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%)
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
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
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
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)
120 mg/m2 nal-IRI Q3W
80 mg/m2 nal-IRI Q2W
Days a
bo
ve
th
resh
old
45
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
• 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)
Unstratified HR = 0.99 (0.77–1.28)
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)
Unstratified HR = 0.56 (0.41–0.75)
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)
Unstratified HR = 0.81 (0.63–1.04)
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?
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
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)
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
P = NR (secondary endpoint)
P = NR (secondary endpoint)
NA NA P = 0.1750
(HR = 0.767; 95% CI, 0.527–1.114)
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
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
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)
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
Segunda línea en CPA: entre Oxaliplatino y Nal-Iri
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
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