

≥ Dem (N=136)

≥ Placebo N=68)

Pro

ba

bili

ty (

%)

Pro

bab

ility

(%

)

Dem vs. Placebo

Hazard Ratio: 0.930

95% CI (0.630-1.375)





Dem vs. Placebo

Hazard Ratio: 1.018

95% CI (0.616-1.683)





Dem vs. Placebo

Hazard Ratio: 0.80

95% CI (0.453-1.416)



Demcizumab: 13.96 (10.3-16.5) mos


0 1

0 2

0 3

0

4

0

50

6

0 7

0 8

0 90

1

00

0 3 6 9 12 15 18 21

0

10

2

0

30

4

0

50

6

0

70

8

0

90

1

00

0

1

0

20

3

0

40

5

0

60

7

0

80

9

0

10

0

0 3 6 9 12 15 18 21

0 3 6 9 12 15 18

LAPACT G-NABP response rate: 31%

FRAGANCE (ECOG 2) ESMO 2017

Hidalgo et al. ESMO 2017

Outcome of Second-Line Treatment MPACT trial

Outcome of Second-Line Treatment Following nab-Paclitaxel + Gemcitabine

or Gemcitabine Alone for Metastatic Pancreatic Cancer

David Goldstein,1 E. Gabriela Chiorean,2 Josef Tabernero,3 Robert El-Maraghi,4 Wen Wee Ma,5 Michele Reni,6 Marian Harris,7 Robert Whorf,8 Jack Shiansong Li,9 Victoria Manax,9 Brian Lu,9 Alfredo Romano,9 Daniel D. Von Hoff10

1Prince of Wales Hospital, Sydney, Australia; 2University of Washington, Seattle, WA; 3Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 4Simcoe Muskoka Regional Cancer Centre, Barrie, ON, Canada; 5Roswell Park Cancer Institute, Buffalo, NY; 6Ospedale San Raffaele, Milan, Italy; 7Dana-Farber Cancer Institute, Boston, MA; 8Florida Cancer Specialists, Bradenton, FL; 9Celgene Corporation, Summit, NJ; 10Translational Genomics Research Institute and HonorHealth, Scottsdale, AZ

INTRODUCTION

Abstract 333

• PC is a highly lethal malignancy, and mortality rates nearly equal incidence1

- ≥ 80% of pts are diagnosed with advanced disease (53% with metastatic

disease)2

• Over the past decade, treatment plans for most pts with MPC have consisted

predominantly of 1 line of therapy3,4

- This may be due, in part, to the aggressive nature of the disease4

- Improvements in 1L efficacy may permit the use of subsequent therapy

• nab®-Paclitaxel (nab-P) + Gem demonstrated superior efficacy vs Gem alone for all

endpoints examined in a phase III MPC trial, including OS, the primary endpoint

(median, 8.7 vs 6.6 mo; P < 0.001)5,6

• Feasibility and efficacy data are needed to guide 2L treatment decisions in MPC

• As nab-P + Gem has become a standard 1L therapeutic option for pts with MPC,3

an analysis of the regimen as part of a treatment plan is necessary

nab® is a registered trademark of Celgene Corporation.

• The current post hoc analysis investigated the feasibility and efficacy of 2L therapy

among pts from the MPACT trial

OBJECTIVE

STUDY DESIGN

• In the phase III trial, pts received nab-P + Gem or Gem alone as 1L treatment as

previously described5

- Pts were treated until disease progression, unacceptable toxicity, or pt or

physician decision

- Pts were followed until discontinuation of 1L therapy, after which only dates and

type of subsequent treatment(s) as well as date of death were collected

• After the closure of the MPACT trial (NCT00844649) in 2013, an observational

extension study was initiated to gather more survival information on pts who were

still alive (NCT02021500).

- The data collected from the extension study is included in this post hoc

evaluation

• The Kaplan-Meier method was used to calculate OS:

- Total OS: from initial randomization

- OS2: survival time from end of 1L therapy

• Multivariate analyses of total OS and OS2 were conducted using a Cox proportional

hazard model to evaluate 1L treatment and use of 2L therapy adjusted for other

prognostic factors (at the end of 1L treatment for OS2); a stepwise procedure was

performed to evaluate the treatment effect and identify the possible factors

associated with OS or OS2

- Total OS: In addition to 1L and 2L treatment effect, the potential influence of the

following prognostic factors was assessed:

Geographic region (North America and other), age, KPS, NLR, PC primary

location, stage at diagnosis, CA19-9 level, presence of liver metastases,

peritoneal carcinomatosis, previous Whipple procedure, presence of biliary

stent, presence of pulmonary metastases, number of metastatic sites

- OS2: The potential influence of the following factors was assessed:

Prognostic factors at baseline: geographic region (North America and

other) and number of metastatic sites

Factors at the end of 1L treatment: age, KPS, NLR, 1L PFS (≥ median and

< median)

RESULTS

Patients

• ≥ 40% of pts in each treatment arm received a 2L therapy (Table 1A)

• 5-FU or cape-containing regimens were the most common 2L therapies (> 75%;

Tables 1A and 1B)

• Pts who received 2L treatment had a better performance status at baseline

compared with those who did not receive 2L treatment (Table 1A)

• Pts treated with FOLFIRINOX as 2L therapy had better performance status at the

end of 1L treatment compared with all other regimens (Tables 2A and 2B)

1L, first-line; 2L, second-line; 5-FU, 5-fluorouracil; CA19-9, carbohydrate antigen 19-9; Cape, capecitabine; ECOG PS,

Eastern Cooperative Oncology Group performance status; FOLFIRINOX, leucovorin, 5-FU, irinotecan, oxaliplatin;

FOLFOX/OFF, leucovorin, 5-FU, oxaliplatin; Gem, gemcitabine; ITT, intent to treat; KPS, Karnofsky performance status; met,

metastatic; MPC, metastatic pancreatic cancer; nab-P, nab-paclitaxel; NLR, neutrophil-to-lymphocyte ratio; OS, overall

survival; PFS, progression-free survival; PFS1, progression-free survival during 1L treatment; PS, performance status; pt,

patient; PC, pancreatic cancer; ULN, upper limit of normal.

Variable

ITT Any 2L Therapy No 2L Therapy5-FU- or Cape-

Containing

nab-P

+ GemGem

nab-P

+ GemGem

nab-P

+ GemGem

nab-P

+ GemGem

n 431 430 170 177 261 253 132 135

Age, median, y 62.0 63.0 61.0 62.0 63.0 64.0 59.5 62.0

KPS, %

90 - 100

70 - 80

58

42

62

38

68

32

75

25

51

49

54

46

64

36

76

24

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 379

2294

52

n = 371

2759

53

n = 152

2644

49

n = 162

2096

46

n = 227

1951

43

n = 209

3664

45

n = 120

2637

51

n = 125

2172

47

No. met. sites, %

1 - 3

> 3

86

14

85

15

88

12

88

12

85

15

84

16

88

12

89

11

NLR, %

≥ 5

> 5

n = 426

62

38

n = 426

65

35

75

25

73

27

55

45

60

40

74

26

72

28

Variable

5-FU or Cape Comboa FOLFIRINOX FOLFOX/OFF

nab-P +

GemGem

nab-P +

GemGem

nab-P +

GemGem

n 98 107 18 17 36 49

Age, median, y 59.0 62.0 53.5 56.0 58.5 64.0

KPS, %

90 - 100

70 - 80

67

33

76

24

72

28

76

24

53

47

67

33

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 90

2601

51

n = 100

2206

48

n = 16

5539

56

n = 17

2368

53

n = 33

2650

53

n = 43

2005

43

No. met. sites, %

1 - 3

> 3

91

9

93

7

100

0

88

12

86

14

92

8

NLR, %

≥ 5

> 5

75

25

70

30

72

28

71

29

78

22

69

31

a 3 pts (2 in the nab-P + Gem arm and 1 in the Gem arm) received 2L FOLFIRI treatment.

Table 1A. Baseline Characteristics by 2L Therapy Received

Table 1B. Baseline Characteristics for Pts who Received 2L 5-FU- or

Cape-Containing Combinations

Reasons for 1L Treatment Discontinuation

• Pts with any 2L treatment: 59% and 74% in the nab-P + Gem and Gem-alone arms,

respectively, discontinued 1L therapy due to progressive disease

- 26% and 14% discontinued 1L therapy due to adverse events

Efficacy

• Pts with any 2L treatment: Total OS (from initial randomization) was significantly

longer with nab-P + Gem vs Gem (median, 12.8 vs 9.9 mo.; P = 0.015; Figure 1)

- Without 2L therapy: longer for nab-P + Gem (median, 6.2 vs 4.7 mo; HR 0.69;

P < 0.001)

• Pts who received a 5-FU- or cape-containing 2L therapy: Total OS was significantly

longer for those in the nab-P + Gem vs Gem-alone arms (median, 13.5 vs 9.5 mo; P

= 0.012)

• In the nab-P + Gem and Gem-alone arms, fewer pts received 5-FU or cape mono-

than combination therapy (34 vs 98 pts and 28 vs 107 pts, respectively)

- Fewer pts who received 5-FU or cape monotherapy had KPS 90 -100 (32%

and 36% for nab-P + Gem and Gem alone, respectively) compared with those

who received 5-FU or cape combination therapy (Table 2B)

• OS2 (from end of 1L therapy) for nab-P + Gem vs Gem alone

- With 2L therapy: median OS similar (6.7 vs 6.4 mo; P = 0.273; Figure 2)


P < 0.001)

Variable

Any 2L Therapy No 2L Therapy5-FU-or Cape-

Containing

nab-P +

GemGem

nab-P +

GemGem

nab-P +

GemGem

n 170 177 261 253 132 135

Age, median, y 61.8 62.5 63.6 65.2 60.4 62.5

KPS, %

90 - 100

80

70

≥ 60

43

37

11

9

n = 176

48

34

10

8

n = 240

26

28

20

27

n = 222

22

32

19

27

43

38

8

11

45

35

12

8

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 144

276

26

n = 131

380

32

n = 170

263

29

n = 121

1669

45

n = 112

276

28

n = 99

514

33

NLR

≥ 5 , % 74

n = 176

67

n = 236

59

n = 215

45 77 64

Variable

5-FU or Cape

Comboa FOLFIRINOX FOLFOX/OFF

nab-P +

GemGem

nab-P +

GemGem

nab-P +

GemGem

n 98 107 18 17 36 49

Age, median, y 59.8 62.5 54.4 56.2 59.5 64.7

KPS, %

90 - 100

80

70

≥ 60

47

38

6

9

48

35

11

7

50

39

6

6

59

12

29

0

44

31

6

19

35

51

10

4

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 84

241

27

n = 76

547

33

n = 16

195

19

n = 10

401

20

n = 32

398

28

n = 33

261

30

NLR ≥ 5 , % 77 65 72 71 69 63

a Three pts (2 in the nab-P + Gem arm and 1 in the Gem arm) received 2L FOLFIRI treatment.

Table 2A. Pt Characteristics at End of 1L Treatment

Table 2B. Pt Characteristics at End of 1L Treatment for Pts who

Received 2L 5-FU- or Cape-Containing Combinations

Poster presented at the 2016 Gastrointestinal Cancers Symposium; January 21-23, 2016; San Francisco, CA

Figure 1. Total OS in Pts Who Received 2L Therapy

Events/nMedian, mo (95%

CI)

161/170 12.8 (10.9 - 14.2)

166/177 9.9 (8.9 - 10.9)

Pro

po

rtio

n o

f S

urv

iva

l

Time, monthsPts at risk

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

177Gem: 174 139 101 63 39 28 21 16 9 8 6 4 2 1 1 0 0

170 165 149 117 87 60 36 29 22 17 13 10 8 4 3 2 2 0nab-P

+ Gem:

HR 0.76

95% CI, 0.61 - 0.95

P = 0.015

Gem

nab-P + Gem


CI)

161/170 6.7 (6.1 - 7.9)

166/177 6.4 (5.3 - 7.7)

Figure 2. OS2 From End of 1L Therapy

Time, months

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Pro

po

rtio

n o

f S

urv

iva

l

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pts at risk

177 142 91 56 32 21 14 9 5 5 4 3 1 1 1 0 0 0Gem:

170 149 98 61 39 24 17 13 10 6 4 4 4 2 2 1 1 0nab-P

+ Gem:

HR 0.89

95% CI, 0.71 - 1.10

P = 0.273

Gem

nab-P + Gem

Covariate HR (95% CI) P value

Treatment group (nab-P + Gem vs Gem alone) 0.73 (0.63 - 0.85) < 0.001

2L therapy (with vs without) 0.47 (0.40 - 0.54) < 0.001

NLR at end of 1L (≥ 5 vs > 5) 0.60 (0.52 - 0.70) < 0.001

KPS at end of 1L

90 -100 vs ≥ 60

70 -80 vs ≥ 60

0.46 (0.37 - 0.57)

0.57 (0.47 - 0.70)

< 0.001

< 0.001

PFS, mo (≥ 4.4 vs < 4.4)a 0.78 (0.67 - 0.91) 0.002

Geographic region (North America vs others) 0.86 (0.74 - 1.00) 0.051

a In this study, the median PFS for the entire ITT population was 4.4 mo.

Table 3. Multivariate Analysis of OS2

Efficacy (continued)

• Factors significantly associated with longer total OS by multivariate analysis

include 1L treatment with nab-P + Gem vs Gem alone, use of 2L therapy, better

KPS at baseline (90 - 100 vs 70 -80), no liver metastases, baseline NLR ≥ 5 vs

> 5 (P < 0.001 for each), and lower CA19-9 at baseline (P = 0.005)

• Factors significantly associated with longer OS2 by multivariate analysis (Table

3) include 1L treatment with nab-P + Gem vs Gem alone, use of 2L therapy, NLR

≥ 5 vs > 5 at end of 1L therapy, better KPS at end of 1L therapy (P < 0.001 for

each), and PFS1 ≥ 4.4 mo vs < 4.4 mo (P = 0.002)

• The longest total OS values were for pts who received 1L nab-P + Gem and 2L

treatment with FOLFIRINOX (median OS, 15.7 mo; Table 4)

This study is supported by Celgene Corporation, Summit, NJ. The authors received editorial and production support in the

preparation of this poster from MediTech Media, Ltd, funded by Celgene Corporation. The authors are fully responsible for all

content and editorial decisions for this poster.

ACKNOWLEDGMENTS

DISCLOSURES

REFERENCES

Dr. David Goldstein - [email protected]

CORRESPONDENCE

CONCLUSIONS

• 2L treatment was feasible and beneficial for pts with MPC, with greater benefit

observed for those who received 1L nab-P + Gem vs Gem alone

• A limitation of this study is that no information was available about treatment

schedule or dose, safety, or efficacy (beyond survival) during 2L therapy

• Receiving 2L therapy was significantly associated with longer total OS, even after

adjusting for baseline characteristics

• 1L therapy may play a role in achieving optimal treatment benefit

- Total OS was significantly longer among pts who received 2L 5-FU– or cape-

containing therapies following 1L nab-P + Gem vs Gem alone

• Pts most likely to benefit from additional therapy include those with a longer PFS

during 1L treatment and lower NLR and better PS at the end of 1L treatment

• The current analysis supports the use of nab-P + Gem as an appropriate 1L therapy

onto which a treatment plan can be built

1. World Health Organization. GLOBOCAN 2012: Estimated cancer incidence, mortality,

and prevalence worldwide in 2012.

http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed December 8, 2015.

2. Surveillance, Epidemiology, and End Results Program. SEER stat facts sheets: pancreas

cancer. http://seer.cancer.gov/statfacts/html/pancreas.html. Updated 2015. Accessed

December 8, 2015.

3. Abrams TA, et al. J Clin Oncol. 2014;32:(5 suppl) [abstract 4131].

4. Smyth EN, et al. Clin Ther. 2015;37:1301-1316.

5. Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

6. Goldstein D, et al. J Natl Cancer Inst. 2015;107(2).

Copies of this poster obtained through Quick Response (QR) Code are for

personal use only and may not be reproduced without permission from ASCO®

and the author of this poster.

DG: research funding, Celgene, Pfizer; consultant or advisory role (unremunerated), Celgene, Pfizer; EGC: research funding,

consultant or advisory role, Celgene; JT: consultant or advisory role, honoraria, Celgene; RE-M: consultant or advisory role, research

funding, Celgene; WWM: research funding, Celgene; MR: consultant or advisory role, honoraria, research funding, Celgene; MH:

nothing to disclose; RW: nothing to disclose; SC: stock ownership, Celgene; JSL, VM, BL, AR: employment, stock ownership,

Celgene; DDVH: consultant or advisory role, honoraria, Celgene; research funding, HonorHealth

Table 4. Survival Outcome Summary in Pts Who Received 2L Therapy

Variable n (%)

Median Duration, mo

OS

From 1L

Randomization to

First Dose of 2L Tx

From First Dose

of 2L Tx to Death

Any 2L therapy

nab-P + Gem

Gem

170 (39)

177 (41)

12.8

9.9

6.6

4.1

5.3

4.5

Othera

nab-P + Gem

Gem

38 (22)

42 (24)

10.9

11.3

6.3

4.5

3.2

4.8

5-FU- or Cape-Containing

nab-P + Gem

Gem

132 (78)

135 (76)

13.5

9.5

6.7

4.1

5.7

4.5

5-FU or Cape combo

nab-P + Gem

Gem

98 (58)

107 (60)

14.0

9.5

6.6

4.0

6.0

4.6

5-FU or Cape mono

nab-P + Gem

Gem

34 (20)

28 (16)

11.9

9.4

6.7

5.3

4.7

3.9

FOLFIRINOX

nab-P + Gem

Gem

18 (11)

17 (10)

15.7

7.2

8.4

4.0

7.2

3.5

FOLFOX/OFF

nab-P + Gem

Gem

36 (21)

49 (28)

13.7

9.8

5.6

4.1

6.4

4.5a Other than 5-FU- or Cape-containing Tx; median total OS for 1L Gem followed by 2L nab-P + Gem (n = 7) or nab-P

alone (n = 11) was 7.9 and 8.8 mo, respectively.

Choirean et al. Br J Cancer 2016

1516 1184 46 24 14 3 1 11

OFF vs FF as 2nd-line therapy for APC*

(CONKO-003)

OFF†

FF

Stratification: Presence of metastases, duration of 1st-line gemcitabine therapy (3, 3–6, or >6 months), KPS (70–80% or 90–

100%)

Primary endpoint: OS

Secondary endpoints: TTP, tolerability

• PD following gemcitabine 1st-line therapy

• KPS ≥70

• Measureable disease

100

80

60

20

0

40

Time (months)860 3 12 15 24 27 38336 9 18 21 30

076 34 6 5 1 1 0114 7 5 3 1184 20 3 3 2 2 129 7 2 2 2FF

OFFNo at risk

100

80

60

20

0

40

Time (months)No at risk

48189 120 3 6 3624 30 42 8654

FFOFF 21022 1576 59 37 46 5 3 01

Ove

rall

su

rviv

al (%

)P

rog

ressio

n-f

ree

su

rviv

al (

%)

OFF median 2.9 months (95% CI 2.4–3.2)

FF median 2.0 months (95% CI 1.6–2.3)

HR 0.68 (95% CI 0.50–0.94) p=0.019

OFF median 5.9 months (95% CI 4.1–7.4)

FF median 3.3 months (95% CI 2.7–4.0)

HR 0.66 (95% CI 0.48–0.91) p=0.010

R 1:1

Oettle et al. JCO 2014;32:2423-9

*>88% of patients had metastatic disease†OFF differs from FOLFOX (folinic acid, fluorouracil, and oxaliplatin) with respect to the

frequency of treatment administration: fluorouracil is administered weekly for the first 4 weeks,

and oxaliplatin is administered on Days 8 and 22 of a 6-week cycle

2ªL Oxaliplatino

mFOLFOX6 as 2nd-line therapy for MPC

(PANCREOX)

201 4 8 12 16

Times (months)

0

0.5

1.0

Ove

rall

su

rviv

al p

rob

ab

ility

mFOLFOX6

(n=54)

5-FU/LV

(n=54)

Median, mo 6.1 9.9

95% CI 3.2–8.0 6.7–16.9

HR (95% CI) 1.78 (1.08–2.93)

p value 0.024

= Canadian, multicentre, open-label trial

= 108 patients with APC previously treated with

gemcitabine-based therapy randomized to receive:

– mFOLFOX6

– 5-FU/LV

= No difference in PFS between treatment arms

– 3.1 vs 2.9 months

= Inferior OS with mFOLFOX6

– 6.1 vs 9.9 months

= mFOLFOX6 associated with more treatment-related

Grade 3/4 AEs

– 63% vs 11%

mFOLFOX6

5-FU/LV

Gill et al. JCO 2014;32(suppl):4022

2ªL Oxaliplatino

Gill et al. JCO 2016

NAPOLI-1: Study Design

NAPOLI-1: Efficacy results

Este enfoque facilita la comparación entre tratamientos, penalizando tratamientos con elevada toxicidad o tiempos más cortos a la progresión de la enfermedad y favoreciendo los que tienen menor toxicidad y mayor tiempo a la progresión.

*Adjusted by utility weight during 12 months of follow-up; AUC, area under the curve

Pelzer U, et al. Oncol Res Treat 2016;39(S3): abstract P865 (and poster)

nal-IRI+5-FU/LV (n = 117) 5-FU/LV (n = 119)

Quality-adjusted survival: time in TOX, TWIST, and REL as measured by AUC*

Months from randomisation

Pro

po

rtio

n

0

0.2

0.4

0.6

1.0

0.8

0 3 6 9 12 18 15

REL

TWiST

TOX

Months from randomisation

Pro

po

rtio

n

0

0.2

0.4

0.6

1.0

0.8

0 3 6 9 12 18 15

REL

TWiST

TOX

Estudio NAPOLI-1, análisis Q-TWiST

Q-TWIST Increase 23,8%

(>10-15%)

More time in TWIST

(No Tox & No PGR)

Comparación de estudios (1)

Comparación de estudios (2)

Sonbol et al. Cancer 2017

PFS

FPIRI vs. FP: HR 0.64; 95%CI, 0.47-0.87; p=0.005

FPOX vs. FP: HR 0.81; 95%CI, 0.67-0.97; p=0.02

5 trials, 895 patients FPIRI: irinotecan formulations

Sonbol et al. Cancer 2017

OS

FPIRI vs. FP: HR 0.70; 95%CI, 0.55-0.89; p=0.004

FPOX vs. FP: HR 1.03; 95%CI, 0.64-1.67; p=0.9

5 trials, 895 patients

Potential treatment sequencing approach for MPC in 2017?

Nab-paclitaxel + gemcitabine

(if no neuropathy)

GemcitabineFOLFIRINOX

Nab-paclitaxel + gemcitabine

MM-398 + 5-FU/LV

OFF

Capecitabine

MM-398 + 5-FU/LV(depending on

prior exposure)

1st line

2nd line

3rd line

NOTE: Nab-paclitaxel is licensed for use in combination with gemcitabine as

1st-line therapy for patients with MPC

Nab-paclitaxel?(depending on

prior exposure)

mFOLFOX6 or CAPOX

Platinum-based tx(depending on

prior exposure)

Supported by RCT data

Supported by retrospective data or small, single arm trials

5-FU

No prospective randomized trial of 2L therapy after FOLFIRINOX providing risk/benefit ratio:

Designing a continuum of care in MPC

= 2nd-line MM-398 + 5-FU/LV provides a break from neurotoxicity, paving the way for subsequent 3rd-line treatment

= Prior exposure to irinotecan (with 1st-line FOLFIRINOX) could increase the potential for resistance to 2nd-line MM-398

1st line 2nd line 3rd line

Nab-paclitaxel +

gemcitabine

8.7 m

MM-398+

5-FU/LV

6.1 m

FOLFOX/OFF

Oettle & Lehmann, Lancet2016;387:507-8

Guía ASCO 2014

Recommendations

1. There are no agents recommended for the prevention of

CIPN

2. Treatment of existing CIPN, the best available data

support a moderate recommendation for treatment with

duloxetine

Loprinzi, Practice Update 2013: “The benefit from duloxetine, however, was not a home run; duloxetine decreased pain, more than was associated with the placebo, by 1 point on a 0-to-10 point scale”

Estudios observacionales retrospectivos de secuenciación

Outcome of Second-Line Treatment MPACT trial

Outcome of Second-Line Treatment Following nab-Paclitaxel + Gemcitabine

or Gemcitabine Alone for Metastatic Pancreatic Cancer

David Goldstein,1 E. Gabriela Chiorean,2 Josef Tabernero,3 Robert El-Maraghi,4 Wen Wee Ma,5 Michele Reni,6 Marian Harris,7 Robert Whorf,8 Jack Shiansong Li,9 Victoria Manax,9 Brian Lu,9 Alfredo Romano,9 Daniel D. Von Hoff10

1Prince of Wales Hospital, Sydney, Australia; 2University of Washington, Seattle, WA; 3Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 4Simcoe Muskoka Regional Cancer Centre, Barrie, ON, Canada; 5Roswell Park Cancer Institute, Buffalo, NY; 6Ospedale San Raffaele, Milan, Italy; 7Dana-Farber Cancer Institute, Boston, MA; 8Florida Cancer Specialists, Bradenton, FL; 9Celgene Corporation, Summit, NJ; 10Translational Genomics Research Institute and HonorHealth, Scottsdale, AZ

INTRODUCTION

Abstract 333

• PC is a highly lethal malignancy, and mortality rates nearly equal incidence1

- ≥ 80% of pts are diagnosed with advanced disease (53% with metastatic

disease)2

• Over the past decade, treatment plans for most pts with MPC have consisted

predominantly of 1 line of therapy3,4

- This may be due, in part, to the aggressive nature of the disease4

- Improvements in 1L efficacy may permit the use of subsequent therapy

• nab®-Paclitaxel (nab-P) + Gem demonstrated superior efficacy vs Gem alone for all

endpoints examined in a phase III MPC trial, including OS, the primary endpoint

(median, 8.7 vs 6.6 mo; P < 0.001)5,6

• Feasibility and efficacy data are needed to guide 2L treatment decisions in MPC

• As nab-P + Gem has become a standard 1L therapeutic option for pts with MPC,3

an analysis of the regimen as part of a treatment plan is necessary

nab® is a registered trademark of Celgene Corporation.

• The current post hoc analysis investigated the feasibility and efficacy of 2L therapy

among pts from the MPACT trial

OBJECTIVE

STUDY DESIGN

• In the phase III trial, pts received nab-P + Gem or Gem alone as 1L treatment as

previously described5

- Pts were treated until disease progression, unacceptable toxicity, or pt or

physician decision

- Pts were followed until discontinuation of 1L therapy, after which only dates and

type of subsequent treatment(s) as well as date of death were collected

• After the closure of the MPACT trial (NCT00844649) in 2013, an observational

extension study was initiated to gather more survival information on pts who were

still alive (NCT02021500).

- The data collected from the extension study is included in this post hoc

evaluation

• The Kaplan-Meier method was used to calculate OS:

- Total OS: from initial randomization

- OS2: survival time from end of 1L therapy

• Multivariate analyses of total OS and OS2 were conducted using a Cox proportional

hazard model to evaluate 1L treatment and use of 2L therapy adjusted for other

prognostic factors (at the end of 1L treatment for OS2); a stepwise procedure was

performed to evaluate the treatment effect and identify the possible factors

associated with OS or OS2

- Total OS: In addition to 1L and 2L treatment effect, the potential influence of the

following prognostic factors was assessed:

Geographic region (North America and other), age, KPS, NLR, PC primary

location, stage at diagnosis, CA19-9 level, presence of liver metastases,

peritoneal carcinomatosis, previous Whipple procedure, presence of biliary

stent, presence of pulmonary metastases, number of metastatic sites

- OS2: The potential influence of the following factors was assessed:

Prognostic factors at baseline: geographic region (North America and

other) and number of metastatic sites

Factors at the end of 1L treatment: age, KPS, NLR, 1L PFS (≥ median and

< median)

RESULTS

Patients

• ≥ 40% of pts in each treatment arm received a 2L therapy (Table 1A)

• 5-FU or cape-containing regimens were the most common 2L therapies (> 75%;

Tables 1A and 1B)

• Pts who received 2L treatment had a better performance status at baseline

compared with those who did not receive 2L treatment (Table 1A)

• Pts treated with FOLFIRINOX as 2L therapy had better performance status at the

end of 1L treatment compared with all other regimens (Tables 2A and 2B)

1L, first-line; 2L, second-line; 5-FU, 5-fluorouracil; CA19-9, carbohydrate antigen 19-9; Cape, capecitabine; ECOG PS,

Eastern Cooperative Oncology Group performance status; FOLFIRINOX, leucovorin, 5-FU, irinotecan, oxaliplatin;

FOLFOX/OFF, leucovorin, 5-FU, oxaliplatin; Gem, gemcitabine; ITT, intent to treat; KPS, Karnofsky performance status; met,

metastatic; MPC, metastatic pancreatic cancer; nab-P, nab-paclitaxel; NLR, neutrophil-to-lymphocyte ratio; OS, overall

survival; PFS, progression-free survival; PFS1, progression-free survival during 1L treatment; PS, performance status; pt,

patient; PC, pancreatic cancer; ULN, upper limit of normal.

Variable

ITT Any 2L Therapy No 2L Therapy5-FU- or Cape-

Containing

nab-P

+ GemGem

nab-P

+ GemGem

nab-P

+ GemGem

nab-P

+ GemGem

n 431 430 170 177 261 253 132 135

Age, median, y 62.0 63.0 61.0 62.0 63.0 64.0 59.5 62.0

KPS, %

90 - 100

70 - 80

58

42

62

38

68

32

75

25

51

49

54

46

64

36

76

24

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 379

2294

52

n = 371

2759

53

n = 152

2644

49

n = 162

2096

46

n = 227

1951

43

n = 209

3664

45

n = 120

2637

51

n = 125

2172

47

No. met. sites, %

1 - 3

> 3

86

14

85

15

88

12

88

12

85

15

84

16

88

12

89

11

NLR, %

≥ 5

> 5

n = 426

62

38

n = 426

65

35

75

25

73

27

55

45

60

40

74

26

72

28

Variable

5-FU or Cape Comboa FOLFIRINOX FOLFOX/OFF

nab-P +

GemGem

nab-P +

GemGem

nab-P +

GemGem

n 98 107 18 17 36 49

Age, median, y 59.0 62.0 53.5 56.0 58.5 64.0

KPS, %

90 - 100

70 - 80

67

33

76

24

72

28

76

24

53

47

67

33

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 90

2601

51

n = 100

2206

48

n = 16

5539

56

n = 17

2368

53

n = 33

2650

53

n = 43

2005

43

No. met. sites, %

1 - 3

> 3

91

9

93

7

100

0

88

12

86

14

92

8

NLR, %

≥ 5

> 5

75

25

70

30

72

28

71

29

78

22

69

31

a 3 pts (2 in the nab-P + Gem arm and 1 in the Gem arm) received 2L FOLFIRI treatment.

Table 1A. Baseline Characteristics by 2L Therapy Received

Table 1B. Baseline Characteristics for Pts who Received 2L 5-FU- or

Cape-Containing Combinations

Reasons for 1L Treatment Discontinuation

• Pts with any 2L treatment: 59% and 74% in the nab-P + Gem and Gem-alone arms,

respectively, discontinued 1L therapy due to progressive disease

- 26% and 14% discontinued 1L therapy due to adverse events

Efficacy

• Pts with any 2L treatment: Total OS (from initial randomization) was significantly

longer with nab-P + Gem vs Gem (median, 12.8 vs 9.9 mo.; P = 0.015; Figure 1)


P < 0.001)

• Pts who received a 5-FU- or cape-containing 2L therapy: Total OS was significantly

longer for those in the nab-P + Gem vs Gem-alone arms (median, 13.5 vs 9.5 mo; P

= 0.012)

• In the nab-P + Gem and Gem-alone arms, fewer pts received 5-FU or cape mono-

than combination therapy (34 vs 98 pts and 28 vs 107 pts, respectively)

- Fewer pts who received 5-FU or cape monotherapy had KPS 90 -100 (32%

and 36% for nab-P + Gem and Gem alone, respectively) compared with those

who received 5-FU or cape combination therapy (Table 2B)

• OS2 (from end of 1L therapy) for nab-P + Gem vs Gem alone

- With 2L therapy: median OS similar (6.7 vs 6.4 mo; P = 0.273; Figure 2)


P < 0.001)

Variable

Any 2L Therapy No 2L Therapy5-FU-or Cape-

Containing

nab-P +

GemGem

nab-P +

GemGem

nab-P +

GemGem

n 170 177 261 253 132 135

Age, median, y 61.8 62.5 63.6 65.2 60.4 62.5

KPS, %

90 - 100

80

70

≥ 60

43

37

11

9

n = 176

48

34

10

8

n = 240

26

28

20

27

n = 222

22

32

19

27

43

38

8

11

45

35

12

8

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 144

276

26

n = 131

380

32

n = 170

263

29

n = 121

1669

45

n = 112

276

28

n = 99

514

33

NLR

≥ 5 , % 74

n = 176

67

n = 236

59

n = 215

45 77 64

Variable

5-FU or Cape

Comboa FOLFIRINOX FOLFOX/OFF

nab-P +

GemGem

nab-P +

GemGem

nab-P +

GemGem

n 98 107 18 17 36 49

Age, median, y 59.8 62.5 54.4 56.2 59.5 64.7

KPS, %

90 - 100

80

70

≥ 60

47

38

6

9

48

35

11

7

50

39

6

6

59

12

29

0

44

31

6

19

35

51

10

4

CA19-9

median, U/mL

≥ 59 × ULN, %

n = 84

241

27

n = 76

547

33

n = 16

195

19

n = 10

401

20

n = 32

398

28

n = 33

261

30

NLR ≥ 5 , % 77 65 72 71 69 63

a Three pts (2 in the nab-P + Gem arm and 1 in the Gem arm) received 2L FOLFIRI treatment.

Table 2A. Pt Characteristics at End of 1L Treatment

Table 2B. Pt Characteristics at End of 1L Treatment for Pts who

Received 2L 5-FU- or Cape-Containing Combinations

Poster presented at the 2016 Gastrointestinal Cancers Symposium; January 21-23, 2016; San Francisco, CA

Figure 1. Total OS in Pts Who Received 2L Therapy


CI)

161/170 12.8 (10.9 - 14.2)

166/177 9.9 (8.9 - 10.9)

Pro

po

rtio

n o

f S

urv

iva

l

Time, monthsPts at risk

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

177Gem: 174 139 101 63 39 28 21 16 9 8 6 4 2 1 1 0 0

170 165 149 117 87 60 36 29 22 17 13 10 8 4 3 2 2 0nab-P

+ Gem:

HR 0.76

95% CI, 0.61 - 0.95

P = 0.015

Gem

nab-P + Gem


CI)

161/170 6.7 (6.1 - 7.9)

166/177 6.4 (5.3 - 7.7)

Figure 2. OS2 From End of 1L Therapy

Time, months

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Pro

po

rtio

n o

f S

urv

iva

l

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pts at risk

177 142 91 56 32 21 14 9 5 5 4 3 1 1 1 0 0 0Gem:

170 149 98 61 39 24 17 13 10 6 4 4 4 2 2 1 1 0nab-P

+ Gem:

HR 0.89

95% CI, 0.71 - 1.10

P = 0.273

Gem

nab-P + Gem

Covariate HR (95% CI) P value

Treatment group (nab-P + Gem vs Gem alone) 0.73 (0.63 - 0.85) < 0.001

2L therapy (with vs without) 0.47 (0.40 - 0.54) < 0.001

NLR at end of 1L (≥ 5 vs > 5) 0.60 (0.52 - 0.70) < 0.001

KPS at end of 1L

90 -100 vs ≥ 60

70 -80 vs ≥ 60

0.46 (0.37 - 0.57)

0.57 (0.47 - 0.70)

< 0.001

< 0.001

PFS, mo (≥ 4.4 vs < 4.4)a 0.78 (0.67 - 0.91) 0.002

Geographic region (North America vs others) 0.86 (0.74 - 1.00) 0.051

a In this study, the median PFS for the entire ITT population was 4.4 mo.

Table 3. Multivariate Analysis of OS2

Efficacy (continued)

• Factors significantly associated with longer total OS by multivariate analysis

include 1L treatment with nab-P + Gem vs Gem alone, use of 2L therapy, better

KPS at baseline (90 - 100 vs 70 -80), no liver metastases, baseline NLR ≥ 5 vs

> 5 (P < 0.001 for each), and lower CA19-9 at baseline (P = 0.005)

• Factors significantly associated with longer OS2 by multivariate analysis (Table

3) include 1L treatment with nab-P + Gem vs Gem alone, use of 2L therapy, NLR

≥ 5 vs > 5 at end of 1L therapy, better KPS at end of 1L therapy (P < 0.001 for

each), and PFS1 ≥ 4.4 mo vs < 4.4 mo (P = 0.002)

• The longest total OS values were for pts who received 1L nab-P + Gem and 2L

treatment with FOLFIRINOX (median OS, 15.7 mo; Table 4)

This study is supported by Celgene Corporation, Summit, NJ. The authors received editorial and production support in the

preparation of this poster from MediTech Media, Ltd, funded by Celgene Corporation. The authors are fully responsible for all

content and editorial decisions for this poster.

ACKNOWLEDGMENTS

DISCLOSURES

REFERENCES

Dr. David Goldstein - [email protected]

CORRESPONDENCE

CONCLUSIONS

• 2L treatment was feasible and beneficial for pts with MPC, with greater benefit

observed for those who received 1L nab-P + Gem vs Gem alone

• A limitation of this study is that no information was available about treatment

schedule or dose, safety, or efficacy (beyond survival) during 2L therapy

• Receiving 2L therapy was significantly associated with longer total OS, even after

adjusting for baseline characteristics

• 1L therapy may play a role in achieving optimal treatment benefit

- Total OS was significantly longer among pts who received 2L 5-FU– or cape-

containing therapies following 1L nab-P + Gem vs Gem alone

• Pts most likely to benefit from additional therapy include those with a longer PFS

during 1L treatment and lower NLR and better PS at the end of 1L treatment

• The current analysis supports the use of nab-P + Gem as an appropriate 1L therapy

onto which a treatment plan can be built

1. World Health Organization. GLOBOCAN 2012: Estimated cancer incidence, mortality,

and prevalence worldwide in 2012.

http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed December 8, 2015.

2. Surveillance, Epidemiology, and End Results Program. SEER stat facts sheets: pancreas

cancer. http://seer.cancer.gov/statfacts/html/pancreas.html. Updated 2015. Accessed

December 8, 2015.

3. Abrams TA, et al. J Clin Oncol. 2014;32:(5 suppl) [abstract 4131].

4. Smyth EN, et al. Clin Ther. 2015;37:1301-1316.

5. Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

6. Goldstein D, et al. J Natl Cancer Inst. 2015;107(2).

Copies of this poster obtained through Quick Response (QR) Code are for

personal use only and may not be reproduced without permission from ASCO®

and the author of this poster.

DG: research funding, Celgene, Pfizer; consultant or advisory role (unremunerated), Celgene, Pfizer; EGC: research funding,

consultant or advisory role, Celgene; JT: consultant or advisory role, honoraria, Celgene; RE-M: consultant or advisory role, research

funding, Celgene; WWM: research funding, Celgene; MR: consultant or advisory role, honoraria, research funding, Celgene; MH:

nothing to disclose; RW: nothing to disclose; SC: stock ownership, Celgene; JSL, VM, BL, AR: employment, stock ownership,

Celgene; DDVH: consultant or advisory role, honoraria, Celgene; research funding, HonorHealth

Table 4. Survival Outcome Summary in Pts Who Received 2L Therapy

Variable n (%)

Median Duration, mo

OS

From 1L

Randomization to

First Dose of 2L Tx

From First Dose

of 2L Tx to Death

Any 2L therapy

nab-P + Gem

Gem

170 (39)

177 (41)

12.8

9.9

6.6

4.1

5.3

4.5

Othera

nab-P + Gem

Gem

38 (22)

42 (24)

10.9

11.3

6.3

4.5

3.2

4.8

5-FU- or Cape-Containing

nab-P + Gem

Gem

132 (78)

135 (76)

13.5

9.5

6.7

4.1

5.7

4.5

5-FU or Cape combo

nab-P + Gem

Gem

98 (58)

107 (60)

14.0

9.5

6.6

4.0

6.0

4.6

5-FU or Cape mono

nab-P + Gem

Gem

34 (20)

28 (16)

11.9

9.4

6.7

5.3

4.7

3.9

FOLFIRINOX

nab-P + Gem

Gem

18 (11)

17 (10)

15.7

7.2

8.4

4.0

7.2

3.5

FOLFOX/OFF

nab-P + Gem

Gem

36 (21)

49 (28)

13.7

9.8

5.6

4.1

6.4

4.5a Other than 5-FU- or Cape-containing Tx; median total OS for 1L Gem followed by 2L nab-P + Gem (n = 7) or nab-P

alone (n = 11) was 7.9 and 8.8 mo, respectively.

Pts who received a 5-FU- or cape-containing 2L therapy: Total OS was significantly longer for those in the nab-P + Gem vs Gem-alone arms

(median, 13.5 vs 9.5 mo; P = 0.012) And combo regimens >14 months…

• G-NP can face to FOLFIRINOX in the same group of patients (very fit or super-fit patients/without restrictions or limitations)? • Interesting “new” data (data from retrospective and randomized clinical

trials)

• 1st-line G-NP permits more 2nd - 3rd line treatment options than 1st-line FOLFIRINOX (1st-line treatment with G-NP does not compromise subsequent treatment options)

• In ECOG 2 patients (tumor load) G-NP is a new regimen with high efficacy

Conclusiones

• In second line setting the combination of naliri and 5FU is a new standard of care after gem combinations

• The combination of naliri and 5FU provides a break from neurotoxicity and paving the way of subsequent 3rd-line

Conclusiones

secuenciación terapéutica en cáncer de...

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