Segunda línea en cáncer de páncreas: entre Oxaliplatino y Nal-Iri · 2017. 6. 27. · 1. Ohkawa...

Dr. Fernando Rivera Herrero

Hospital Universitario Marqués de Valdecilla. Santander

Segunda línea en cáncer de páncreas:

entre Oxaliplatino y Nal-Iri

Segunda línea en CPA: entre Oxaliplatino y Nal-Iri

- Introducción - Estudios Rand con Oxaliplatino en 2ªl de CPA

- Nal-Iri - Mecanismo de acción - Fase III Napoli-1

- Estudios con Irinotecan en 2ªl CPA - Guías (NCCN, ESMO,SEOM…)

- Secuencia de tto en CPA - Conclusiones

En los últimos años hemos avanzado (discretamente)

en el tto de los pacientes con CPA:

Primeras líneas más activas (Sv, RR, SLP, QoL):

FOLFIRINOX Gem-Abx

El uso de la 2ª línea se ha consolidado y es importante

considerar la secuencia de tratamiento

Algunos pacientes (aún muy pocos) llegan a ser “largos

supervivientes” (>2-3 años)

Segunda línea en CP: entre Oxaliplatino y Nal-Iri

Aunque no es suficiente…

Hidalgo M et al. CTO 2016

% of pts ??

30% ? 35% ? 35% ?

¿Cuántos pts con CPA reciben 2ª línea?

2ª linea 80 pts (46%) 85 pts (49%)

Gem 82% Combi Gem 12%

Folfirinox 4% Gem-Ox 17% FOLFOX 49% Gem-Cis 16%

Sv desde inicio de 2ª línea 4,4 m en ambos grupos

1.- Chiorean EJ et al. BJC 2016

2ª linea 1 170 pts (40%) 177 pts (44%) Fu/Cape 78% (combi 74%)

FU/Cape 76% (combi 79%) Abx 6% Gem-Abx 4%

Sv desde inicio de 2ª línea 5,3 m (GA) 4,5 m (G)

Gem-Abx Gemcitabine (N= 421) (n= 402)

3ª linea 1 29 pts (7%) 40 pts (10%)

Oxaliplatin has been assessed in the 2nd-line setting in patients with gemcitabine-refractory pancreatic cancer

1. Ohkawa S, et al. Br J Cancer 2015;112:1428 2. Oettle H, et al. J Clin Oncol 2014;32:2423

3. Gill S, et al. J Clin Oncol 2016 [Epub ahead of print]

Japanese phase II study1 CONKO-003 phase III trial2

PANCREOX phase III trial3

SOX n = 136

S-1 n = 135

OFF n = 76

FF n = 84

mFOLFOX-6 n = 54

Infusional 5-FU/LV n = 54

Median OS 7.4 mo 6.9 mo 5.9 mo 3.3 mo 6.1 mo 9.9 mo

P = 0.82 (HR = 1.03;

95% CI, 0.79–1.34)

P = 0.010 (HR = 0.66;

95% CI, 0.48–0.91)

P = 0.024 (HR = 1.78;

95% CI, 1.08–2.93)

Median PFS 3.0 mo 2.8 mo 2.9 mo 2.0 mo 3.1 mo 2.9 mo

P = 0.18 (HR = 0.84; 95% CI,

0.65–1.08)

P = 0.019 (HR = 0.68;

95% CI, 0.50–0.94)

P = 0.99 (HR = 1.00;

95% CI, 0.66–1.53)

CI, confidence interval; HR, hazard ratio; mo, months; OS, overall survival; PFS, progression-free survival

Cross-trial comparisons should be interpreted with caution due to differences in study design and patient populations

A phase II study assessed S-1 vs. S-1+oxaliplatin in gemcitabine-resistant metastatic pancreatic cancer

Ohkawa S, et al. Br J Cancer 2015;112:1428

S-1 (80/100/120 mg/d, based on

BSA, for 4Q6W)

SOX (S-1 80/100/120 mg/d based on BSA for 2Q3W; oxaliplatin 100

mg/m2 1Q3W)

Patients with metastatic

pancreatic cancer who

are refractory to

gemcitabine

(n = 271)

R

n = 136

n = 135

R

Stratification: centre, ECOG PS (0 or 1), duration of previous gemcitabine treatment (<90 days, 90 to <180 days, or ≥180 days) Primary endpoint: PFS Secondary endpoints: OS, time to treatment failure, response rate, disease control rate, safety Key inclusion criteria: histologically or cytologically confirmed pancreatic adenocarcinoma or adenosquamous carcinoma, a measurable metastatic lesion, age ≥20 years, ECOG PS 0–1, adequate renal/hepatic/haematological function Selected baseline patient characteristics (SOX arm), n (%): • ECOG PS 1: 41 (30.6) • Age ≥65 years: 68 (50.7)

OS, overall survival; PFS, progression-free survival; PS, performance status;

No significant survival improvement with SOX vs. S-1 in gemcitabine-resistant metastatic pancreatic cancer

CI, confidence interval; HR, hazard ratio; mo, months; OS, overall survival; PFS, progression-free survival; SOX, S-1 + oxaliplatin Ohkawa S, et al. Br J Cancer 2015;112:1428

Progression-free survival

Time (months) P

rogre

ssio

n-f

ree s

urv

iva

l (%

)

0

20

40

60

100

80

0 6 12 18 24 30

SOX

S-1

S-1 SOX

No. at risk

130

143

26

29

7

5

2

2

1

0

0

0

Median PFS (mo)

HR (95% CI) P-value

SOX 3.0 0.84 (0.65–1.08)

0.18 S-1 2.8

Overall survival

Time (months)

Ove

rall

su

rviv

al (%

)

0

20

40

60

100

80

0 6 12 18 24 30

S-1 SOX

No. at risk

130

134

72

81

36

31

8

4

1

2

0

0

SOX

S-1

Median OS (mo)

HR (95% CI) P-value

SOX 7.4 1.03 (0.79–1.34)

0.82 S-1 6.9

Date of preparation March 2016 INT-ABR160015

151611844624 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)

86 0 3 12 15 24 27 38 33 6 9 18 21 30

0 76 34 6 5 1 1 0 1 14 7 5 3 1 1 84 20 3 3 2 2 1 2 9 7 2 2 2 FF

OFF No at risk

100

80

60

20

0

40

Time (months) No at risk

48 18 9 12 0 3 6 36 24 30 42 86 54

FF OFF 2 10 22 15 76 59 37 4 6 5 3 0 1

Overa

ll s

urv

ival (%

) P

rogre

ssio

n-f

ree s

urv

iva

l (%

)

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

Oettle H, et al. J Clin Oncol 2014;32:2423

A phase III study assessed 2nd-line mFOLFOX6 vs. 5-FU/LV in advanced pancreatic cancer (PANCREOX)

Gill S, et al. J Clin Oncol 2016 [Epub ahead of print]

Study was closed

before its target

enrolment of 128

patients due to

slow accrual

mFOLFOX6 (As below + oxaliplatin

85 mg/m2 Q2W)

5-FU/LV (400 mg/m2 bolus + 2,400

mg/m2/400mg/m2 Q2W)

Advanced

pancreatic cancer

patients after prior

gemcitabine-based

therapy

(n = 108)

R

n = 54

n = 54 n = 54

n = 54

Analysed

R

Stratification: age (<70 years, ≥70 years), sex, ECOG PS (0, 1, or 2), presence of liver metastases Primary endpoint: PFS Secondary endpoints: OS, ORR, duration of response, disease control rate Key inclusion criteria: histologically or cytologically confirmed advanced, unresectable pancreatic cancer, ECOG PS 0–2, adequate renal/hepatic/haematological function, prior 1st-line treatment with gemcitabine, confirmed radiographic evidence of disease progression Selected baseline patient characteristics (mFOLFOX6 arm), n (%): • ECOG PS 1: 41 (75.9) • ECOG PS 2: 6 (11.1) • Metastatic disease: 50 (92.6)

ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status;

mFOLFOX6 did not significantly improve OS or PFS compared with 5-FU/LV (PANCREOX)

Gill S, et al. J Clin Oncol 2016 [Epub ahead of print]

Months P

rob

ab

ility

of P

FS

0.00

0.50

4 1 8 16 20 12

Median PFS, mo

mFOLFOX6

(n = 54) 3.1

5-FU/LV

(n = 54) 2.9

HR (95% CI) = 1.00 (0.66–1.53)

P = 0.989

Pro

ba

bili

ty o

f O

S

Median OS, mo

mFOLFOX6

(n = 54) 6.1

5-FU/LV

(n = 54) 9.9

HR (95% CI) = 1.78 (1.08–2.93)

P = 0.024

Months

4 1 8 16 20 12

0.00

0.50

1.00 1.00

CI, confidence interval; HR, hazard ratio; mFOLFOX, oxaliplatin + 5-FU/LV; mo, months; OS, overall survival

Progression-free survival Overall survival

CONKO-3 / PANCREOX

Vogel A et al. CancerTtreatment Reviews 2016

Conventional irinotecan is primarily metabolised in the liver

de Jong FA, et al. Cancer Lett 2006;234:90

Irinotecan is converted to its active metabolite, SN-38, by CES and subsequently glucuronidised to inactive SN-38G* by UGT1A

*SN-38G may be reactivated by bacterial β-glucuronidase in the intestine

Liposomal irinotecan (nal-IRI) is a novel carrier technology design to protect irinotecan from premature metabolism

Also known as MM-398 or PEP-02; Image not to scale Drummond DC, et al. Cancer Res 2006;66:3271

Leaky vasculature allows nal-IRI to penetrate the tumour microenvironment

Image not to scale Hashizume H, et al. Am J Pathol 2000;156:1363;

Kalra AV, et al. Cancer Res 2014;74:7003

Healthy vasculature Leaky tumour vasculature

nal-IRI is preferentially taken up by tumour-associated macrophages

Image not to scale Drummond DC, et al. Cancer Res 2006;66:3271

Degradation of nal-IRI releases irinotecan, which is activated by CES present in the macrophage

Image not to scale

van der Bol JM, et al. J Clin Oncol 2007;25:2719; Kalra AV, et al. Cancer Res 2014;74:7003;74:7003; Kawato Y, et al.

Cancer Res 1991,51:4187

nal-IRI may be directly taken up by tumour cells for irinotecan release and conversion to SN-38

Adapted from Peer D, et al. Nat Nanotechnol 2007;2:751; Kalra AV, et al. Cancer Res 2014;74:7003;

1. Drummond DC, et al. Cancer Res 2006;66:3271

Blood vessel

Lymphatic vessel

Macrophages

Tumour cells

nal-IRI may be directly taken up by tumour cells for irinotecan release and

conversion to SN-38 here1

At the tumour, nal-IRI is thought to be taken up by tumour-associated macrophages. These convert irinotecan to SN-38, which then diffuses into the

tumour cells1

Liposomal-encapsulated irinotecan has benefits

h, hours Kalra AV, et al. Cancer Res 2014;74:7003

Advantage of nal-IRI encapsulation Conventional irinotecan nal-IRI

Prolonged exposure in plasma Irinotecan and SN-38

plasma levels cleared from

circulation within 8 h

Irinotecan and SN-38

remained in circulation

for >50 h

Prolonged exposure in tumours >90% irinotecan was

cleared from tumours

within 24 h

SN-38 exposure in

tumours <48 h

Irinotecan levels persisted

above 10,000 nmol/l for 168 h

in tumours

Prolonged SN-38 exposure

above activity threshold for

up to168 h

Dose needed to achieve similar

SN-38 exposure in plasma

and tumours

50 mg/kg 10 mg/kg

Enhanced tumour growth inhibition

in animal models ~40% ~110%

In mice bearing human colon carcinoma xenografts

• Longer exposure in tumour vs. plasma for nal-IRI and conventional irinotecan

• Longer circulation for nal-IRI vs. conventional irinotecan

• Similar AUC in the tumour but sustained inhibition of tumour growth with nal-IRI vs. conventional irinotecan

• An increased time over the tumour growth inhibition threshold with nal-IRI vs. conventional irinotecan

In preclinical studies, tumour growth was inhibited and SN-38 exposure was higher with nal-IRI vs. conventional irinotecan

*P <0.05 vs. saline and IRI Kalra AV, et al. Cancer Res 2014;74:7003;

Drummond DC, et al. Cancer Res 2006;66:3271

Predicted similar SN-38 tumour exposure with lower doses of nal-IRI than conventional

irinotecan in a PK model

Observed significant and sustained inhibition of tumour growth with nal-IRI in a HT-29

mouse xenograft model

Tum

ou

r vo

lum

e (m

m3)

1600

0

400

800

2000

2400

1200

Days

* * *

6 8 10 12 14 16 18 20 22 24 26 28 30 32

Dose administration Saline Irinotecan 50 mg/kg nal-IRI 10 mg/kg

Plasma Tumour

0

1

2

3

4

5 Irinotecan 50 mg/kg nal-IRI 10 mg/kg

SN-3

8 A

UC

(n

mo

I/l/

min

x1

06)

Tumour SN-38 concentration and duration over threshold were the basis for bi-weekly nal-IRI dosing

Merrimack, data on file and amendment to study design

Tumour SN-38 concentration Duration of SN-38 tumour concentration above threshold

Days

0 10 20 30 40

100

101

102

120 mg/m2 nal-IRI Q3W

80 mg/m2 nal-IRI Q2W 103

Tum

ou

r co

nce

ntr

atio

n (

nM

)

0

5

10

15

20

25

30

35

40

30 60 120

Threshold SN-38 concentration (nM)



Days a

bo

ve

th

resh

old

45

• Study endpoints: OS (1°); PFS, time to treatment failure and ORR (2°); other endpoints included CA19-9 (tumour marker) response and safety

• Stratification factors: serum albumin levels, KPS, ethnicity

NAPOLI-1 was a randomised, open-label, global, multicentre, phase III study of nal-IRI+5-FU/LV

KPS, Karnofsky performance status; ORR, objective response rate; PFS, progression-free survival Wang-Gillam A, et al. Lancet 2016;387:545

R

NAPOLI:

nal-IRI+5-FU/LV (80 mg/m2 + 2400/400

mg/m2 Q2W)

Initial design

n = 33

n = 30

n = 118

n = 119

n = 117

n = 151

n = 149

n = 117

Total

nal-IRI (120 mg/m² Q3W)

Post- amendment

Patients with metastatic pancreatic cancer that progressed

after previous gemcitabine-

based treatment

(n = 417)

5-FU/LV (2000/200 mg/m2

QW x 4, Q6W)

NAPOLI-1 was a global study at 76 sites in 14 countries

Chen LT, et al. J Clin Oncol 2015;33(S3):abstract 234 (and presentation)

17% Canada,

USA

4% Argentina,

Brazil

37% Czech Republic,

France, Germany,

Hungary, Italy, Spain, United

Kingdom 32% South Korea, Taiwan

10% Australia

Enrolment: 417 patients (11 January 2012 – 11 September 2013)

Baseline characteristics of the ITT population were balanced between treatment arms (1)1

*12 patients (10%) were aged >75 years in the combination arm2 KPS, Karnofsky performance status; IQR=inter-quartile range

1. Wang-Gillam A, et al. Lancet 2016;387:545 2. ONIVYDE® Summary of Product Characteristics

Age, y

Median years (IQR)

Male, n (%)

Female, n (%)

Ethnic origin, n (%)

East Asian

Black or African American

White

Other

KPS, n (%)

90–100

70–80

Pancreatic tumour location, n (%)

Head

Other

Amount of CA19-9, n (%)

≥40 U/ml

<40 U/ml

Combination

therapy

nal-IRI+5-FU/LV

(n = 117)

Combination

therapy control

5-FU/LV

(n = 119)

63 (57–70)* 62 (55–69)

69 (59%) 67 (56%)

48 (41%) 52 (44%)

34 (29%) 36 (30%)

4 (3%) 3 (3%)

72 (62%) 76 (64%)

7 (6%) 4 (3%)

69 (59%) 57 (48%)

45 (38%) 61 (51%)

76 (65%) 69 (58%)

41 (35%) 50 (42%)

92/114 (81%) 91/114 (80%)

22/114 (19%) 23/114 (20%)

Monotherapy

nal-IRI

(n = 151)

Monotherapy

control 5-FU/LV

(n = 149)

65 (58–70) 63 (55–69)

87 (58%) 81 (54%)

64 (42%) 68 (46%)

52 (34%) 50 (34%)

3 (2%) 3 (2%)

89 (59%) 92 (62%)

7 (5%) 4 (3%)

86 (57%) 76 (51%)

65 (43%) 72 (48%)

99 (66%) 81 (54%)

52 (34%) 68 (46%)

125/146 (86%) 116/144 (81%)

21/146 (14%) 28/144 (39%)

Baseline characteristics of the ITT population were balanced between treatment arms (2)

Wang-Gillam A, et al. Lancet 2016;387:545

†Patients received neoadjuvant, adjuvant, or locally advanced treatment but no previous therapy for metastatic disease ITT, intent to treat

Previous therapies

or procedures, n (%)

Radiotherapy

Whipple procedure

Biliary stent

Previous lines of metastatic

therapy, n (%)

0†

1

≥2

Previous anticancer therapy, n (%)

Gemcitabine alone

Gemcitabine combination

Fluorouracil-based

Irinotecan-based

Platinum-based

Combination

therapy

nal-IRI+5-FU/LV

(n = 117)

Combination

therapy control

5-FU/LV

(n = 119)

24 (21%) 27 (23%)

30 (26%) 33 (28%)

15 (13%) 8 (7%)

15 (13%) 15 (13%)

62 (53%) 67 (56%)

40 (34%) 37 (31%)

53 (45%) 55 (46%)

64 (55%) 64 (54%)

50 (43%) 52 (44%)

12 (10%) 17 (14%)

38 (32%) 41 (34%)

Monotherapy

nal-IRI

(n = 151)

Monotherapy

control 5-FU/LV

(n = 149)

40 (26%) 33 (22%)

47 (31%) 36 (24%)

13 (9%) 9 (6%)

17 (11%) 19 (13%)

86 (57%) 86 (58%)

48 (32%) 44 (30%)

67 (44%) 66 (44%)

84 (56%) 83 (56%)

70 (46%) 63 (42%)

17 (11%) 17 (11%)

54 (36%) 45 (30%)

NAPOLI-1: a 1.9 month (45%) increase in median OS was observed with nal-IRI+5-FU/LV combination therapy (2)

Survival analysis after 313 deaths on 14 February 2014; Vertical bars indicate censoring points CI, confidence interval; mo, month; OS, overall survival

Wang-Gillam A, et al. Lancet 2016;387:545; Chen LT, et al. J Clin Oncol 2015;33(S3):abstract 234

(and presentation)

nal-IRI monotherapy vs. 5-FU/LV nal-IRI+5-FU/LV combination therapy vs. 5-FU/LV

Median,

mo (95% CI)

nal-IRI+5-FU/LV 6.1 (4.8–8.9)

5-FU/LV 4.2 (3.3–5.3)

Stratified HR = 0.57 (0.41–0.80)

Unstratified HR = 0.67 (0.49–0.92)

P = 0.012

100

Time (months)

Su

rviv

al p

rob

ab

ility

(%

)

0

20

40

60

80

0 3 6 9 12 15 18

117 97 51 20 8 0 0

119 68 34 11 6 1 0

nal-IRI+5-FU/LV

5-FU/LV

Number at risk

100

Time (months)

Surv

ival pro

babili

ty (

%)

0

20

40

60

80

0 3 6 9 12 15 18

151 109 53 21 10 2 2

149 89 41 16 9 3 1

nal-IRI

5-FU/LV

Number at risk

Median,

mo (95% CI)

nal-IRI 4.9 (4.2–5.6)

5-FU/LV 4.2 (3.6–4.9)

Stratified HR = 0.93 (0.71–1.21)


P = 0.094

NAPOLI-1: a statistically significant increase in PFS was observed with nal-IRI+5-FU/LV combination therapy (2)

Vertical bars indicate censoring points CI, confidence interval; mo, month; PFS, progression-free survival Wang-Gillam A, et al. Lancet 2016;387:545

nal-IRI monotherapy vs. 5-FU/LV nal-IRI+5-FU/LV combination therapy vs. 5-FU/LV

Median,

mo (95% CI)

nal-IRI+5-FU/LV 3.1 (2.7–4.2)

5-FU/LV 1.5 (1.4–1.8)

Stratified HR = 0.57 (0.41–0.80)


P = 0.0001

100

Time (months)

Su

rviv

al p

rob

ab

ility

(%

)

0

20

40

60

80

0 3 6 9 12 15 18

117 50 22 7 2 0 0

119 23 8 3 2 1 0

nal-IRI+5-FU/LV

5-FU/LV

Number at risk

100

Time (months) S

urv

ival pro

babili

ty (

%)

0

20

40

60

80

0 3 6 9 12 15 18

151 49 14 2 0 0 0

149 31 9 5 3 1 0

nal-IRI

5-FU/LV

Number at risk

Median,

mo (95% CI)

nal-IRI 2.7 (2.1–2.9)

5-FU/LV 1.6 (1.4–1.8)

Stratified HR = 0.93 (0.71–1.21)


P = 0.1

NAPOLI-1: a significant improvement in PFS, ORR and CA19-9 response was observed with nal-IRI+5-FU/LV

Wang-Gillam A, et al. Lancet 2016;387:545 CI, confidence interval; ORR, objective response rate; PFS, progression-free survival

Monotherapy

nal-IRI

(n = 151)

Monotherapy

control

5-FU/LV

(n = 149)

2.7 1.6

2.1–2.9 1.4–1.8

9 (6) 1 (1)

5.3 (1.3–9.3)

0.02

24 11

29/123 12/105

0.024

Combination

therapy

nal-IRI+5-FU/LV

(n = 117)

Combination

therapy control

5-FU/LV

(n = 119)

3.1 1.5

2.7–4.2 1.4–1.8

19 (16) 1 (1)

15.4 (8.5–22.3)

<0.0001

29 9

28/97 7/81

0.0006

Median PFS

Months

95% CI

ORR*

n (%)

Difference, % (95% CI)

P-value

CA19-9 response**

%

(responders/evaluable, n)

P-value

NAPOLI-1: Subgroup analysis

for OS

Wang-Gillam A, et al. Lancet 2016;387:545

NAPOLI-1: grade ≥3 adverse events (safety population)

*Includes agranulocytosis, febrile neutropenia, granulocytopenia, neutropenia, neutropenic sepsis, decreased neutrophil count, and pancytopenia. **Alopecia by definition can only be grade 1 or 2 AE, adverse event

Wang-Gillam A, et al. Lancet 2016;387:545; CTCAE v4.03, June 2010

AEs in ≥5% patients, n (%)

Diarrhoea

Vomiting

Nausea

Decreased appetite

Fatigue

Neutropenia* Fb+Np

Anaemia

Hypokalaemia

Alopecia, any grade**

Combination

therapy

nal-IRI+5-FU/LV

(n = 117)

Combination

therapy control

5-FU/LV

(n = 134)

15 (13) 6 (4)

13 (11) 4 (3)

9 (8) 4 (3)

5 (4) 3 (2)

16 (14) 5 (4)

32 (27) (3%) 2 (1) (0%)

11 (9) 9 (7)

4 (3) 3 (2)

16 (14) 6 (5)

Monotherapy

nal-IRI

(n = 147)

Combination

therapy control

5-FU/LV

(n = 134)

31 (21) 6 (4)

20 (14) 4 (3)

8 (5) 4 (3)

13 (19) 3 (2)

9 (6) 5 (4)

22 (15) (4%) 2 (1) (0%)

16 (11) 9 (7)

17 (12) 3 (2)

32 (22) 6 (5)

TEAEs, n (%)

nal-IRI+5-FU/LV 5-FU/LV

<65 years (n = 63) ≥65 years (n = 54) <65 years (n = 78) ≥65 years (n = 56)

Any TEAE 63 (100) 53 (98.1) 77 (98.7) 55 (98.2)

Any TEAE, grade ≥3 53 (84.1) 37 (68.5) 44 (56.4) 31 (55.4)

Any TEAE resulting in dose modification*

46 (73.0) 37 (68.5) 25 (32.1) 23 (41.1)

TEAEs (reported in ≥30% of patients in any arm)

Any grade Grade

≥3 Any grade

Grade ≥3

Any grade Grade

≥3 Any grade

Grade ≥3

Vomiting 41 (65.1) 9 (14.3) 20 (37.0) 4 (7.4) 22 (28.2) 2 (2.6) 13 (23.2) 2 (3.6)

Diarrhoea 39 (61.9) 9 (14.3) 30 (55.6) 6 (11.1) 22 (28.2) 5 (6.4) 13 (23.2) 1 (1.8)

Nausea 38 (60.3) 3 (4.8) 22 (40.7) 6 (11.1) 29 (37.2) 1 (1.3) 17 (30.4) 3 (5.4)

Decreased appetite 30 (47.6) 2 (3.2) 22 (40.7) 3 (5.6) 22 (28.2) 3 (3.8) 21 (37.5) 0

Neutropenia† 24 (38.1) 17 (27.0) 22 (40.7) 15 (27.8) 4 (5.1) 2 (2.6) 3 (5.4) 0

Fatigue 23 (36.5) 8 (12.7) 24 (44.4) 8 (14.8) 21 (26.9) 3 (3.8) 16 (28.6) 2 (3.6)

Anaemia 19 (30.2) 5 (7.9) 25 (46.3) 6 (11.1) 13 (16.7) 5 (6.4) 18 (32.1) 4 (7.1)

Abdominal pain 17 (27.0) 5 (7.9) 10 (18.5) 3 (5.6) 23 (29.5) 6 (7.7) 19 (33.9) 2 (3.6)

NAPOLI-1: Toxicity by age

*Including dose reduction, dose delay and dose discontinuation †Including agranulocytosis, febrile neutropenia, granulocytopenia, neutropenia, neutrophil sepsis, neutrophil count decreased, and pancytopenia TEAE, treatment-emergent adverse event

Chen LT, et al. Ann Oncol 2016;27(S2): abstract PD-023 (and poster).

TEAEs, n (%)

nal-IRI+5-FU/LV 5-FU/LV

KPS score ≥90 (n = 69)

KPS score <90 (n = 48)

KPS score ≥90 (n = 66)

KPS score <90 (n = 68)

Any TEAE 69 (100) 47 (97.9) 65 (98.5) 67 (98.5)

Any TEAE, grade ≥3 52 (75.4) 38 (79.2) 27 (40.9) 48 (70.6)

Any TEAE resulting in dose modification*

48 (69.6) 35 (72.9) 19 (28.8) 29 (42.6)

TEAEs (reported in ≥30% of patients in any arm)

Any grade Grade

≥3 Any grade

Grade ≥3

Any grade Grade

≥3 Any grade

Grade ≥3

Diarrhoea 40 (58.0) 8 (11.6) 29 (60.4) 7 (14.6) 22 (33.3) 3 (4.5) 13 (19.1) 3 (4.4)

Nausea 37 (53.6) 4 (5.8) 23 (47.9) 5 (10.4) 19 (28.8) 1 (1.5) 27 (39.7) 3 (4.4)

Vomiting 36 (52.2) 8 (11.6) 25 (52.1) 5 (10.4) 16 (24.2) 2 (3.0) 19 (27.9) 2 (2.9)

Fatigue 29 (42.0) 8 (11.6) 18 (37.5) 8 (16.7) 18 (27.3) 1 (1.5) 19 (27.9) 4 (5.9)

Neutropenia† 29 (42.0) 20 (29.0) 17 (35.4) 12 (25.0) 4 (6.1) 1 (1.5) 3 (4.4) 1 (1.5)

Decreased appetite 28 (40.6) 1 (1.4) 24 (50.0) 4 (8.3) 21 (31.8) 0 22 (32.4) 3 (4.4)

Anaemia 25 (36.2) 6 (8.7) 19 (39.6) 5 (10.4) 18 (27.3) 4 (6.1) 13 (19.1) 5 (7.4)

Abdominal pain 16 (23.2) 3 (4.3) 11 (22.9) 5 (10.4) 18 (27.3) 2 (3.0) 24 (35.3) 6 (8.8)

Constipation 11 (15.9) 0 15 (31.3) 0 12 (18.2) 0 20 (29.4) 2 (2.9)

NAPOLI-1: Toxicity by KPS score

*Including dose reduction, dose delay and dose discontinuation †Including agranulocytosis, febrile neutropenia, granulocytopenia, neutropenia, neutrophil sepsis, neutrophil count decreased, and pancytopenia TEAE, treatment-emergent adverse event

Chen LT, et al. Ann Oncol 2016;27(S2): abstract PD-023 (and poster).

No appreciable change from baseline in global health status and functional scale scores between the two arms

0

Physical functioning

-5

-10

Baseline Week 6 Week 12

SCO

RE,

ch

ange

fro

m b

ase

line

0 Global health status 0

0 -5

-10

0

0

0

0

0

0

0

0

Role functioning

nal-IRI+ 5-FU/LV (n = 71)

5-FU/LV (n = 57)

Hubner R, et al. Ann Oncol 2016;27(S2):

abstract O-004 (and poster)

Emotional functioning

Cognitive functioning

Social functioning

0

No appreciable change from baseline in symptom scale scores between the two arms

Baseline Week 6 Week 12

SCO

RE,

ch

ange

fro

m b

ase

line

12

Fatigue 6

0

0

0 Nausea and vomiting

0

0 Pain 0

0 Dyspnoea 0

0 Insomnia

0

0 Appetite loss 0

0 Constipation

0

0 Diarrhoea

Hubner R, et al. Ann Oncol 2016;27(S2):

abstract O-004 (and poster)

nal-IRI+ 5-FU/LV (n = 71)

5-FU/LV (n = 57)

Overall, patients treated with nal-IRI + 5-FU/LV had no deterioration in QoL over 12 weeks, despite the addition of a second chemotherapeutic agent

QoL, quality of life

NAPOLI-1: Análisis de subgrupos de pts con Gem combi previa

Chen LT, et al. ASCO-GI 2016 #303

Tratamiento del adenocarcinoma de páncreas metastásico, en combinación con 5-fluorouracilo (5-FU) y ácido folínico (AF), en pacientes adultos que han empeorado tras un tratamiento

con gemcitabina

Nal-Iri (ONIVYDE): AEMPS / Uso Expandido

Julio 2016: dictamen positivo por comisión de expertos de la AEMPS Pendiente de Precio/reembolso

Uso Expandido NalIri-Fu-Lv en España - 190 pts incluidos - ¿Análisis de pts con previo Gem-Abx / FOLFIRINOX?

Sultana et al JCO 2007

Meta-análisis Gem vs Gem + 2ª QT Sultana et al (JCO-07)

Evidence showed some activity for irinotecan in the 2nd-line setting in pancreatic cancer patients

5-FU, fluorouracil; IRI, irinotecan; LV, folinic acid /leucovorin; FOLFOX, 5-FU, LV and oxaliplatin; FOLFIRI, 5-FU, LV and irinotecan; NA, not applicable; NR, not reported; OS, overall survival; PFS, progression-free survival

1. Ulrich-Pur H, et al. Br J Cancer 2003;88:1180; 2. Yoo C, et al. Br J Cancer 2009;101:1658; 3. Yi SS, et al. Cancer Chemother Pharmacol 2009;63:1141; 4. Zaniboni A, et al. Cancer

Chemother Pharmacol 2012;69:1641; 5. Mizuno N, et al. J Clin Oncol 2013;31(S4);abstract 263

Ulrich-Pur et al.1 Yoo et al.2 Yi et al.3

Zaniboni et al.4 Mizuno et al.5

Raltitrexed n = 19

IRI + raltitrexed

n = 19 mFOLFOX

n = 30 mFOLFIRI.3

n = 31 IRI

n = 33 FOLFIRI n = 50

S-1 + IRI n = 60

S-1 n = 67

Median OS

4.3 months

6.5 months

14.9 weeks

16.6 weeks

6.6 months

5.0 months

208 days

176 days

P = NR (secondary endpoint)


NA NA P = 0.1338 (HR = 0.749; 95% CI,

0.512–1.093)

Median PFS

2.5 months

4.0 months

6.0 weeks

8.3 weeks

2.0 months

3.2 months

107 days

58 days



NA NA P = 0.1750

(HR = 0.767; 95% CI, 0.527–1.114)

Potential treatment sequencing approach for MPC in 2017?

FOLFIRINOX

Nab-paclitaxel + gemcitabine

(if no neuropathy)

Gemcitabine

FOLFIRINOX

Nab-paclitaxel + gemcitabine

MM-398 + 5-FU/LV

OFF

Capecitabine / 5 FU

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

mFOLFOX6 or CAPOX

Platinum-based tx (depending on

prior exposure)

Supported by RCT data

Supported by retrospective data or small,

single arm trials

¿¿FOLFIRI??

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

prior exposure)

Platinum-based tx (depending on

prior exposure)


Conclusiones

- Con oxaliplatino resultados discordantes para Sv (CONKO-003 + PANCREOX -)

- Nal-Iri: mecanismo de acción distinto a irinotecán, ventajas parmacocinéticas y más eficacia en modelos preclínicos

- NalIri-FFol vs FFol (NAPOLI-1): mejor Sv,SLP,Rta. Tox moderada y se mantiene QoL

- Las guías recogen que NalIri-FFol es la opción con más evidencia Sin embargo hay diferencias en posibles esquemas alternativos

- Se necesita más evidencia sobre NalIri-FFol tras GemAbx o Folfirinox en CP

- Son posibles distintas secuencias de tratamiento. Una secuencia posible con buen apoyo de evidencia sería Gem-Abx NaiIri-Ffol ¿Ox-F?

Gracias

Segunda línea en cáncer de páncreas: entre Oxaliplatino y Nal-Iri · 2017. 6. 27. · 1. Ohkawa...

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