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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

sara.lonardi@iov.veneto.it