Best Practices and Promising Agents in Pancreatic Cancerjaxelection.altervista.org/pancreatic/CCO_Pancreatic_TU_2016... · Best Practices and Promising Agents in Pancreatic Cancer

Best Practices and Promising Agents in Pancreatic Cancer

This program is supported by educational grants from Celgene Corporation and Incyte.

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Core Faculty

Tanios S. Bekaii-Saab, MDCo-Leader, GI Cancer Program

Mayo Clinic Cancer CenterProfessor of MedicineDivision of Hematology and OncologyMayo Clinic

Phoenix, Arizona

Andrew H. Ko, MDProfessor

Division of Hematology/OncologyDepartment of MedicineUniversity of California, San FranciscoSan Francisco, California

Agenda

� Diagnosis and Staging Considerations

� Current Therapeutic Options for Metastatic Pancreatic Cancer

� Second-line Agents for Pancreatic Cancer

� Emerging Agents for Pancreatic Cancer

� Other Signaling Pathway Targets in Pancreatic Cancer

Diagnosis and Staging Considerations

Pancreatic Cancer: Scope of the Problem

� Projected 53,070 new cases of pancreatic cancer in US pts with 41,780 deaths in 2016

� Stage for stage, pancreatic cancer is associated with the lowest survival rates of any major cancer type

� Within the decade, pancreatic cancer is expected to rise to the second leading cause of cancer-related mortality in the United States (behind lung cancer)

� The vast majority of pts (80% to 85%) are inoperable at time of diagnosis

Slide credit: clinicaloptions.comSiegel RS, et al. Cancer facts & figures 2016.

Stage Classification* % at Diagnosis

5-Yr Survival, %

Localized/resectable

9 26

Localized/unresectable

28 10

Metastatic 53 2

Siegel R, et al. CA Cancer J Clin. 2015;65:5-29.

Pancreatic Cancer by Stage (SEER Database)

*Unknown: 10%; 5-yr survival 4.4%

Slide credit: clinicaloptions.com

Screening for Pancreatic Cancer: Screening for Pancreatic Cancer: Identifying HighIdentifying High --Risk IndividualsRisk Individuals

Demographic Factors Advancing Age, Male, Black, Ashkenazi Jewish Ancest ry

Known genetic syndromes � Lynch syndrome (HNPCC)� Familial breast cancer (BRCA2)

� Peutz-Jeghers� Ataxia-telangiectasia

� Familial atypical multiple mole-melanoma� Hereditary pancreatitis

Family history As number of first-degree relatives increases (1 → 2 → 3+), risk increases by 4.6→ 6.4→ 32.0 fold

Host/environmental factors � Diabetes mellitus (T2DM)• Meta-analysis: odds ratio = 1.82

• Need to distinguish T2DM as early symptom of pancreatic cancer vs an independent risk factor

� Chronic pancreatitis� Tobacco use

� Obesity


American Cancer Society. www.cancer.org. 2016.Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma. V.1.2016. © 2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Current TherapeuticOptions for Metastatic

Pancreatic Cancer

Guidelines for Chemotherapy for Pts With Metastatic Pancreatic Adenocarcinoma

First-line Treatment

Category 1 NCCN Regimens

Other NCCN Regimens

Good performance

status

� FOLFIRINOX (preferred)� Gem + nab-paclitaxel

(preferred)� Gem + erlotinib

Category 2A�Gem + cape�Gem + cisplatin

Category 2B�GTX�FP + Ox

Poor performance status

� Gem monotherapyCategory 2B

�FDR gem�Cape or continuous infusion 5-FU

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma. V.1.2016. © 2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Clinical trial is the recommended first option for all pts.


Phase III Study: FOLFIRINOX vs Gemcitabine in Met Pancreatic Cancer

Pts with untreated metastatic pancreatic

cancer; ECOG PS 0/1; adequate BM, platelet count, liver and renal

function(N = 342)

Gemcitabine 1000 mg/m 2

weekly x 7 of 8, then weekly x 3 of 4

(n = 171)

FOLFIRINOXOxaliplatin 85 mg/m 2 +

LV 400 mg/m 2 +Irinotecan 180 mg/m 2 +

5-FU bolus 400 mg/m 2, then 2400 mg/m 2 IV over 46 hrs

(n = 171)

Stratified by ECOG PS (0 vs 1), center,tumor location (head vs other)

Conroy T, et al. N Engl J Med. 2011;364:1817-1825. Slide credit: clinicaloptions.com

FOLFIRINOX vs Gemcitabine: Baseline Characteristics (ITT)

Characteristic FOLFIRINOX (n = 171) Gemcitabine (n = 171)

Median age, yrs (range) 61 (25-76) 61 (34-75)

Male, n (%) 106 (62.0) 105 (61.4)

ECOG PS, n (%)

� 0 64 (37.4) 66 (38.6)

� 1 106 (61.9) 105 (61.4)

Pancreatic tumor location, n (%)

� Head 67 (39.2) 63 (36.8)

� Body 53 (31.0) 58 (33.9)

� Tail 45 (26.3) 45 (26.3)

Biliary stent, n (%)

� No 144 (84.2) 149 (87.1)


FOLFIRINOX vs Gemcitabine: OS and PFS

100

75

50

00 3 6 9 12 15 1821 24 27 42

Mos

OS

(%

)

25

39363330

Median OS: 11.1 vs 6.8 mosHR: 0.57 (95% CI: 0.45-0.73; P < .001)

100

75

50

00 3 6 9 12 15 18 21 36

MosP

FS

(%

)

25

33302724

Median PFS: 6.4 vs 3.3 mos HR: 0.47 (95% CI: 0.37-0.59; P < .001)

Conroy T, et al. N Engl J Med. 2011;364:1817-1825.

GemcitabineFOLFIRINOX


OS PFS


FOLFIRINOX vs Gemcitabine: Efficacy

Outcome FOLFIRINOX (n = 171)

Gemcitabine (n = 171)

HR(95% CI)

ORR,* % 31.6 9.4

Median PFS, mos 6.4 3.3 0.47 (0.37-0.59)P < .001

Median OS, mos 11.1 6.8 0.57 (0.45-0.73)P < .001

1-yr survival, % 48.4 20.6


*RR, FOLFIRINOX vs gemcitabine: CR, 0.6% vs 0%, PR, 31.0% vs 9.4%.

FOLFIRINOX vs Gemcitabine: AEs

Grade 3/4 AE, % FOLFIRINOX (n = 171)


P Value

Hematologic

� Neutropenia 45.7 21.0 < .001

� Febrile neutropenia 5.4 1.2 .03

� Thrombocytopenia 9.1 3.6 .04

Nonhematologic

� Fatigue 23.6 17.8 NS

� Vomiting 14.5 8.3 NS

� Diarrhea 12.7 1.8 < .001

� Sensory neuropathy 9.0 0.0 < .001

� Elevated ALT 7.3 20.8 < .001


Management of AEs: Irinotecan

� Diarrhea: early diarrhea usually transient, treat with atropine;late diarrhea (≥ 24 hrs after injection) may be life threatening, treat promptly with loperamide, fluids, and electrolytes

– Delay chemotherapy until pretreatment bowel ≥ 24 hrs without need for antidiarrhea medication; if grades 2-4 late diarrhea occurs, treat and decrease subsequent doses in current cycle

� Neutropenia: manage complications promptly with antibiotics

– Omit irinotecan during a cycle if neutropenic fever occurs or if ANC < 1500/mm3; after pt recovers to ANC ≥ 1500/mm3, subsequent doses should be reduced depending on the level of neutropenia observed

– Growth factor prophylaxis should be used with FOLFIRINOX

Irinotecan [package insert]. 2014. Slide credit: clinicaloptions.com

Management of AEs: Oxaliplatin

� Peripheral neuropathy: reduce dose if persistent grade 2 neurosensory events do not resolve; consider discontinuing oxaliplatin if persistent grade 3 neurosensory events

� GI AEs: delay treatment and reduce dose after recovery from grade 3/4 GI toxicities

� Neutropenia: delay until neutrophils ≥ 1.5 × 109/L after grade 4 neutropenia or febrile neutropenia and reduce next dose

� Growth factor prophylaxis should be used with FOLFIRINOX

� Thrombocytopenia: delay until platelets ≥ 75 × 109/L after grade 3/4 thrombocytopenia and reduce next dose

Oxaliplatin [package insert]. 2015. Slide credit: clinicaloptions.com

FOLFIRINOX vs Gemcitabine: Quality of Life

� Time until definitive deterioration > 20 points, EORTC-C30 global health status/QoL questionnaire

� Prolongation of QoL in pts treated with FOLFIRINOX compared with gemcitabine, despite greater toxicity

� Specifically, longer time to deterioration in:

– Global health status

– Physical, cognitive, and social functioning

– Symptoms such as fatigue, N/V, pain, and anorexia

Gourgou-Bourgade S, et al. J Clin Oncol. 2013;31:23-29 Slide credit: clinicaloptions.com

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12


P < .001

Mos

Det

erio

ratio

n (P

roba

bilit

y)

MPACT: Phase III Gemcitabine ± Nab -Paclitaxel in Metastatic Pancreatic Cancer

� Primary endpoint: OS

� Secondary endpoints: PFS, ORR, safety

Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

Pts with metastatic pancreatic cancer, no previous treatment for

metastatic disease, KPS ≥ 70, bilirubin

≤ ULN(N = 861)

Gemcitabine 1000 mg/m 2/wk IV +Nab-Paclitaxel 125 mg/m 2/wk IV

for 7 wks, and then on Days 1, 8, 15 Q4W(n = 431)

Gemcitabine 1000 mg/m 2/wk IV for 7 wks, and then on Days 1, 8, 15 Q4W

(n = 430)

Treat until PD

Stratified by KPS, region, liver metastasis


MPACT: Gemcitabine ± Nab -Paclitaxel in Metastatic Pancreatic Cancer—OS


Gem + Nab-P

(n = 431)

Gem (n = 430)

HR (95% CI)

Median OS, mos

8.5 6.7 0.72 (0.62-0.83)P < .001


100

80

60

40

20

00 393 6 9 12 15 18 21 24 27 30 33 36

Gemcitabine + nab-paclitaxelGemcitabine

Mos

OS

(%

)

MPACT: Gemcitabine ± Nab -Paclitaxel in Metastatic Pancreatic Cancer—PFS*

Gem + Nab-P

(n = 431)

Gem (n = 430)

HR (95% CI)

Median PFS, Mos

5.5 3.7 0.69 (0.58-0.82)P < .001


Mos

PF

S (

%)

Gemcitabine + nab-paclitaxelGemcitabine

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24

*Based on independent review.


MPACT: Gemcitabine ± Nab -Paclitaxel in Metastatic Pancreatic Cancer: Efficacy

Outcome Gem + Nab-P(n = 431)


HR(95% CI)

ORR, % 23 7 P < .001

Median PFS, mos 5.5 3.7 0.69 (0.58-0.82)P < .001

Median OS, mos 8.5 6.7 0.72 (0.62-0.83)P < .001

1-yr survival, % 35 22

Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703. Slide credit: clinicaloptions.com

MPACT: Gemcitabine ± Nab -Paclitaxel in Pancreatic Cancer—OS by Subgroup


Favors Gem + Nab-Pac Favors Gem Monotherapy


OS HR for Death (95% CI)

0.72 (0.62-0.83)

0.65 (0.53-0.79)0.81 (0.63-1.03)

0.72 (0.57-0.93)0.72 (0.59-0.88)

0.61 (0.48-0.78)0.75 (0.65-0.92)

0.59 (0.46-0.75)0.80 (0.65-0.98)

0.69 (0.59-0.81)0.86 (0.56-1.33)0.41 (0.19-0.88)0.75 (0.60-0.95)0.79 (0.61-1.04)0.50 (0.33-0.76)

1.07 (0.69-1.66)0.83 (0.61-1.12)0.61 (0.48-0.77)

All ptsAgeYounger than 65 yrs65 yrs or olderSexFemaleMaleKarnofsky performance status70-8090-100Primary tumor locationHeadOtherLiver metastasesYesNoNo. of metastatic sites123> 3Level of CA19-9Normal< 59 x ULN≥ 59 x ULN

MPACT: Gemcitabine ± Nab -Paclitaxel in Pancreatic Cancer—AEs

Event, % Gem + Nab-P(n = 421)

Gem Only(n = 402)

AE leading to death 4 4

Hematolgic AEs grade ≥ 3

� Neutropenia 38 27

� Leukopenia 31 16

� Thrombocytopenia 13 9

� Anemia 13 12

Receipt of growth factors 26 15

Febrile neutropenia 3 1

Nonhematologic AEs grade ≥ 3*

� Fatigue 17 7

� Peripheral neuropathy 17 1

� Diarrhea 6 1

*≥ 5% of pts.Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703. Slide credit: clinicaloptions.com

Frontline Regimens for Pts With Metastatic Pancreatic Cancer

FOLFIRINOX vs Gem(N = 342)[1]

Nab-Pac + Gem vs Gem(N = 861)[2]

Median age, yrs (range) 61 (25-76) 62 (27-86)

Male, % 62 57

Region (NA/WE/EE/A), % 0/100 (France)/0/0 62/9/15/14

ECOG PS/KPS(0/100, 1/80-90, 2/60-70), %

37/62/1 16/76/8

Pan tumor location (H/B/T), % 39/31/26 43/31/25

Median involved metastatic sites, n 2 2.5

ORR, % 32 vs 9 23 vs 7

Disease control rate, % 70 vs 51 48 vs 33

Median PFS, mos 6.4 vs 3.3 5.5 vs 3.7

Median OS, mos 11.1 vs 6.8 8.5 vs 6.7

1. Conroy T, et al. N Engl J Med. 2011;364:1817-1825.2. Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703. Slide credit: clinicaloptions.com

First-line FOLFIRINOX vs Gemcitabine -Based Tx: OS (Retrospective Analysis)

� EMR data from US Oncology Network June 2010 to November 2013

� Dosing based on standard doses in US Oncology system

First-line Treatment N Median OS, Mos

FOLFIRINOX 666 11

Gem only or gem + other chemotherapy*

1567 7

Gem + nab-paclitaxel 189 10

Cartwright T, et al. ASCO 2014. Abstract 4132.

OS

(%

) *Gem only, n = 1141.


1.0

0.8

0.6

0.4

0.2

00 10 20 30 40 50

Mos

P < .0001

FOLFIRINOXGem-based therapyGem + nab-paclitaxel

Metastatic Pancreatic Cancer: Cost of First-line Chemotherapy

� Direct costs in 2014 US$

� Drug costs: Centers for Medicare and Medicaid services average sales price

� Administration costs: Medicare physician fee schedule

� Costs for grade 3/4 AEs:

– 5-day hospitalization for FN

– Outpatient for nausea, vomiting, diarrhea

– Growth factor support

– Blood product transfusion

Goldstein D, et al. ASCO GI Symposium 2015. Abstract 368.

14,000

12,000

10,000

8000

6000

4000

2000

0

Mon

thly

Cos

t (U

S$)

Gem

/N

ab-P

ac

FO

LFIR

INO

X

Gem

Dos

e-M

odifi

edG

em/

Nab

-Pac

Car

bopl

atin

/P

ac

AEs AdministrationDrugs


Second -line Agents for Pancreatic Cancer

Novel Formulation: Nanoliposomal Irinotecan (MM -398)

� Nanoliposomal irinotecan

– Irinotecan: topoisomerase I inhibitor

– Liposomal formulation associated with preferentially increased tumor exposure to irinotecan

– Longer half-life, increased AUC, slower clearance, reduced volume of distribution vs free drug

– FDA approved October 2015 in combination with 5-FU and leucovorin for the treatment of pts with metastatic adenocarcinoma of the pancreas whose disease has progressed following gemcitabine-based therapy

Roy AC, et al. Ann Oncol. 2013;24:1567-1573.Drummond DC, et al. Cancer Res. 2006;66:3271-3277. Slide credit: clinicaloptions.com

NAPOLI-1: Nanoliposomal Irinotecan ±5-FU/LV vs 5 -FU/LV

� Phase III trial

Wang-Gillam A, et al. Lancet. 2016;387:545-557.

Nal-IRI 120 mg/m 2 Q3W(n = 151)

5-FU/LV2000/200 mg/m 2/wk x 4 Q6W

(n = 119)

*Combination arm added after safety data were available. Pts in 5-FU/LV arm used as controls for combination arm.

Nal-IRI 80 mg/m 2 + 5-FU/LV* 2400/400 mg/m 2 Q2W

(n = 117)

Pts with metastatic pancreatic cancer who

progressed on gemcitabine-

based therapy, KPS ≥ 70(N = 417)


NAPOLI-1: Nanoliposomal Irinotecan ±5-FU/LV vs 5 -FU/LV—Results

Tumor Response and Control

Nal-IRI + 5-FU/LV (n = 117)

5-FU/LV (n = 119)

Median PFS, mos(95% CI)

3.1(2.7-4.2)

1.5(1.4-1.8)

P = .0001

ORR, %(95% CI)

16(9.6-22.9)

1(0-2.5)

P < .001

CA19-9 reduction, % 36 12

P = .0009

Wang-Gillam A, et al. Lancet. 2016;387:545-557. Slide credit: clinicaloptions.com

NAPOLI-1: Nanoliposomal Irinotecan ±5-FU/LV vs 5 -FU/LV—OS

1.00.90.80.70.60.50.40.30.20.1

0

OS

(%

)

0 3 6 9 12 15 18Mos From Randomization

Nal-IRI + 5-FU/LV5-FU/LV

1.00.90.80.70.60.50.40.30.20.1

0O

S (

%)

0 3 6 9 12 15 18

Mos From Randomization

Nal-IRI5-FU/LV

Nal-IRI + 5-FU/LV Nal-IRI


Median OS: 6.1 vs 4.2 mos HR: 0.57 (95% CI: 0.41-0.80; P = .0009)

Median PFS: 4.9 vs 4.2 mos HR: 0.93 (95% CI: 0.71-1.21; P = .5545)



AEs, % Safety Population

Nal-IRI + 5-FU/LV(n = 117)

5-FU/LVControl(n = 134)

Any Grade Grade 3/4 Any Grade Grade 3.4

Diarrhea 59 13 26 4

Vomiting 52 11 26 3

Nausea 51 8 34 3

Decreased appetite 44 4 32 2

Fatigue 40 14 28 4

Neutropenia 39 27 5 1

Anemia 38 9 23 7

Hypokalemia 12 3 9 2

NAPOLI-1: Nanoliposomal Irinotecan ±5-FU/LV vs 5 -FU/LV in mPC: AEs


Phase III Experience: Second -line Chemotherapy With Oxaliplatin

CONKO-003 [1] PANCREOX[2]

Pts (N = 268) PD on gem tx (n = 160) Previous gem tx (n = 108)

Treatment OFF 5-FU/LV mFOLFOX6 5-FU/LV

(n = 76) (n = 84) (n = 54) (n = 54)

OS, median 5.9 mos 3.3 mos 6.1 mos 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

ORR, median NR 13.2% 8.5%

P = .36

1. Oettle H, et al. J Clin Oncol. 2014;32:2423-2429. 2. Gill S, et al. ASCO 2014. Abstract 4022. Slide credit: clinicaloptions.com

Current Treatment Sequencing for Metastatic Pancreatic Cancer


NCCN Category 1 recommended therapies in bold.

NCCN. Pancreatic adenocarcinoma. v1.2016.

FOLFIRINOX; fluoropyrimidine-based therapy

+ oxaliplatin

(PS 0/1): Gemcitabine-based (eg, gem/nab-paclitaxel,

gemcitabine)(PS 2 or less): Gemcitabine

monotherapy or BSC

??

Gemcitabine based (eg, gem/nab-paclitaxel,

gem/erlotinib )(Poor PS) Gemcitabine

(PS 0/1): Nanoliposomal irinotecan + 5-FU ;

fluoropyrimidine-based therapy(PS 2) Fluoropyrimidine alone

or BSC

(PS 0/1): Platinum-(??) based regimen if no prior exposure or

BSC

Firs

t Li

neS

econ

d Li

neT

hird

line

Emerging Agents for Pancreatic Cancer

Investigational Agents for Advanced Pancreatic Cancer

Class Examples

Novel cytotoxics� TH-302 (evofosfamide, hypoxia-activated

mustard) did not improve OS in pancreatic trial (2015)—Negative

Stromal-depleting agents� PEGPH20 (recombinant hyaluronidase)

� Vitamin D analogues� Necuparanib

Signal transduction inhibitors

� JAK inhibitors (ruxolitinib) —Negative� MM-141 (bispecific anti-IGFR/HER3 antibody)

� BTK inhibitors (ibrutinib)� Notch inhibitors (eg, demcizumab, tarextumab)—

Negative� PARP inhibitors (eg, olaparib)

Slide credit: clinicaloptions.comClinicalTrials.gov.

Investigational Immunotherapies for Advanced Pancreatic Cancer

Category Agent(s)

Vaccines � CRS-207 (mesothelin-expressing Listeria)—Negative in ECLIPSE trial combined with GVAX

� GVAX� Algenpantucel-L (‘Hyperacute’ vaccine)� Reolysin—Negative

Immune checkpoint inhibitors

� Anti–PD-1 and anti–PD-L1 antibodies (eg, PD-1 nivolumab, pembrolizumab; PD-L1, atezolizumab)� Anti–CTLA-4 antibodies (eg, tremelimumab)

� IDO inhibitors (eg, indoximod)

Anti-CD40 MAbs � Multiple agents

CCR2 inhibitors � PF-04136309

Slide credit: clinicaloptions.comClinicalTrials.gov.


Stromal-Depleting Therapies: Do They Impede Drug Delivery?

Courtesy of E. Collisson.

Stromal-Targeted Agents

� Hedgehog inhibitors[1]

� Recombinant human hyaluronidase: PEGylated-rHuPH20[2]

� Anti-CD40 monoclonal antibodies[3]

� Vitamin D analogues[4]

1. Olive KP, et al. Science. 2009;324:1457-1461.2. Provenzano PP, et al. Cancer Cell. 2012;21:418-429.3. Beatty GL, et al. Science. 2011;331:1612-1616.4. Sherman MH, et al. Cell. 2014;159:80-93. Slide credit: clinicaloptions.com

Phase II HALO -109-202: Addition of PEGPH20 to Gem/Nab -P in Metastatic PC

� Primary endpoint: PFS

� Secondary endpoints: ORR, OS, safety, PK

Pts with stage IV pancreatic cancer,

no prior tx for metastatic disease,

KPS ≥ 70%(planned N = 279)

Gemcitabine 1000 mg/m 2 +Nab-Paclitaxel 125 mg/m 2

1x/wk for 3/4 wks/cycle

PEGPH20 3 µg/kg IV 2x/wk in cycle 1 then weekly +Gemcitabine 1000 mg/m 2 +Nab-Paclitaxel 125 mg/m 2

1x/wk for 3/4 wks/cycle

Slide credit: clinicaloptions.comClinicalTrials.gov. NCT01839487.

Treat until progression, intolerable

toxicity, death, or choice to

discontinue

Phase II HALO -109-202: Results

Population, % (Responders/Total)

Gemcitabine +Nab-Paclitaxel +

PEGPH20

Gemcitabine + Nab-Paclitaxel

P Value

Total 41 (30/74) 34 (21/61) .48

HA-high 52 (12/23) 24 (5/21) .04

HA-low 37 (14/38) 38 (9/24) .96

Hingorani SR, et al. ASCO 2015. Abstract 4006.

Higher rate of thromboembolic events on PEGPH20-containing arm during first stage of enrollment (42 vs 25%); mitigated during second stage with addition of

prophylactic enoxaparin


How Immunogenic Is Pancreatic Cancer?

� Limited infiltrating effector T-cells seen in tumor specimens

� Modest mutational burden relative to more immunogenic tumors

� Minimal clinical activity observed in unselected pancreatic cancer pts with anti–CTLA-4 and anti–PD-1 monoclonal antibodies

� Can pancreatic cancers be “primed” to become more immunogenic?


von Bernstorff W, et al. Clin Cancer Res. 2001;7(3 suppl):925s-932s.Clark CE, et al. Cancer Lett. 2009;279:1-7. Royal RE, et al. J Immunother. 2010;33:828-833. Topalian S, et al. N Engl J Med. 2012;366:2443-2454. Alexandrov LB, et al. Nature. 2013;500:415-421.

Pilocytic astrocytomaALL

MedulloblastomaAML

Kidney chromophobe

ThyroidCLL

Neuroblastoma

Glioblastoma

PancreasBreast

Gliona low grade

Lymphoma B-cell

Myeloma

ProstateOvary

Kidney papillary

Kidney clear cellLiver

Uterus

Stomach

Head and neckCervix

Colorectum

Esophagus

Melanoma

Lung squamous

Lung adenocarcinoma

Bladder

1,000

100

10

1.0

0.001

0.01

0.1

Som

atic

Mut

atio

n P

reva

lenc

e (N

umbe

r M

utat

ions

per

Meg

abas

e)

Lung small cell

� Potent activation of innate and antigen-specific immune response

� Deletion of virulence genes (actA, inlB)

� Insertion of mesothelin expression cassette –validated immune target

Immunotherapy Platforms in Pancreatic Cancer

GVAX PancreasIrradiated, whole-cell tumor vaccine

CRS-207 Live-attenuated Listeria monocytogenes

GVAX

GM-CSF

Dendritic cell

Antigen uptake and activation

T-cell

Tumor antigens

Tumor celldestruction

Slide credit: clinicaloptions.comLe DT, et al. J Clin Oncol. 2015;33:1325-1333.Le DT, et al. ASCO GI 2014. Abstract 177.

∆actA ∆inlB

Phase II Study: GVAX/CRS -207 vs GVAX Alone in Metastatic Pancreatic Cancer

� Prior phase I trial of CRS-207 showed markedly improved survival (17 months) in 3 pancreatic cancer pts who had previously undergone “boost” with GVAX vaccine

� Primary objective: OS

Arm A (n = 60)

Arm B (n = 30)

20-wk treatment course*: 6 doses, Q3W

Le DT, et al. Clin Cancer Res. 2012;18:858-868. Le DT, et al. J Clin Oncol 2015;33:1325-1333. Slide credit: clinicaloptions.com

R

Pts with metastatic pancreatic cancer; failed or refused chemotherapy

24 mos of follow-up

24 mos of follow-up

*Additional courses if clinically stable

Randomized 2:1

CY/GVAX

CRS-207

Toxicities related to CRS-207: transient fevers, rigors, lymphopenia

GVAX/CRS-207 vs GVAX Alone in Metastatic Pancreatic Cancer: Results

� 2 randomized trials are evaluating GVAX/CRS-207 vs SOC chemotherapy

– ECLIPSE (NCT02004262)

– STELLAR: second- or third-line treatment ± nivolumab (NCT02243371)

Le DT, et al. J Clin Oncol 2015;33:1325-1333 Slide credit: clinicaloptions.com

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21

Mos

OS

(P

roba

bilit

y)

Cy/GVAX + CRS-207Cy/GVAX

34/45 (75.6)17/21 (81.0)

9.7 (6.1-10.5)4.6 (3.8-8.5)

P = .017 (1 sided)P = .033 (2 sided)

HR: 0.53

Events, n/N (%)

Median, Mos (95% CI)

Phase IIb ECLIPSE: GVAX/CRS -207 vs CRS-207 or Chemo Alone in mPC

� Primary endpoint: OS

� Secondary endpoints: safety, response

Pts 18 yrs of age or older

with previously treated metastatic pancreatic cancer,

ECOG PS 0/1(N = 301)

Cyclophosphamide 200 mg/m 2

Day 0 of Wks 1, 4 +GVAX Pancreas Vaccine (5 × 10e8 cells)

Day 1 of Wks 1, 4 +CRS-207 (1 × 10e9 CFU)

Wks 7, 10, 13, 16

CRS-207Wks 1, 4, 7, 10, 13, 16

Slide credit: clinicaloptions.comClinicalTrials.gov. NCT02004262.

Chemotherapy(various)

Other Signaling Pathway Targets in Pancreatic Cancer

Molecular Subtypes of Pancreatic Cancer

� Genomic analyses of 456 pancreatic ductal adenocarcinomas identified molecular subtypes of pancreatic cancer

� 32 recurrently mutated genes

– KRAS, TP53, SMAD4, CDKN2A

– 10 pathways

– KRAS, TGF-b, WNT, NOTCH, ROBO/SLIT signaling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing

� Expression analyses defined subtypes that correlate with histology:

– Squamous

– Pancreatic progenitor

– Immunogenic

– Aberrantly differentiated endocrine/exocrine (ADEX)

Bailey P, et al. Nature. 2016;531:47-52. Slide credit: clinicaloptions.com

Core Signaling Pathways Are Altered in Most Pancreatic Cancers

Regulatory Pathway or Process Genetic Alteration of ≥ 1 Gene, %

Apoptosis 100

Hedgehog signaling 100

KRAS signaling 100

Regulation of G1/S phase transition 100

TGF-b 100

Wnt/Notch 100

JNK signaling 96

Regulation of invasion 92

DNA damage control 83

Homophilic cell adhesion 79

Small GTPase-DEP signaling 79

Integrin signaling 67

Jones S, et al. Science. 2008;321:1801-1806. Slide credit: clinicaloptions.com

Agent* MOA Phase PlannedN

Comments

Ibrutinib[1]

(RESOLVE)BTK inhibitor II/III 326 Stage IV, KPS ≥ 70

Necuparanib[2] Heparin sulfate mimetic

I/II (randomized) 180 Drug engineered to reduce anticoagulant

activity

MM-141[3] Bispecific mAb: IGF-IR and

ERBB3

II (randomized) 260 Pts selected for high free serum IGF-1

Indoximod[4] IDO (indoleamine

2,3-dioxygenase)

inhibitor

Ib/II (nonrandomized)

98 IDO = enzyme that catalyzes degradation

of L-tryptophan �suppresses T cell

function (= immune checkpoint inhibitor)

Other Novel Signaling Pathway Inhibitors Under Investigation in Metastatic PDAC

*All being studied in combination with gemcitabine/nab-paclitaxel.

1. ClinicalTrials.gov. NCT02436668. 2. ClinicalTrials.gov. NCT01621243. 3. ClinicalTrials.gov. NCT02399137. 4. ClinicalTrials.gov. NCT02077881. Slide credit: clinicaloptions.com

Which Subsets of Pts Might Benefit From Specific Therapies?

� BRCA- or PALB2- mutation carriers

– Olaparib: 5/23 pts (22%) with objective response, 8/23 (35%) with stable disease > 8 wks[1]

– Veliparib: 0/16 pts with objective response, 5/16 (31%) with stable disease > 8 wks[2]

� MSI-high/mismatch repair-deficient (dMMR)

– 2 of 4 pts with dMMR pancreatic cancers showed objective response by RECIST to pembrolizumab[3]

1. Kaufman, et al. J Clin Oncol. 2015;33:244-250. 2. Lowery, et al. ASCO 2015. Abstract 358. 3. Le D, et al. ASCO 2015. Abstract 195. Slide credit: clinicaloptions.com

Conclusion

� Improving frontline and second-line treatment options

– 2 frontline regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel, have demonstrated survival benefit (vs gemcitabine alone) in phase III studies

– Evidence for second-line/salvage treatment in this disease with nanoliposomal irinotecan and 5-FU after gemcitabine-based therapy

– Fluoropyrimidine-based and gemcitabine-based regimens are additional options for second-line/salvage therapy

� Novel therapeutics

– Active area of research

– Multiple ongoing randomized phase II/III trials

– Biomarker evaluation underway Slide credit: clinicaloptions.com

Go Online for More CCO Coverage of Pancreatic Cancer!

Slides of key data from this and other programs on pancreatic cancer

CME-certified video module on pancreatic cancer with expert faculty commentary on key studies

clinicaloptions.com/oncology

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