Understanding Recent Progress in Pancreatic Cancer Clinical Implications and Perspectives

Steven Cohen, MDChief, Gastrointestinal Hematology Oncology

Fox Chase Cancer Center

Disclosures

Dr. Cohen discloses the following commercial relationships:

– Advisory Board: Celgene, Merrimack

Learning Objectives

Evaluate current options, new agents, and clinical trials for patients with metastatic pancreatic cancer

Assess treatment selection considerations and clinical trials for patients with locally advanced pancreatic cancer

Understand and manage side effects of standard and new therapies for pancreatic cancer

Activity Agenda Pancreatic cancer background Metastatic disease

– First-line– Second-line– Current options– New agents– Current clinical trials

Locally advanced/borderline– Current options– Current clinical trials

Case studies

Siegel et al, 2016.

4th Leading Cause of Cancer Death

Risk Factors

Strong:– Cigarette smoking

Weaker:– Diabetes >5 years – cause and effect?– Obesity/physical activity– Diet – inconsistent – Chronic pancreatitis

Inherited Pancreatic Cancer Syndromes

BRCA2: relative risk ~3.5 Familial atypical multiple mole melanoma

syndrome (p16 mutation): relative risk ~2 Peutz-Jeghers (STK11/LKB1): 40% risk of

pancreatic cancer by age 70 Familial pancreatitis (PRSS1) Hereditary nonpolyposis colorectal cancer

syndrome Ataxia-telangiectasia (ATM gene) Familial adenomatous polyposis relative risk 4.5

NCCN, 2016.

Pancreatic Cancer: Circa 2000

Locally advanced Resection

5-year survival

20-25%

5-year survival: <5%Metastatic: 6 moLocally advanced: 8-10 moResected for cure: 15 mo

20-25%

Metastatic

20-25%

50%

Pancreatic Cancer: 2016

Locally advanced Resection

5-year survival

20-25%

5-year survival: <5%Metastatic: ~11 moLocally advanced: 12-15 moResected for cure: 18+ mo

20-25% Metastatic

20-25%

50%

Borderlineresectable

Unresectable

??%??%

Specific Challenges

Poor survival at all stages Majority of patients have locally

advanced/metastatic disease at diagnosis Even among those who undergo resection,

vast majority (~75%) recur– Micrometastatic disease in most

Debilitating symptoms– Pain, nausea, cachexia, jaundice

Metastatic Disease

State of the Art Circa 1995

Fluorouracil (5-FU) bolus 5-FU infusion 5-FU a different way Hospice

State of the Art Circa 2000

Gemcitabine (gem) 5-FU bolus 5-FU infusion 5-FU a different way Hospice

How Did We Begin to Use Gemcitabine?

160 patients entered,126 completed pain stabilization and were randomly assigned

Gemcitabine 5-FU

Median age (yr) 62 61

Stage II/III/IV (%) 14/14/72 8/16/76

Karnofsky PS 50-70(%) 70 68

PS = performance status.Burris et al, 1997.

Results

Gemcitabine 5-FU

Clinical benefit response (%) 24 5

Antitumor response rate (%) 5 0

Median survival (mo) 5.7 4.4

Burris et al, 1997.

Gemcitabine Survival

Burris et al, 1997.

GEM (n=63, 12.7%

censored)

5-FU (n=63, 4.8% censored)

Median survival (mo) 5.65 4.41

Survival duration:

6 months 45% 31%

9 months 24% 6%

12 months 18% 2%

Log-rank test:

P=0.0025

Gemcitabine

Pro– Relatively little toxicity:

• Myelosuppression• Flu-like symptoms• Rash• Fluid retention

Con– Limited clinical activity

• Response rate (RR) ~5%

– Difficult to combine with other agents

Thus began >1 decade of “innovative” trial designs:

Gemcitabine ± “Your Drug Here”

(Props to Jordan Berlin, MD)

Phase III Trials of Gemcitabine ± Cytotoxic

# Patients

Overall SurvivalControl Arm (mo)

Overall SurvivalStudy Arm (mo)

Gem vs (gem + cisplatin) 192 6.0 7.5Gem vs (gem + oxaliplatin) 313 7.1 9.0

Gem vs (gem + 5-FU) 322 5.4 6.7

Gem vs (gem + capecitabine)

533 6.2 7.1

Gem vs (gem + pemetrexed) 565 6.3 6.2

Gem vs (gem + irinotecan) 360 6.6 6.3Gem vs (gem + exatecan) 349 6.2 6.7

Those supporting combination chemotherapy were not deterred.

Time for a meta-analysis!

Meta-Analysis ofGemcitabine-Based Doublets

Combination # HR (vs Gem Alone)

Gemcitabine plus platinum analog (cisplatin, oxaliplatin)

5 studies, N=1,248 0.85 (P=0.01)

Gemcitabine plus fluoropyrimidine (5-FU, capecitabine, S-1)

6 studies,N=1,813 0.90 (P=0.03)

Gemcitabine plus other(pemetrexed, irinotecan, exatecan)

4 studies,N=1,404 0.99 (P=0.80)

Any combination, according to performance status:

ECOG PS 0-1/KPS 90-100 5 studies, N=1,108 0.76 (P<0.001)

ECOG PS 2/KPS 60-80 5 studies,N=574 1.08 (P=0.40)

HR = hazard ratio; ECOG PS = Eastern Cooperative Oncology Group PS; KPS = Karnofsky performance status. Heinemann et al, 2008.

Thankfully our European colleagues took a different approach!

FOLFIRINOX = leucovorin/fluorouracil/irinotecan/oxaliplatin; CT = computed tomography. Conroy et al, 2010.

Prodige 4 – ACCORD 11 Trial Design

Experimental Arm: FOLFIRINOX

Conroy et al, 2010.

Patient Characteristics

NS = not significant.Conroy et al, 2010.

Safety: Hematological Adverse Events

AE = adverse event.Conroy et al, 2010.

Objective Response Rate

CR = complete response; PR = partial response; SD = stable disease; CI = confidence interval.Conroy et al, 2010.

Progression-Free Survival

PFS = progression-free survival. Conroy et al, 2010.

Survival

Conroy et al, 2011.

Quality of Life

Gourgou-Bourgade et al, 2013.

FOLFIRINOX Concern for toxicity Took some time for clinicians to become

“comfortable”– Routine growth factor support limits febrile neutropenia– Diarrhea (irinotecan), neuropathy (oxaliplatin)

Can the regimen be modified to minimize toxicity?– Elimination of 5-FU bolus– Decrease irinotecan

Can we build upon this?

Meanwhile back in the States…

MPACT Trial

Metastatic Pancreatic CancerN=861

Gemcitabine 1,000 mg/m2

weekly x 7 of 8 (cycle 1), then weekly x 3 of 4 (cycle 2 and

subsequent cycles)

Gemcitabine 1,000 mg/m2

plusnab-paclitaxel 125 mg/m2

weekly x 3 of 4

Von Hoff et al, 2013.

Baseline Characteristics

Variable nab-P + Gem(n=431)

Gem(n=430)

All Patients(N=861)

AgeMedian years (min, max) 62 (27, 86) 63 (32,

88) 63 (27, 88)

≥65 years old, % 41 44 42

Sex Male, % 57 60 58

KPS90-100, % 58 62 60

70-80, % 42 38 40

nab-P = nab-paclitaxel. Von Hoff et al, 2013.

Baseline Characteristics (cont.)

Variable nab-P + Gem(n=431)

Gem(n=430)

All Patients(N=861)

Pancreatic primary location

Head, % 44 42 43 Body, % 31 32 31Tail, % 24 26 25

Current site(s) of metastasis

Lung, % 35 43 39Liver, % 85 84 84

# of metastatic sites

1, % 8 5 62, % 47 48 47≥3, % 45 47 46

Previous Whipple Yes, % 7 7 7

Biliary stent Yes, % 19 16 17 Von Hoff et al, 2013.

Preferred Term nab-P + Gem(n=421)

Gem(n=402)

Pt with at least 1 AE leading to death, % 4 4Grade ≥3 hematologic AEa, % Neutropenia Leukopenia Thrombocytopenia Anemia

38311313

27169

12Pts who received growth factors, % 26 15Febrile neutropeniab, % 3 1

Safety

aBased on lab values; bbased on investigator assessment of treatment-related events; cgrouped term.Von Hoff et al, 2013.

Preferred Term nab-P + Gem(n=421)

Gem(n=402)

Grade ≥3 nonhematologic AEa in >5% pts, % Fatigue Peripheral neuropathyb

Diarrhea

17176

7<11

Grade ≥3 neuropathy Time to onset, median days Time to improvement by 1 grade, median days Time to improvement to grade ≤1, median days Pts who resumed nab-P, %

140212944

11329––

Safety (cont.)

aBased on investigator assessment of treatment-related events; bgrouped term.Von Hoff et al, 2013.

Gem/nab-Paclitaxel

(n=431)Gem

(n=430)HR (P Value)

Overall survival 8.5 mo 6.7 mo 0.72 (P<0.001)

1-year survival 35% 22%

Progression-free survival 5.5 mo 3.7 mo 0.69

(P<0.001)

6-month PFS 44% 25%Response rate 23% 7% (P<0.001)

Treatment duration 3.9 mo (range, 0.1-21.9)

2.8 mo (range, 0.1-21.5)

% protocol dose - nab-Paclitaxel - Gemcitabine

80.6%75.2%

–84.6%

Efficacy

Von Hoff et al, 2013.

Months

Prop

ortio

n of

Sur

viva

l

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1.0

0.00 3 6 9 12 15 18 21 24 27 30 33 36 39

Pts at Risknab-P + Gem:

Gem:431430

357340

269220

169124

10869

6740

4026

2715

167

93

41

10

10

00

nab-P + GemGem

Overall Survival (mo)

Events/N (%) Median (95% CI)

75th Percentile

333/431 (77) 8.5 (7.89–9.53) 14.8

359/430 (83) 6.7 (6.01–7.23) 11.4

HR=0.7295% CI (0.617–0.835)P=0.000015

Overall Survival

Von Hoff et al, 2013.

Months

Prop

ortio

n of

Pr

ogre

ssio

n-Fr

ee S

urvi

val 0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1.0

0.00 3 6 9 12 15 18 21 24

Pts at Risknab-P + Gem:

Gem:431430

281209

12251

6223

2410

86

44

20

00

nab-P + Gem

Gem

PFS (mo)Events/N (%)

Median (95% CI)

75th Percentile

277/431 (64) 5.5 (4.47-5.95) 9.2265/430 (62) 3.7 (3.61-4.04) 5.9

HR=0.6995% CI (0.581-0.821)P=0.000024

PFS Rate at nab-P + Gem Gem % Increase

6 months 44% 25% 76%

12 months 16% 9% 78%

PFS by Independent Review

Von Hoff et al, 2013.

Gemcitabine/nab-Paclitaxel

Toxicity– nab-Paclitaxel adds neuropathy, fatigue,

myelosuppression– Generally viewed as “less toxic” than FOLFIRINOX– However, modifications common

• Ohio State experience with every other week dosing How do clinical results of gemcitabine/

nab-paclitaxel compare to FOLFIRINOX?– Not compared head to head

Can we build on gem/nab-paclitaxel?

Modified Gem/nab-Paclitaxel: The Ohio State Experience

Chemotherapy Dose Administration FrequencyGemcitabine 1,000 mg/m2 IVPB over 30 min

given q 2 wk nab-Paclitaxel 125 mg/m2 IVPB over 30 min

Survival Analyses N Median (mo) 95% CI (mo)

Progression-free survival 47 4.8 (2.6, 7.4))

Overall survival 47 11.1 (5.3, NR)

A N (%)Grades All Grades Grade 3/4

Neutropenia 12 (25) 5 (10)Febrile neutropenia 1 (2.1) –Thrombocytopenia 9 (15) 3 (2)Neuropathy 13 (27) 1 (2)Fatigue -- 3 (6)

Krishna et al, 2015.

We teach our trainees to NEVER, EVER compare between studies…

FOLFIRINOX vs Gem/nab-Paclitaxel

QoL = quality of life.

Frontline Therapy Takeaways Two efficacious combination regimens

– FOLFIRINOX– Gemcitabine/nab-paclitaxel– No clear “best” regimen

In practice clinicians tend to:– Give FOLFIRINOX to the “best” patients– Give gemcitabine/nab-paclitaxel to “not quite as good” patients– Give single agent gemcitabine to shaky patients

NCCN Guidelines:Frontline, Good PS

Category 1– FOLFIRINOX– Gemcitabine/nab-paclitaxel– Gemcitabine/erlotinib– Gemcitabine

Category 2B– Capecitabine (single agent 5-FU)– FOLFOX

FOLFOX = leucovorin/fluorouracil/oxaliplatin. NCCN, 2016.

NCCN Guidelines:Frontline, Poor PS

Category 1– Gemcitabine– Palliative/supportive care

NCCN, 2016.

What about second-line therapy?

Platinum-based Camptothecin-based

CONKO-003 Regimen

Oettle et al, 2014.

Progression-Free Survival

Oettle et al, 2014.

Overall Survival

Oettle et al, 2014.

PANCREOX: Phase III Open-Label Study

R

Patients with advanced pancreatic cancer previously treated with gemcitabine

Stratification factors• Age (<70 & ≥70 years)• Gender• ECOG (0, 1, 2)• Liver metastases

mFOLFOX6, n=54

5FU/LV, n=54

Primary end point: PFS (RECIST)Secondary end points: ORR, OS, quality of life, Safety

4-month follow-up

Planned enrollment of 128 patients. Study was terminated early because of slow recruitment.12 centers in Canada.

Treatment until disease progression

ORR = overall response rate; OS = overall survival. Gill et al, 2014.

Progression-Free SurvivalPrimary end point, ITT

Surv

ival

Pro

babi

lity

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

Ti me ( Days)

0 42 84 126 168 210 252 294 336 378 420 462 504 546 588

OXALI _L_4918 PANCREOX Sanofi Canada 2ef 0001t . pdf 14J AN2014 9: 52 Page 1 of 1

15. 2. 1. 1 Kapl an- Mei er cur ves f or t i me t o pr ogr essi on by t r eat ment - i nt ent - t o- t r eat pat i ent s

Oxal i pl at i nNo of Pat i ent sEventCensor edMedi an Sur vi val95% CILog Rank P- Val ue: 0. 8897Hazar d Rat i o: 0. 9754p( Hazar d Rat i o) : 0. 9051

5447 ( 87. 0%)7 ( 13. 0%)92. 00 Days[ 51. 00, 154. 00]

No Oxal i p.5449 ( 90. 7. %)5 ( 9. 3. %)86. 00 Days[ 56. 00, 215. 00]

Pat i ent s at Ri sk

Oxal i pl at i n 54 42 28 23 18 13 10 10 7 6 4 4 3 2 2No Oxal i p. 54 47 28 24 21 20 15 10 6 6 3 2 1 1 1

mFOLFOX6 (n=54)

5-FU/LV (n=54)

Median (months) 3.1 2.9HR (95% CI) 1.00 (0.66-1.53)P value 0.989

Gill et al, 2014.

Overall SurvivalSecondary End Point, ITT

Surv

ival

Pro

babi

lity

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

Ti me ( Days)

0 42 84 126 168 210 252 294 336 378 420 462 504 546 588

OXALI _L_4918 PANCREOX Sanofi Canada 2ef 0006t . pdf 14J AN2014 9: 00 Page 1 of 1

15. 2. 1. 6 Kapl an- Mei er cur ves f or t i me t o deat h by t r eat ment - i nt ent - t o- t r eat pat i ent s

Oxal i pl at i nNo of Pat i ent sEventCensor edMedi an Sur vi val95% CILog Rank P- Val ue: 0. 0355Hazar d Rat i o: 1. 6819p( Hazar d Rat i o) : 0. 0334

5441 ( 75. 9%)13 ( 24. 1%)183. 00 Days[ 95. 00, 241. 00]

No Oxal i p.5429 ( 53. 7. %)25 ( 46. 3. %)298. 00 Days[ 200. 00, 507. 00]

Pat i ent s at Ri sk

Oxal i pl at i n 54 49 39 31 26 20 13 12 7 7 5 5 3 3 3No Oxal i p. 54 52 45 40 32 24 18 16 13 11 5 4 3 2 1

mFOLFOX6 (n=54) 5-FU/LV (n=54)

Median (months) 6.1 9.9

95% CI 3.2-8.0 6.7-16.9

HR (95% CI) 1.78 (1.08-2.93)

P value 024

Gill et al, 2014.

Oxaliplatin Second-Line Takeaways

CONKO with survival benefit PANCREOX a small trial Reasonable second-line option

– Neuropathy from prior nab-paclitaxel can be issue What about irinotecan-based?

MM-398, Nanoliposomal Irinotecan (nal-IRI)a

MM-398 (120 mg/m2) clinical PK show extended circulation – 70x higher AUC of total

irinotecan in blood vs conventional irinotecan (300 mg/m2)

MM-398 achieved 5x higher levels of SN-38 (active metabolite) in tumor compared to blood at 72 hours

56

~80,000 irinotecan molecules/liposome

Lipid membrane

Internal aqueous space ~ 100

nm

PEG-DSPE

Irinotecan

• Median OS of 5.2 months in phase II study of gemcitabine-refractory metastatic pancreatic cancer

aAlso known as PEP02, PharmaEngine, Inc., Taiwan.PK = pharmacokinetics. Roy et al, 2013; Ramanathan et al, 2014; Ko et al, 2013; Von Hoff et al, 2014.

NAPOLI-1 Study Design

Primary end point: Overall survival

Secondary end points: PFS, ORR, CA19-9 response, safety

Stratification factors: Albumin, KPS and ethnicityStudy was amended to add the MM-398+5-FU/LV arm once safety data on the combination became available; 63 patients had been enrolled in the original two-arm study at the time of amendment.

5-FU/LV: 2,000 mg/m2 over 24 h/

200 mg/m2 weekly x 4, q 6 w n=149

Metastatic pancreatic cancer

Received prior gemcitabine-based therapy

N= 417

MM-398: 120 mg/m2 q 3 w

n=151

R1:1:1

MM-398+5-FU/LV*: 80 mg/m2 +

2,400 mg/m2 over 46 h/400 mg/m2 q 2 w n=117

Von Hoff et al, 2014.

Safety

aNonhematologic AEs in >5% patients, %, per CTCAE version 4.Von Hoff et al, 2014.

Grade ≥3 AEsa (%)MM-398 + 5-FU/LV (n=117)

MM-398 (n=147)

5-FU/LV All (n=134)

Fatigue 14 6 4

Diarrhea 13 21 5

Vomiting 11 14 3

Nausea 8 5 3

Asthenia 8 7 7

Abdominal pain 7 8 6

Decreased appetite 4 9 2

Hypokalemia 3 12 2

Hypernatremia 3 6 2

At least 1 AE leading to death (all causes) 2 10 7

Ove

rall

Surv

ival

Pro

port

ion

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

MM-398 Monotherapy: OS

3 6 9 12 15 18 21 24 27Months

00

# at risk:149151

89109

4153

1621

910

32

12

10

10

Median (95% CI)

MM-3985-FU/LV

OS, months

4.9 (4.2-5.6)4.2 (3.6-4.9)

HR=0.99 (0.77-1.28); P=0.9416

Von Hoff et al, 2014.

MM-398 + 5-FU/LV: OS O

vera

ll Su

rviv

al P

ropo

rtio

n

Months0 3 6 9 12 15 18

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

# at risk:119117

6897

3451

1120

68

10

Median (95% CI)

MM-398 + 5-FU/LV5-FU/LV

OS, months

6.1 (4.8-8.9)4.2 (3.3-5.3)

HR=0.67 (0.49-0.92); P=0.0122

Von Hoff et al, 2014.

Tumor Response and Control

aPer RECIST version 1.1.Von Hoff et al, 2014.

MM-398 + 5-FU/LV (n=117)

5-FU/LV Post-

Amendment (n=119)

MM-398 (n=151)

5-FU/LV ALL

(n=149)

ORR (%)a 16 1 6 1

(95% CI) (9.6-22.9) (0.0-2.5) (2.2-9.7) (0-2.0)

P value <0.001 0.019

PFS rate at 12 weeks (%)

57 26 47 28

(95% CI) (47-66) (18-35) (38-55) (21-36)

Takeaways on MM-398

Is this drug any better/different than irinotecan?– “Supposed to be”– Toxicity seems comparable– Most patients had NOT received irinotecan

Approved in Fall 2015– In combination with 5-FU/LV– Prior progression on gemcitabine

Second-Line Treatment “Give whatever you did not already give”

– If FOLFIRINOX first, give gem-based– If gem/nab-paclitaxel first, give 5-FU-based

Some supportive data for FOLFOX MM-398 approved with 5-FU/LV Limited data for gem/nab-paclitaxel Single agent therapy “reasonable” since limited

combination data Ripe for a trial

NCCN Guidelines: Second-Line Therapy

Fluoropyrimidine-based chemotherapy if previously treated with gemcitabine-based therapy

Gemcitabine-based chemotherapy if previously treated with fluoropyrimidine-based therapy

NCCN, 2016.

Ongoing Cooperative Group Metastatic Trials

EA2131: A Phase I and Randomized Phase II Study of nab-Paclitaxel/Gemcitabine ± AZD1775 for Treatment of Metastatic Adenocarcinoma of

the Pancreas

Jennifer Eads, MDUniversity Hospitals Seidman Cancer Center

Case Western Reserve University

Background Combination therapy with gemcitabine and

nab-paclitaxel is standard of care for patients with metastatic pancreatic adenocarcinoma

Given that p53-deficient cancer cells rely on S and G2/M checkpoints in response to DNA damage, a Wee1 inhibitor (inhibitor of G2 checkpoint and regulator of genomic stability during S-phase) works in synergy with DNA damaging chemotherapy in enhancing tumor cell death

AZD1775 (dose level 1-100 mg PO)

nab-Paclitaxel (125 mg/m2 IV)Gemcitabine (1,000 mg/m2 IV)

D1 D8 D15 D28

Treatment-naive metastatic or unresectable locally advanced pancreatic adenocarcinoma

AZD1775 (dose level 2-125 mg PO)

Arm ADose

Level 1

Arm BDose

Level 2

If no dose limiting toxicity

Phase I

ClinicalTrials.gov.

D

CTreatment-naive metastatic pancreasadeno-carcinomaN=84

AZD1775 (RP2D, PO)

Gemcitabine 1,000 mg/m2 IV, nab-Paclitaxel 125 mg/m2 IV

nab-Paclitaxel (RP2D, IV)Gemcitabine (RP2D, IV)D1 D8 D15 D28

RANDOMIZED

Pre-Rx

Pre-Rx

D2 D25±3

Pre-Rx

Pre-Rx D2

FDG-PET, N=60FLT-PET, N=10Tumor tissue

Skin punch biopsy

Correlatives (Cycle 1 Only)

1° End point: PFS

Phase II

ClinicalTrials.gov.

A Phase IB/II Randomized Study of mFOLFIRINOX + Pegylated Recombinant Human Hyaluronidase (PEG-PH20) Versus Modified FOLFIRINOX Alone in Patients With Good Performance Status

Metastatic Pancreatic Adenocarcinoma

Ramesh Ramanathan, MDSunil Hingorani, MD

Philip Philip, MD

Hyaluronan as a Target in Pancreatic Cancer

Hyaluronic acid (HA) overexpression in >80% of pancreatic cancers

Tumors that accumulate HA develop high interstitial fluid pressure and drug resistance

HA is associated with disease progression and poor prognosis

Phase II Study Gem/nab-Paclitaxel ± PEGPH20

DMC = data monitoring committee; TE = thromboembolic; PAG = PEGPH20 with nab-P and gem; AG = nab-P and gem; LMWH = low-molecular-weight heparin.ClinicalTrials.gov.

Interim Analysis

(N=17)

(N=18)

(N=17)

(N=10)

PAG AG

High HA

Low HA

Hingorani et al, 2015.

Preliminary Data From Randomized Phase II Gem/nab-Paclitaxel ± PEGH20

Gem + nab-P + PEGH20

(n=61)Gem + nab-P

(n=45)

Objective responses (%)High hyaluronan 52 24Low hyaluronan 37 38

mPFS (mo)High hyaluronan 9.2 4.3Low hyaluronan 5.3 5.6

Hingorani et al, 2015.

PFS in HA-High Patients

Hingorani et al, 2015.

S1313 Schema(Activated 01/06/2014)

MetastaticECOG 0/1

RANDOMIZATION

mFOLFIRINOX+

PEGH20 + Aspirin 81 mg

+ LMWH 1 mg/kg(01/15/16)

mFOLFIRINOX+ Aspirin 81 mg

mFOLFIRINOX+

PEGH20+ Aspirin 81 mg

(10/10/14)

Phase Ib (run-in) Phase IIPhase I (3+3) Phase II (n=138)

ClinicalTrials.gov.

SWOGRandomized Phase II Study of Second-Line Therapy with FOLFIRI and PARPi ABT888 in

Metastatic Pancreatic Cancer

Gabriela Chiorean, MDPhilip Philip, MD

Ramesh Ramanathan, MD

FOLFIRI = leucovorin/fluorouracil/irinotecan.

Veliparib (ABT-888) and/or irinotecan (irino) was administered to 14 groups of 10 mice in a HCT116 model of human colorectal carcinoma.

Veliparib + Irinotecan Preclinical Activity

Schema

RANDOMIZE

FOLFIRI

+ABT888

N=66

FOLFIRI+

Placebo

N=66

TumorBiopsy

- Homologous recombination deficiency test (HRD)- BROCA-HR

Objectives:- Primary: OS- Secondary: RR, PFS, safety, biomarker correlatives

Statistics:Ho: OS 6 monthsHa: OS 9 months

Power 80%1-sided alpha 10% Accrual 2 yr/FU 1.5 yr

Pre-specified subgroup analysis (for HRD ≥10) Ha: OS 12 months

ClinicalTrials.gov.

Locally Advanced Disease

Borderline Resectable vsLocally Advanced Unresectable

Locally advanced Resection

5-year survival

20-25%

5-year survival: <5%Metastatic: ~11 moLocally advanced: 12-15 moResected for cure: 18+ mo

20-25% Metastatic

20-25%

50%

Borderlineresectable Unresectable

??%??%

Pancreatic Cancer 2016

Locally Advanced Disease: Rationale for Chemo/XRT

Moertel (GITSG - 1981) – randomized 194 pts (ECOG 0-3) with no distant disease and radiation encompassable to:

XRT alone (60 Gy) 40 Gy XRT/5-FU 60 Gy XRT + 5-FU XRT given as split-course 20 Gy over 2 weeks 5-FU as bolus 500 mg/m2 on first 3 days of XRT and maintenance for

2 years or progression

XRT = radiation therapy. Moertel el al, 1981.

Results

194 patients entered but after 106, XRT-alone arm inferior and accrual halted

Myelosuppression increased in high-dose XRT + 5-FU arm

XRT alone (n=25)

40 GY/5-FU (n=83)

60 GY/5-FU (n=86)

Median TTP (wk) 12.6 30.4 33.0 (P<0.01)

Median survival (wk) 22.9 42.2 40.3 (P<0.01)

TTP = time to progression.Moertel el al, 1981.

Basis of Current Paradigm

LA = locally advanced.Huguet et al, 2007.

Progression-Free Survival

CRT = chemoradiotherapy.Huguet et al, 2007.

Overall Survival

Huguet et al, 2007.

So we are moving (have moved) to chemo first…

…and consider XRT if no metastases

But what is the role of radiation therapy?

Comparison of Chemoradiotherapy (CRT) and Chemotherapy (CT) in Patients With a Locally

Advanced Pancreatic Cancer (LAPC) Controlled After 4 Months of Gemcitabine Erlotinib: Final Results of the

International Phase III LAP 07 Study

Pascal Hammel*, Florence Huguet, Jean-Luc van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Ivan Borbath, Olivier Bouché,

Jenny Shannon, Thierry André, Laurent Mineur, Benoist Chibaudel, Franck Bonnetain, and Christophe Louvet

*Hopital Beaujon (APHP), Clichy & Faculty Denis Diderot, Paris VII, France

France, Belgium, Australia, Sweden

LAP07 Study Design

1 month = gemcitabine 1,000 mg/m2/wk x 3 Erlotinib with gemcitabine: 100 mg/d

EVA

LUAT

ION

: Non

prog

ress

ive

Random 1

EVA

LUAT

ION

: Non

prog

ress

ive

Hammel et al, 2013.

LAP07 Study Design (cont.)

1 month = Gemcitabine 1,000 mg/m2/wk x 3 Erlotinib with gem: 100 mg/d

150 mg/d as single agent (maintenance)

Cape RT

Secondary surgery allowed at any timeCapecitabine 1,600 mg/m2/d +radiation therapy 54 Gy (5 x 1.8 Gy/d)

RTCape

EVA

LUAT

ION

: Non

prog

ress

ive

UntilProgression

EVA

LUAT

ION

EVA

LUAT

ION

EVA

LUAT

ION

Random 1

EVA

LUAT

ION

: Non

prog

ress

ive

RTCape

Random 2

Hammel et al, 2013.

Overall Survival by Random 2 Status

Hammel et al, 2013.

A Randomized Phase III Study of Gemcitabine in Combination With Radiation Therapy Versus Gemcitabine Alone in Patients With Localized

Unresectable Pancreatic Cancer: E4201

PJ Loehrer Sr, M Powell, H Cardenes, L Wagner, J Brell, R Ramanathan, C Crane, S Alberts, AB Benson

On behalf ofThe Eastern Cooperative Oncology Group

Survival Curves

Loehrer et al, 2011.

Ongoing Cooperative Group Trials in Locally Advanced/Borderline Disease

Preoperative mFOLFIRINOX Followed by Chemoradiation for Borderline Resectable PDAC

Initial Results From Alliance Trial A021101

Matthew H.G. Katz, Qian Shi, Syed Ahmad, Joe Herman, Robert Marsh, Eric Collisson, Lawrence Schwartz, Robert Martin, William Conway,

Mark Truty, Hedy Kindler, Andrew M. Lowy, Tanios Bekaii-Saab, Philip Philip, Dana Cardin, Noelle LoConte, Alan Venook

Enrollment: Intergroup Definition

Potentially Resectable

BORDERLINE RESECTABLE

LocallyAdvanced

Portal V TVI <180º TVI ≥180º and/or reconstructable occlusion

Unreconstructable Occlusion

Superior mesenteric A No TVI TVI <180º TVI ≥180º

Hepatic A No TVIReconstructable short-segment

TVI of any degreeUnreconstructable

Celiac trunk No TVI TVI <180º TVI ≥180

Radiographic interface between tumor and one or more of the following vessels:

TVI = tumor-vessel interface.Katz el al, 2013.

Treatment Schema

Patient With BLR PDAC (Intergroup Definition)

PRE-REGISTER

ENROLL

mFOLFIRINOX

2 months

RESTAGE

RESTAGE

SURGERY

RESTAGE

50.4g EBRT

+ CAPE

FOLLOW

GEM

2 months

Real-time centralized review of all radiographic studies and enrollment criteria

Prospective quality control of all modalities

BLR PDAC = borderline resectable pancreatic adenocarcinoma; EBRT = external beam radiation therapy. Katz el al, 2013.

RECIST Response

PRE-REGISTE

R

mFOLFIRINOX2 MONTHS

RESTAGE

RESTAGE

50.4g EBRT + CAPE

2 CR 2 CR

2 PR 2 PR

16 SD

2 PR

11 SD

3 PD

SURGERY

2 PD**

Best Response:CR: 2 (9%)PR: 4 (18%)SD: 14 (64%)PD: 2 (9%)

2 res

2 res

2 res

9 res*

1 mets identified at surgery, 1 refused surgery**1 local progression kept on protocol, 1 metastatic Katz et al, 2013.

Surgery and Pathology

Operation Na %

Type

PD/PPPD 14 93

Total 1 6.7

Vascular resection 12 80

Pathologic Variable N %b %c

R0 14 64 93

N0 10 46 67

<5% residual cells 5 22 33

pCR 2 9.1 13

aAmong patients who underwent surgical resection; bAmong patients who initiated mFOLFIRINOX (n=22);cAmong patients who underwent surgical resection (n=15).PD = pancreatoduodectomy; PPPD = pylorus preserving pancreatoduodectomy.Katz et al, 2013.

Locally Advanced Disease Overview

Field moving toward chemotherapy first Optimal chemotherapy unclear

– Most extrapolate from metastatic studies Role of radiotherapy debated in unresectable Soon to open borderline study to evaluate role of

XRT in borderline Dedicated studies are possible and ongoing

NCCN Guidelines:Locally Advanced Disease

Good PS– FOLFIRINOX– Gemcitabine– Gemcitabine/nab-paclitaxel– Other gemcitabine-based– Chemoradiation in selected patients, preferably

following an adequate course of chemotherapy Poor PS

– Gemcitabine or best supportive care

NCCN, 2016.

Case Study 1

60-year-old man in good health Few week history of abdominal pain CT scan: pancreatic body mass and liver lesions Liver biopsy: adenocarcinoma consistent with

pancreatic primary Labs unremarkable CA 19-9 2,500 PS 1

Choice of Initial Therapy?

a. FOLFIRINOXb. Gemcitabine/nab-paclitaxelc. Gemcitabine aloned. Gemcitabine + erlotinib

Case Study (cont.)

Patient received FOLFIRINOX for 6 months – Follow-up CT demonstrated progressive disease

in liver PS remains 1

What to Do Now?

a. Gemcitabineb. Gemcitabine/nab-paclitaxelc. Other gemcitabine combod. Capecitabine

Case Study 2

52-year-old man in good health Few day history of jaundice CT scan: pancreatic head lesion with abutment of

SMA, no distant disease EUS/ERCP – stent placed

– FNA: adenocarcinoma– Bilirubin normalizes

CA 19-9 500 PS 1

What to Do Next?

a. Resectionb. Gemcitabine/nab-paclitaxelc. FOLFIRINOXd. 5-FU + radiotherapy

Conclusion

We have new agents We are making progress Please continue to support clinical trials! Thank you for your attention!

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Conroy T, Desseigne F, Ychou M, et al (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med, 364(19):1817-1825. DOI:10.1056/NEJMoa1011923

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