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
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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