DiscussionPancreatic Cancer

Abstracts 145, LBA146, 147, & LBA148

Philip Agop Philip, MD, PhD, FRCP

Karmanos Cancer Center

Wayne State University

Detroit, Michigan

Randomized phase III trial of adjuvant chemotherapy with gemcitabine vs. S-1for resected pancreatic cancer patients

(JASPAC 01 study)

K. Uesaka, et al.Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC)

Abstract #145

#145 2013 ASCO GI

JASPAC 01

Randomization

GEM 1000 mg/m2

Q 4 weeksX 6 cycles

S-1 40-60mg, BID, PO4 wks on/2 wks off

X 4 cycles

Surgery

Stratification• Center• R0/R1• N0/N1

#145 2013 ASCO GI

JASPAC 01

Randomization

GEM 1000 mg/m2

X 6 cycles

S-1 40-60mg, BID, PO4 wks on/2 wks off

X 4 cycles

Surgery

Stratification• Center• R0/R1• N0/N1

No Radiotherapy!

JASPAC 01 Overall SurvivalPrimary Endpoint

0

50

100

0 1 2 3 4 5 years

(%) P<0.0001 for non-inferiorityP<0.0001 for superiority

70%

53%

S-1

GEM

Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies

CONKO-001 RTOG 97-04 ESPAC-3 JASPAC 01

GEM v Obs GEM v inf-FU+ C-RT

GEM v b-FU GEM v S-1

mDFS monGEM 13.4 11.4 14.3 11.2

FP - 10.1 14.1 23.2

mOS monGEM 22.8 20.5 23.6 25.5

FP - 16.9 23 46.3

Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;

Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies

CONKO-001 RTOG 97-04 ESPAC-3 JASPAC 01

GEM v Obs GEM v inf-FU+ C-RT

GEM v b-FU GEM v S-1

mDFS monGEM 13.4 11.4 14.3 11.2

FP - 10.1 14.1 23.2

mOS monGEM 22.8 20.5 23.6 25.5

FP - 16.9 23 46.3

Node positive, % 72 67 72 63

R0, % 81 66 65 87

JASPAC 01

• Superiority of adjuvant S-1 over GEM in Japanese patients with resected panc. ca.

• “Non-Japanese” studies must be considered to define the role of S-1 in early and late stage disease in conjunction with biomarkers studies (e.g., S-1 metabolism)

• The role of adjuvant radiation therapy in panc. ca will be determined by the ongoing RTOG/SWOG/EORTC study

Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the

Pancreas (MPACT)

Daniel D. Von Hoff, et al.

Abstract #148

Study Design

Planned N = 842

• Stage IV• No prior treatment for

metastatic disease• Karnofsky PS ≥70 • Measurable disease• Total bilirubin ≤ULN

nab-Paclitaxel 125 mg/m2 IV qw 3/4 weeks

+

Gemcitabine1000 mg/m2 IV qw 3/4 weeks

Gemcitabine1000 mg/m2 IV qw for 7 weeks then qw 3/4

weeks

Von Hoff

IMPACT: Efficacy

nab-Pacli + GEM

GEM Hazard ratiop value

Med OS, mos 8.5 6.7 0.72/0.000015

Med PFS, mos 5.5 3.7 0.69/0.000024

12-mon alive, % 35 22 0.0002Objective response, %

23 7 1.1x10-10

Major Treatment Options for Metastatic Pancreatic Cancer

• Gemcitabine +/- erlotinib• FOLFIRINOX• Nab-paclitaxel plus gemcitabine• Others (e.g., GemCape, GTX) • Clinical trial

Major Treatment Options for Metastatic Pancreatic Cancer

• Gemcitabine +/- erlotinib• FOLFIRINOX• Nab-paclitaxel plus gemcitabine• Others (e.g., GemCape, GTX) • Clinical trials

Tolerability:Selected Grade 3+ Toxicities, %

nab-pacli + GEM

FOLFIRINOX

Fatigue 17 23.6Diahhrea 6 12.7Neuropathy 17 9Neutropenia 38 45.7Neutropenic fever 3 5.4Thrombocytopenia 13 9.1

Conroy et al, NEJM, 364:1817-1825, 2011

Efficacy

nab-pacli + GEM

FOLFIRINOX

Median OS, mos 8.7 11.1Median PFS, mos

5.5 6.4

ORR (%) 23.0 31.6

Conroy et al, NEJM, 364:1817-1825, 2011

Study PopulationsIMPACT PRODIGE/

ACCORDMedian age median 63 61

Liver, % 84 88

Head of pancreas, % 43 38

Males, % 58 61

Good PS, % 60 38

Median sites of mets 3 2

Number of patients 861 342

Treatment centers Multiple countries

Conroy et al, NEJM, 364:1817-1825, 2011

IMPACT• Is an example of pre-clinical to pilot testing to

Phase III drug stepwise developmental program• Nab-paclitaxel plus GEM is a new frontline

regimen in patients with metastatic panc. ca. and favorable performance status

• Nab-paclitaxel +/- GEM (or other drugs) must be investigated in earlier stage disease and in combinations with biologicals

• The molecular basis of nab-paclitaxel’s activity and its association with a biomarker(s) must be determined (going back to the lab!)

Induction GEMCAP Chemotherapy followed by Gemcitabine (Gem) or

Capecitabine (Cap)-based Chemoradiation (CRT) for Locally

Advanced Pancreatic Cancer (LAPC): the Final Results of the SCALOP Trial

S Mukherjee, et al.SCALOP Investigators

Abstract LBA146

GEMCAP x 3 cyclesGem 1000mg/m2 D1,8,15 q 4wCap 830mg/m2 BD D 1-21 q 4w

RANDOMIZATION

GEMCAP x 1 cycle GEMCAP x 1 cycle

Gemcitabine 300mg/m2/week + RT 50.4Gy

Capecitabine 830mg/m2 bd + RT 50.4Gy

• Progressive dx• Tumor >6cm diameter• PS 2• >10% wt loss• Not encompassable

in radiation volume

SCALOP

GEMCAP x 3 cyclesGem 1000mg/m2 D1,8,15 q 4wCap 830mg/m2 BD D 1-21 q 4w

RANDOMIZATION

GEMCAP x 1 cycle GEMCAP x 1 cycle

Gemcitabine 300mg/m2/week + RT 50.4Gy

Capecitabine 830mg/m2 bd + RT 50.4Gy

• Progressive ds• Tumor >6cm diameter• PS 2• >10% wt loss• Not encompassable

in radiation volume

SCALOP

35%

GEMCAP x 3 cyclesGem 1000mg/m2 D1,8,15 q 4wCap 830mg/m2 BD D 1-21 q 4w

RANDOMIZATION

GEMCAP x 1 cycle GEMCAP x 1 cycle

Gemcitabine 300mg/m2/week + RT 50.4Gy

Capecitabine 830mg/m2 bd + RT 50.4Gy

• Progressive ds• Tumor >6cm diameter• PS 2• >10% wt loss• Not encompassable

in radiation volume

SCALOP

4 cycles/4 monthsof systemic therapy

Summary of Efficacy DataCAPE-RT GEM-RT p

PFS at 9 mos, % 62.9 51.4 NSMedian PFS, mos 12.0 10.4 NSMed OS, mos 15.2 13.4 0.025

All Randomized Taken offN 114 74 40Med OS, mos 12.7 14.6 8.1

What do we learn from SCALOP?

• Cape-RT is the current preferred standard and will continue as such

• Ongoing research questions– The contribution of chemo-RT (GERCOR, Dr P. Hammel;

ALLIANCE, Dr A. Ko)– Molecular selection for chemo-RT (RTOG, Dr E. Ben

Josef) – More effective systemic therapies

• Develop study designs and endpoints that are appropriate to each question

M. J. Pishvaian, et al.

A Phase I/II Study of ABT-888, 5-Fluorouracil and Oxaliplatin in Patients

with Metastatic Pancreatic Cancer

Abstract #147

Phase Ib

• No patient selection• Pre-treatment biopsies for BRCA-1, -2, PALB-

B3, FANC gene expression, others

PARPi and Pancreatic Cancer

• A platinum +/- PARPi strategy is worth pursuing in patients with BRCA-2 mutations

• Explore biologic combinations with PARPi • Need to determine relative contributions of

platinum vs. PARPi to anti-tumor activity• National or “preferably” international

collaborative effort is necessary for a timely completion of clinical trials (e.g., ARCAD)

Thank you

backup

Take Home Messages

• Adjuvant S-1 is a new standard for resected pancreas ca. with a potential for its development outside of Japan

• nab-Paclitaxel/GEM is a new treatment standard for patients with metastatic pancreas ca. warranting further development in conjunction with a biomarker discovery strategy

Take Home Messages (2)

• Capecitabine 1.66 grams/m2/day will continue to be our radisoenstizer of choice in pancreas ca.

• A treatment strategy of a platinum compound +/- PARPi needs pre-clinical/pilot clinical evaluations in BRCA-2 mutated panc. ca.

• More tissue-based research and stronger collaborative efforts are necessary for successful studies in pancreatic cancer!

Gemcitabine vs. Fluoropyrimidine (FP): Phase III Adjuvant Studies

CONKO-001 RTOG 97-04 ESPAC-3 JASPAC 01

GEM v Obs GEM v inf-FU+ C-RT

GEM v b-FU GEM v S-1

mDFS monGEM 13.4 11.4 14.3 12

FP - 10.1 14.1 24

mOS monGEM 22.8 20.5 23.6 23

FP - 16.9 23 46

Hazard ratio for overall survival 0.80 0.94 0.56

Oettle et al, JAMA, 297:267-277, 2007; Regine et al, 299:1019-1026, 2008; Neoptolemus et al, 304:1073-1081, 2010;