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Dopo la prima linea
Sara Lonardi
Regione del Veneto
SS Neoplasie Gastroenteriche
UOC Oncologia Medica 1
Dipartimento di Oncologia Clinica e Sperimentale
Istituto Oncologico Veneto – IRCCS, Padova
Convegno AIOM – Questioni aperte nel carcinoma pancreatico
Milano, 28 novembre 2017
Second line therapies in clinical trials
Second line therapies in clinical practice
Abrams et al. The Oncologist 2017
Gemcitabine based
(eg, gemcitabine,
gem/nab paclitaxel,
gem/erlotinib)
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?) /
Oxaliplatin + 5-FU
or
(PS 2): Fluoropyrimidine
alone; BSC
(PS 0-1): Platinum-(??)
based regimen if no
prior exposure
FOLFIRINOX
(PS 0-1): Gemcitabine/
nab paclitaxel?
(PS 2 or less): Gemcitabine
monotherapy; BSC
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?)
3rd
lin
e
2n
d l
ine
1st lin
e
Potential sequencing approach
Gem monotherapy after FOLFIRINOX
Gem-nab after FOLFIRINOX
Chan et al. ASCO GI 2016
Gemcitabine based
(eg, gemcitabine,
gem/nab paclitaxel,
gem/erlotinib)
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?) /
Oxaliplatin + 5-FU
or
(PS 2): Fluoropyrimidine
alone; BSC
(PS 0-1): Platinum-(??)
based regimen if no
prior exposure
FOLFIRINOX
(PS 0-1): Gemcitabine/
nab paclitaxel?
(PS 2): Gemcitabine
monotherapy; BSC
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?)
3rd
lin
e
2n
d l
ine
1st lin
e
Potential sequencing approach
Gemcitabine based
(eg, gemcitabine,
gem/nab paclitaxel,
gem/erlotinib)
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?) /
Oxaliplatin + 5-FU
or
(PS 2): Fluoropyrimidine
alone; BSC
(PS 0-1): Platinum-(??)
based regimen if no
prior exposure
FOLFIRINOX
(PS 0-1): Gemcitabine/
nab paclitaxel?
(PS 2): Gemcitabine
monotherapy; BSC
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?)
3rd
lin
e
2n
d l
ine
1st lin
e
Potential sequencing approach
Benefit from second-line after gem-nab
Chiorean et al. B J Cancer 2017
Variable n, % OS
median, mo
Time from randomization
to 1st dose of 2L tx,
median, mo
Time from 1st dose
of 2L tx to death,
median, months
Any 2L Therapy
nab-P + Gem
Gem
170 (39)
177 (41)
12.8
9.9
6.6
4.1
5.3
4.5
5FU/cape containing
nab-P + Gem
Gem
132 (39)
135 (41)
13.5
9.5
6.7
4.1
5.7
4.5
Other than 5/Fu/cape)
nab-P + Gem
Gem
38 (22)
42 (24)
10.9
11.3
6.3
4.5
3.2
4.8
5-FU or Cape Combo
nab-P + Gem
Gem
98 (74)
107 (79)
14.0
9.5
6.6
4.0
6.0
4.6
5-FU or Cape Mono
nab-P + Gem
Gem
34 (26)
28 (21)
11.9
9.4
6.7
5.3
4.7
3.9
FOLFIRINOX
nab-P + Gem
Gem
18 (14)
17 (13)
15.7
7.2
8.4
4.0
7.2
3.5
FOLFOX/OFF
nab-P + Gem
Gem
36 (27)
49 (36)
13.7
9.8
5.6
4.1
6.4
4.5
Goldstein D and Chiorean EG et al, Abstract 333; 2016, Gastrointestinal Cancers Symposium; January 21-23, 2016; San Francisco, CA
Benefit from second-line after gem-nab
Chiorean et al. B J Cancer 2017
Median total survival (1L randomisation to death) for patients who received 2L
treatment after 1L nab-P + Gem vs Gem alone was 12.8 vs 9.9 months
(P<0.015), for patients with a fluoropyrimidine-containing 2L therapy after nab-
P + Gem vs Gem was 13.5 vs 9.5 months (P<0.012).
Benefit from second-line after gem-nab
Chiorean et al. B J Cancer 2017
Unresectable pancreatic cancer with PD on Gem as
1-line
(n 342)
R
A
N
D
O
M
I
Z
E
FF (5FU + FA) (91 pts) (5FU 2000 mg/m2 [24h] +
FA 200 mg/m2 [30’] d1, 8, 15, 22
OFF (77 pts) (FF plus oxaliplatin 85 mg/m2 d8, 22)
Primary endpoint OS
Oettle H, et al. JCO 2014
CONKO-003 trial: oxa-FU in gem refractory pts
CONKO-003 PANCREOX
Pts [N = 268] PD on gem tx [n = 160] Previous gem tx [n = 108]
Treatment OS, median
OFF
(n = 76) 5.9 mos
5-FU/LV
(n = 84) 3.3 mos
mFOLFOX6
(n = 54) 6.1 mos
5-FU/LV
(n = 54) 9.9 mos
HR: 0.66 (95% CI: 0.48-0.91) P = .01
HR: 1.78 (95% CI: 1.08-2.93) P = .02
PFS, median 2.9 mos 2.0 mos 3.1 mos 2.9 mos
HR: 0.68 (95% CI: 0.50-0.94) P = .02
HR: 1.00 (95% CI: 0.66-1.53) P = .99
Oettle H, et al. J Clin Oncol. 2014 Gill S, et al. J Clin Oncol. 2016
Conflicting results with second-line oxa-based regimens
FU-based chemotherapy in second-line treatment
Petrelli F, et al. EJC 2017
Liposomal irinotecan (MM-398, PEP02)
Liposomal irinotecan (nal-IRI): novel formulation developed by using nanotechnology and liposome encapsulation with the aim to improve free drug’s therapeutic window
Ko et al, Int J Nanomedicine, ‘16
• liposomes tend to preferentially accumulate in tumors as a result of an enhanced permeability and retention (EPR) effect
• prevents premature clearance and metabolism: longer circulation times (t1/2 = 10.7 h compared to 0.27 h of free drug); slow release of irinotecan from liposomes (t1/2 for irinotecan release = 56.8 h)
Enrollment for combination therapy comparison
mPDAC Received prior gemcitabine- based therapy
R
nal-IRI 120 mg/m2,
Enrollment for monotherapy comparison
5-FU/LV 2000/200 mg/m2, weekly x4, q6w
nal-IRI + 5-FU/LV 80 mg/m2, 2400 mg/m2, q2w
n = 33
n = 30
n = 118
n = 119
n = 117
n = 151
n = 149
n = 117
Protocol Version 1
Protocol Version 2a
Total Enrollment
Wang-Gillam A, et al. Lancet. 2016
Napoli-1 trial
NAPOLI-1 trial: OS and PFS
N = 151
N = 149
N = 117
Wang-Gillam et al, Lancet. 2016
mOS 6.1 months vs 4.2 months mPFS 3.1 months vs 1.5 months
NAPOLI-1 trial: efficacy in CA19.9 quartiles
Wang-Gillam et al, Lancet. 2016
NAPOLI-1 trial: post-hoc analisys
Wang-Gillam et al, ASCO GI 2017
NAPOLI-1 trial: safety
Wang-Gillam et al, Lancet. 2016
NAPOLI-1 CONKO-003 PANCREOX
Nal-IRI/5-
FU/LV
5-FU/LV Oxali-FU 5-FU/LV mFOLFOX 5-FU/LV
Centers 14 1 1
Pts number 117 134 76 84 54 54
mPFS, months 3.1 1.5 2.9 2.0 3.1 2.9
mOS, months 6.1 4.2 5.9 3.3 6.1 9.9
Interruptions due
to toxicity%
11.1 7.5 20 2
Response rate, % 16 1 13.2 8.5
Second-line summary
Gemcitabine based
(eg, gemcitabine,
gem/nab paclitaxel,
gem/erlotinib)
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?) /
Oxaliplatin + 5-FU
or
(PS 2): Fluoropyrimidine
alone; BSC
(PS 0-1): Platinum-(??)
based regimen if no
prior exposure
FOLFIRINOX
(PS 0-1): Gemcitabine/
nab paclitaxel?
(PS 2): Gemcitabine
monotherapy; BSC
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?)
3rd
lin
e
2n
d l
ine
1st lin
e
Potential sequencing approach
Nal-IRI approval pathway
Nal-IRI, in combination with 5-FU/LV, has been approved by FDA (2015) and EMA (2016) for the treatment of patients with MPC who have progressed following gemcitabine-based therapy Use of nal-IRI plus 5-FU/LV in 2L setting has been recently suggested by ESMO and NCCN guidelines In Italy is not yet approved, however, it is available in a nominal use program
AIOM Guidelines 2016
AIOM Guidelines 2017
Trial world
Real world
Younger patients
Best PS
Limited disease
No biliary obstruction
Bile drainage
Pain relief
Nutritional support
Bowel obstruction control
Diabetes control
Implications in clinical practice
Courtesy S. Cascinu
1) How to choose the best candidate for treatment
2) How to better manage concomitant symptoms
Issues in clinical practice
Development of a prognostic nomogram
Vienot et al, ASCO GI 2017
Development of a prognostic nomogram
Vienot et al, ASCO GI 2017
Meta-analysis of randomized trials confirms that performance status is an
important factor in determining who is more likely to benefit from combination chemotherapy
Benefit From Combination Therapy? Yes (HR: 0.76; P<.0001) No (HR: 1.08; P = .40)
Performance Status ECOG PS 0-1/Karnofsky PS 90% to 100% ECOG PS 2/Karnofsky PS 60% to 80%
Impact of PS on benefit from combination treatment
Heinemann V, et al. BMC Cancer. 2008
Lower PS was significantly associated with pancreatic pain, digestive symptoms, cachexia, and ascites. Management may result in improved symptoms and better outcomes.
Moningi S, et al. J Oncol Pract. 2015
Cancer Symptoms may contribute to a poor PS
Maltoni M. et al EJC 2016
Systematic versus on-demand early palliative care: QoL
Treatment aggressiveness near the end of life
Standard Arm Interventional Arm p
CT administration N (%)
< 30 days before death 20/72 (27.8) 14/75 (18.7) 0.036
> 14 days before death 8/72 (11.1) 10/75 (13.3) 0.826
hospice adm. mean value (SD)
number of total admission 0.97 (0.37) 1.38(0.64) 0.001
days in hospice 14.9 (11.1) 25.2 (24) 0.025
Place of death N (%)
Home + hospice 48/72 (66.7) 56/72 (77.8) 0.102
Hospital 22/72 (30.6) 15/72 (20.8) NS
Maltoni M et al EJC 2016
Gemcitabine based
(eg, gemcitabine,
gem/nab paclitaxel,
gem/erlotinib)
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?) /
Oxaliplatin + 5-FU
or
(PS 2): Fluoropyrimidine
alone; BSC
(PS 0-1): Platinum-(??)
based regimen if no
prior exposure
FOLFIRINOX
(PS 0-1): Gemcitabine/
nab paclitaxel?
(PS 2): Gemcitabine
monotherapy; BSC
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?)
3rd
lin
e
2n
d l
ine
1st lin
e
Potential sequencing approach
Gemcitabine based
(eg, gemcitabine,
gem/nab paclitaxel,
gem/erlotinib)
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?) /
Oxaliplatin + 5-FU
or
(PS 2): Fluoropyrimidine
alone; BSC
(PS 0-1): Platinum-(??)
based regimen if no
prior exposure
FOLFIRINOX
(PS 0-1): Gemcitabine/
nab paclitaxel?
(PS 2): Gemcitabine
monotherapy; BSC
(PS 0-1): Nanoliposomal
irinotecan + 5-FU (?)
3rd
lin
e
2n
d l
ine
1st lin
e
Potential sequencing approach
Immunotherapy in pancreatic cancer
Lemery et al, N Engl J Med 2017
High response rate in MSI-H pancreatic cancer
Secondary Endpoint: Progression-Free Survival HA-High (Combined Stages 1 & 2)
Phase II trial of gem-nab + PEGPH20 in HA-high: PFS
Hingorani et al, ASCO Annual Meeting 2017
HALO phase III trial of gem-nab + PEGPH20 in HA-high
Trials ongoing: PARP inhibitors in BRCA mut