Dopo la I linea

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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

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Second line therapies in clinical trials

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Second line therapies in clinical practice

Abrams et al. The Oncologist 2017

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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 line2nd line1st line

Potential sequencing approach

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Gem monotherapy after FOLFIRINOX

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Gem-nab after FOLFIRINOX

Chan et al. ASCO GI 2016

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gem/erlotinib)

nab paclitaxel?

(PS 2): Gemcitabine monotherapy; BSC

Potential sequencing approach

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gem/erlotinib)

nab paclitaxel?

Potential sequencing approach

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Benefit from second-line after gem-nab

Chiorean et al. B J Cancer 2017

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Variable n, % OS median, mo

Time from randomization to 1^st dose of 2L tx,

median, mo

Time from 1^st 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

132 (39) 135 (41)

13.5 9.5

6.7 4.1

5.7 4.5 Other than 5/Fu/cape)

38 (22) 42 (24)

10.9 11.3

6.3 4.5

3.2 4.8 5-FU or Cape Combo

98 (74) 107 (79)

14.0 9.5

6.6 4.0

6.0 4.6 5-FU or Cape Mono

34 (26) 28 (21)

11.9 9.4

6.7 5.3

4.7 3.9 FOLFIRINOX

18 (14) 17 (13)

15.7 7.2

8.4 4.0

7.2 3.5 FOLFOX/OFF

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

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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

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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

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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

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FU-based chemotherapy in second-line treatment

Petrelli F, et al. EJC 2017

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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

(t

_1/2

= 10.7 h compared to 0.27 h of free drug); slow release of irinotecan

from liposomes (t

_1/2

for irinotecan release = 56.8 h)

(16)

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

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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

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NAPOLI-1 trial: efficacy in CA19.9 quartiles

Wang-Gillam et al, Lancet. 2016

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NAPOLI-1 trial: post-hoc analisys

Wang-Gillam et al, ASCO GI 2017

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NAPOLI-1 trial: safety

Wang-Gillam et al, Lancet. 2016

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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

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gem/erlotinib)

nab paclitaxel?

Potential sequencing approach

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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

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AIOM Guidelines 2016

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AIOM Guidelines 2017

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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

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1) How to choose the best candidate for treatment 2) How to better manage concomitant symptoms

Issues in clinical practice

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Development of a prognostic nomogram

Vienot et al, ASCO GI 2017

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Development of a prognostic nomogram

Vienot et al, ASCO GI 2017

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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

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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

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Maltoni M. et al EJC 2016

Systematic versus on-demand early palliative care: QoL

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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

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gem/erlotinib)

nab paclitaxel?

Potential sequencing approach

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gem/erlotinib)

nab paclitaxel?

Potential sequencing approach

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Immunotherapy in pancreatic cancer

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Lemery et al, N Engl J Med 2017

High response rate in MSI-H pancreatic cancer

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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

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HALO phase III trial of gem-nab + PEGPH20 in HA-high

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Trials ongoing: PARP inhibitors in BRCA mut

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