OCU Andrew Ko PPT - SFBAONS Membership Update

What’s New in
Gastrointestinal
Cancers?
Pancreatic cancer: The
past, present and future
Andrew H. Ko, MD
Division of Hematology/
Oncology
GI Malignancies Program, UCSF
Estimated new cancer cases and deaths, United States,
2014 (Siegel, CA Cancer J Clin 2014;64:9-29)
Estimated new cases
Estimated deaths
Esophagus
18,170
15,450
Stomach
22,220
10,990
Small intestine
9,160
1,210
Colon
96,830
50,310
Rectum
40,000
Anus
7,210
950
Liver/intrahepatic bile duct
33,190
23,000
Gallbladder and other biliary 9,810
3,630
Pancreas
46,420
39,590
Other digestive
5,760
2,130
Total digestive system
289,610
147,260
Overall total
1,665,540
585,720
Stage
Stage classification
classification
Localized
Localized
BORDERLINE
Locally
RESECTABLE
advanced/
Locally
unresectable
advanced/
unresectable
Metastatic
Metastatic
%
% at
at
diagnosis
diagnosis
8
8
5-year
5-year survival
survival
?
31
?
8%
31
8%
61
61
2%
2%
20%
20%
Point #1: Current therapies for pancreatic cancer
produce survival times of often greater than one
year, even for patients with metastatic disease.
Treatment of Metastatic Disease:
Moving Beyond Gemcitabine Monotherapy
• Gemcitabine originally approved
in 1997 for first-line therapy of
advanced PDAC
– Median survival (vs. bolus 5-FU):
5.65 vs. 4.41 months (p=0.0025)
– 1-year survival: 18% vs. 2%
– Clinical benefit response: 23.8%
vs. 4.8% **
– RR 5.4% vs. 0%
Survival with treatment
with gemcitabine and 5-FU
gemcitabine
5-FU
** Composite of performance status, weight change, and analgesic requirement.
Burris et al, J Clin Oncol 1997.
Previous phase III trials in advanced pancreatic cancer
# Patients
Overall Survival
Control arm
(gemcitabine alone)
Overall Survival
Study arm
(combined)
Gemcitabine + cisplatin
192
6.0 months
7.5 months
Gemcitabine + oxaliplatin
313
7.1 months
9.0 months
Gemcitabine + 5-FU
322
5.4 months
6.7 months
Gemcitabine + capecitabine
533
6.2 months
7.1 months
Gemcitabine + pemetrexed
565
6.3 months
6.2 months
Gemcitabine + irinotecan
360
6.6 months
6.3 months
Gemcitabine + tipifarnib
688
6.3 months
6.0 months
Gemcitabine + erlotinib
569
6.0 months
6.4 months
Gemcitabine + bevacizumab
602
6.1 months
5.8 months
Gemcitabine + cetuximab
735
5.9 months
6.4 months
Gemcitabine + axitinib
632
8.3 months
8.5 months
Gemcitabine vs.:
FOLFIRINOX emerges as a new gold standard:
Results of the PRODIGE 4/ACCORD 11 Trial
Gemcitabine (n=171)
1,000 mg/m2 weekly x 7 of 8, then weekly x 3 of 4
Metastatic PDAC
Stratified by ECOG PS (0 vs. 1),
center, tumor location (head vs. other)
FOLFIRINOX (n=171)
Oxaliplatin 85 mg/m2
Irinotecan 180 mg/m2
leucovorin 400 mg/m2
5-FU bolus 400 mg/m2, then 2,400 mg/m2
infusional over 46 hours
6 months of chemo planned for each arm
Conroy et al, NEJM 2011.
Demographics: Representative of Real-World
Population?
Characteristic
FOLFIRINOX (n=171)
Gemcitabine (n=171)
Age (median)
61 y.o.
61 y.o.
0
37.4%
38.6%
1
61.9%
61.4%
2
0.6%
0%
Head
39.2%
36.8%
Body
31.0%
33.9%
Tail
26.3%
26.3%
15.8 / 84.2%
12.9 / 87.1%
ECOG PS
Tumor location
Biliary stent – yes/no
Conroy et al, NEJM 2011.
Efficacy Results
FOLFIRINOX
Gemcitabine
ORR
31.6%
9.4%
Median PFS
6.4 months
3.3 months
Median survival*
11.1 months
6.8 months
1 year survival
48.4%
20.6%
* HR 0.57, p<0.001. Median follow-up = 26.6 months
Conroy et al, NEJM 2011.
Survival Curves Showing Benefit of FOLFIRINOX vs.
Gemcitabine
Conroy et al, NEJM 2011.
Safety and Toxicity Results
Event
FOLFIRINOX (n=171)
Gemcitabine (n=171)
P value
Neutropenia
45.7%*
21.0%
< 0.001
Febrile neutropenia
5.4%
1.2%
0.03
Thrombocytopenia
9.1%
3.6%
0.04
Fatigue
23.6%
17.8%
NS
Vomiting
14.5%
8.3%
NS
Diarrhea
12.7%
1.8%
< 0.001
Sensory neuropathy
9.0%
0.0%
<0.001
Hematologic
Non-hematologic
*No 1o prophylaxis with G-CSF, but 42.5% on FOLFIRINOX used at some point.
Conroy et al, NEJM 2011.
QoL Assessment on FOLFIRINOX Study
•
Time until definitive deterioration >20 points, EORTC-C30 global health STATUS/QoL
questionnaire
Prolongation of QoL in patients
treated with FOLFIRINOX compared
to gemcitabine, despite greater
toxicity – longer time to
deterioration in:
– Global health score
– Physical, cognitive, and social
functioning
– Symptoms such as fatigue,
N/V, pain, and anorexia
Gourgou-Bourgade et al, J Clin Oncol 2013.
A second new first-line option for metastatic pancreatic
cancer: Gemcitabine/nab-Paclitaxel
ALBUMIN-BOUND PACLITAXEL
www.drugdiscovery.com
Phase III trial (MPACT) in Advanced Pancreatic Cancer
Pancreatic cancer
(locally advanced
or metastatic)
N = 861
Gemcitabine
1,000 mg/m2
weekly x 7 of 8 (cycle 1), then
weekly x 3 of 4 (cycle 2 and
subsequent cycles)
Von Hoff et al, NEJM 2013.
Stratification by KPS,
region, liver metastases
Gemcitabine 1,000 mg/m2
plus
nab-paclitaxel 125 mg/m2
weekly x 3 of 4
Study Results: Efficacy
Gemcitabine/
nab-paclitaxel
(n=431)
Gemcitabine
(n = 430)
8.5 months
6.7 months
35%
22%
5.5 months
3.7 months
6-month PFS
44%
25%
Response rate
23%
7%
Treatment duration
3.9 months
(range, 0.1-21.9)
2.8 months (range,
0.1-21.5)
80.6%
75.2%
--84.6%
Overall survival
One-year survival
Progression-free survival
% protocol dose
- nab-paclitaxel
- Gemcitabine
Von Hoff et al, NEJM 2013.
HR 0.72
(p<0.001)
HR 0.69
(p<0.001)
p<0.001
Gemcitabine/nab-Paclitaxel Confers Improvement
in Overall Survival
Von Hoff et al, NEJM 2013.
Study Results: Safety
Grade 3/4 AEs
Gemcitabine/
Nab-paclitaxel
Gemcitabine
Neutropenia
38%
27%
Febrile neutropenia
3%
1%
Received growth factors
26%
15%
Thrombocytopenia
13%
9%
Fatigue
17%
7%
Peripheral neuropathy
17%
1%
Diarrhea
6%
1%
Von Hoff et al, NEJM 2013.
Comparison: FOLFIRINOX vs.
Gemcitabine/nab-Paclitaxel phase III trials
FOLFIRINOX
Gemcitabine/nab-paclitaxel
Sample size
342
861
Locations
France
N America, Eastern + Western
Europe, Australia
Eligibility criteria, PS
ECOG 0-1
KPS 70-100
% head/non-head (location)
39%/61%
44%/56%
Survival, median (months)
% at one-year
11.1 months
48%
8.5 months
35%
Toxicity (grade 3/4)
Fatigue 23.6%
Neutropenia 45.7%
Fatigue 17%
Neutropenia 38%
QoL data?
Yes
No
1. Will (or should) a head-to-head comparison between these two regimens
ever be performed?
2. Can we now start thinking about sequencing regimens in pancreatic cancer?
3. Are these regimens appropriate to use in earlier-stage (e.g. adjuvant) settings?
Point #2: Although we have an expanding array of
therapeutic options for advanced pancreatic cancer,
currently there is NO established standard of care for
patients who have progressed on first-line treatment –
but some intriguing possibilities are coming down the
pike.
1st line
Gemcitabine-based
(e.g. gemcitabine, gem/erlotinib,
gem/nab-paclitaxel)
FOLFIRINOX
2nd line
(PS 0-1): FOLFOX, CapOx, maybe
FOLFIRINOX
(PS 2 or less): Capecitabine; BSC
(PS 0-1): Gemcitabine/nabpacitaxel
(PS 2 or less): Gemcitabine
monotherapy; BSC
3rd line
Current approach in treatment sequencing
for advanced pancreatic cancer
(PS 0-1): Irinotecan-based regimen if no
prior exposure
??
Regimen for refractory
advanced pancreatic cancer
Sample Median PFS/TTP
size
(months)
Median OS
(months)
OFF (oxaliplatin, 5-FU, folinic acid)1
76
3.0
6.1
FOLFOX2
46
3.7
5.8
CapOx3
41
2.3
5.4
FOLFIRI4
63
3.0
6.6
Irinotecan5
56
2.9
5.3
Capecitabine6
39
2.3
7.6
MM-398 (nanoliposomal CPT11)7
40
2.4
5.2
Erlotinib8
50
1.6
4.1
Capecitabine/erlotinib9
30
3.4
6.5
Sunitinib10
77
1.3
3.7
Selumetinib/erlotinib11
46
1.9
7.5
1. Pelzer, J Clin Oncol 2008 (abstract); 2. Berk, Hepatogastroent 2012; 3. Xiong, Cancer 2008; 4. Neuzillet, World J
Gastroent 2012; 5.Takahara, Cancer Chemother Pharmacol 2013; 6. Boeck, Oncology 2007; 7. Ko, Br J Cancer 2013;
8. Tang, J Clin Oncol 2009 (abstract); 9. Kulke, J Clin Oncol 2007; 10. O’Reilly, Oncologist 2010; 11. Ko, J Clin Oncol 2013
(abstract).
Novel Drugs in Development for Advanced/Metastatic
Pancreatic Cancer
• Next-generation cytotoxic agents
– Example: MM-398 (nanoliposomal irinotecan)
• Novel signaling pathway inhibitors
– Example: Ruxolitinib (JAK-STAT inhibitor)
• Immunotherapeutic approaches
– Example: CRS-207 (attenuated Listeria vaccine)
Novel Cytotoxic Agents: MM-398
Taking the old, and making it better
A
• Novel nanoliposomal
encapsulation of
irinotecan with
improved
pharmacokinetics and
tumour bio-distribution
Drummond et al, Cancer Res 2006
Phase III NAPOLI-1 Trial (NCT01494506)
Metastatic pancreatic cancer
N = 417
s/p gemcitabine-based
chemotherapy
MM-398
(120
mg/m2
q3 weeks
IV)
Stratified by:
- Baseline albumin
- KPS
- Ethnicity
5-FU (2000 mg/m2 IV x 24 hrs)
5-FU (2400 mg/m2 IV x 46 hrs)
+
LV 400 mg/m2 IV)
LV (200 mg/m2 IV)
+ MM-398 (80 mg/m2 IV)
Weekly x 4 of 6 weeks
Every 2 weeks
Primary endpoint: overall survival
Phase III NAPOLI-1 trial results
5-FU/LV
MM-398
MM-398 + 5-FU/LV
ORR
1%
6%
16%
CA19-9 decline > 50%
12%
31%
36%
Von Hoff, ESMO World Congress on GI Cancer, 2014 (abstract)
Where will MM-398 fit into the treatment paradigm for
advanced PDAC?
• Currently under review for FDA approval – would be the
first agent indicated for use in the salvage setting for
metastatic pancreatic cancer
• Is newer really better?
– How much better is MM-398/5-FU/LV compared to, say,
FOLFIRI?
• How will a drug in this setting be priced? What is the
cost value relative to clinical benefit?
Seeking novel targets
in pancreatic cancer
Figure adapted
from Ryan DP, N
Engl J Med 2010
Enter ruxolitinib, an inhibitor of JAK-STAT signaling
• Janus kinases (JAKs): mediate cytokine
signaling by activating STAT transcription
factors
Inflammatory
Cytokines
• Persistent activation of Stat3 is oncogenic
and prevalent in many solid tumors1
• In mouse models of pancreatic cancer, JAKSTAT signaling is required for cancer
progression2 and contributes to cancerrelated cachexia3
• Pancreatic cancer: clinical hallmarks of
weight loss, cachexia, anorexia all reflect
systemic inflammation
JAK1
JAK2, JAK3,TYK2
P
P
STAT
• Ruxolitinib reduced levels of inflammatory
cytokines and improved symptoms and
1) Hedvat, Cancer Cell 2009. 2) Lesina Cancer Cell. 2011;
4-5
3) Gilabert, J Cell Physiol 2014; 4) Verstovsek S, N Engl J Med 2012;
overall survival in myelofibrosis
28
5) Harrison C, et al. N Engl J Med 2012.
RECAP study design
Patient Eligibility
• Histologically confirmed
metastatic PDAC
• Karnofsky PS ≥60
• Failed gemcitabine
R
A
N
D
O
M
I
Z
E
D
n=64
Ruxolitinib
(15 mg BID, days 1–21)
Capecitabine
(1000 mg/m2 BID, days 1–
14)
1:1
Placebo
(BID, days 1–21)
n=63
Capecitabine
(1000 mg/m2 BID, days 1–
14)
Endpoints
• Primary: OVERALL SURVIVAL
• Secondary: Clinical benefit response, ORR (RECIST), PFS, QoL, safety
• Prospectively defined subgroup analyses, including C-reactive protein,
albumin, and performance status, were conducted to explore an
inflammation hypothesis
Entire study population (n=127)
 Med OS 136.5 v 129.5 days
 6-mo surv 42% v 35%
 HR 0.79 (p=0.25)
CRP > 13 mg/L (n=60)
 Med OS 83 v 55 days
 6-mo surv 42% vs 11%
 HR 0.47 (p=0.01)
Is C-reactive protein a reasonable predictive biomarker?
• C-reactive protein Well-characterized and sensitive marker of
systemic inflammation and tissue damage
• First acute-phase protein to be described (originally identified
in serum of patients with Strep pneumoniae – precipitates the
somatic C-polysaccharide of bacteria)
• Classic examples in predictive biomarkers in cancer therapy:
HER2 trastuzumab; KRAS cetuximab; BRAF  vemurafenib
• Advantage sof CRP:
• Blood-based rather than tissue-based
• Separate companion diagnostic test would not need to be
developed!
Dancey, Clin Cancer Res 2010.
Objective response rate (ORR) and clinical benefit
response (CBR)
Ruxolitinib
+ Cape
Placebo
+ Cape
ITT, n (%)
Overall response (CR + PR)
CR
PR
Stable disease (SD)
64
63
5 (7.8)
1 (1.6)
4 (6.3)
21 (32.8)
1 (1.6)
0
1 (1.6)
22 (34.9)
Disease control (CR + PR + SD)
26 (40.6)
23 (36.5)
Clinical benefit response*
8 (12.5)
1 (1.6)
31
29
Overall response (CR + PR)
CR
PR
2 (6.5)
0
2 (6.5)
1 (3.4)
0
1(3.4)
Stable disease (SD)
9 (29.0)
5 (17.2)
Disease control (CR + PR + SD)
11 (35.5)
6 (20.7)
Clinical benefit response*
6 (19.4)
1 (3.4)
CRP > 13 mg/L, n (%)
32
* Composite of pain, weight, and performance status
Grade 3 or 4 Adverse Events
Adverse event, n (%)
Ruxolitinib
+ Cape (n = 59)
Placebo
+ Cape (n = 60)
Mean exposure, days
99.6
67.4
Anemia
9 (15.3)
1 (1.7)
Thrombocytopenia
1 (1.7)
2 (3.3)
0
1 (1.7)
44 (74.6)
49 (81.7)
Neutropenia
Patients with any grade ≥ 3 AE
33
Recapping RECAP
• Smart trial design and drug development strategy!
 Start with enrollment of broader, unselected patient
population, but with pre-planned analysis of subgroup(s) of
interest (those with higher levels of systemic inflammation as
reflected by elevated CRP levels)
 Phase III registrational trials (JANUS-1 and -2) now ongoing,
limited to this select subgroup of patients
• Survival benefit of ruxolitinib may relate to alleviating cachexia
and inanition, as much as reducing tumor burden
Immunotherapy Platforms in Pancreatic Cancer
GVAX Pancreas
Irradiated, whole-cell tumor vaccine
GVAX
CRS-207 (Aduro Biosciences)
Live-attenuated Listeria monocytogenes
•
Dendritic Cell
GM-CSF
Potent activation of innate and antigenspecific immune response
ΔactA ΔinlB
Tumor antigens
Antigen uptake
& Activation
Tumor Cell
Destruction
T Cell
Le et al, Gastrointestinal Cancers Sympsosium 2014.
- Deletion of virulence genes (actA, inlB)
- Insertion of mesothelin expression
cassette – validated immune target
Phase 2 Study of GVAX/CRS-207 vs. GVAX Alone in
Metastatic Pancreatic Cancer
CY/GVAX
CRS-207
Arm A, n=60
24 months follow-up
Subjects with
metastatic pancreatic
cancer; failed or
refused chemotherapy
R
R
20-wk treatment Course*: 6 doses, q3w
2:1
Arm B, n=30
randomization
24 months follow-up
Primary objective: overall survival
Le et al, Gastrointestinal Cancers Sympsosium 2014.
* Additional courses
if clinically stable
Overall Survival – Full Analysis Set
Median OS, Full analysis set:
Arm A: 6.0 months
Arm B: 3.4 months
p=0.0057, HR 0.4477
Median OS, Per-protocol set (subjects
receiving at least one dose of CRS-207):
Arm A: 9.7 months
Arm B: 4.6 months
p=0.0167, HR 0.5290
Toxicities related to CRS-207: transient fevers, rigors, lymphopenia
Phase II ECLIPSE Trial (NCT02004262)
(Recruiting)
Metastatic pancreatic cancer
s/p 1+ prior lines of rx
(Stratified: 2nd line vs. 3rd-plus line)
GVAX/Cy (weeks 1, 4)
CRS-207 (weeks 7, 10, 13,
16)
CRS-207 (weeks 1, 4,
7, 10, 13, 16)
Single-agent
chemotherapy
(Physician’s choice)
Primary endpoint = overall survival
Point #3: As is frequently the case in oncology,
more does not always mean better in pancreatic
cancer (case in point: radiation).
Locally advanced pancreatic cancer:
unresolved questions
WHAT WE KNOW
WHAT WE STILL DON’T KNOW
 ChemoRT is superior to
RT alone1 (GITSG 1981)
 Does radiation improve patient
outcomes?
 Biology and outcomes are  If so, when should it be given?
different from those with
 Most studies to date have examined
metastatic disease –
initial chemoRT, with very mixed
should be studied in
results3-6
separate clinical trials, or
 There may be a better rationale for
stratified within a given
delaying radiation until later7
 Greatest impact on patient survival: eradicating
study2
micrometastatic disease
 Select out patients who develop metastases during
initial chemotherapy, avoid morbidities associated
with radiation (13-35% in select series)7-10
1. Moertel, Cancer 1981; 2. Philip, J Clin Oncol 2009; 3. J Natl Cancer Instit 1988; 4. Klaassen, J Clin Oncol 1985;
3:373. 5. Chauffert, Ann Oncol 2008; 6. Loehrer, J Clin Oncol 2011; 7. Huguet, J Clin Oncol 2007; 8. Ko, Int J
Radiat Oncol Biol Phys 2007; 9. Crane, J Clin Oncol 2011; 10. Mukherjee, Lancet Oncol 2013.
LAP-07 was the largest trial conducted for patients
with locally advanced pancreatic cancer
MEDIAN OS 16.4 mos
MEDIAN PFS 8.4 mos
After 4 months:
442 enrolled,
received induction
chemotherapy
(gemcitabine +/erlotinib)
136 continued
with chemo alone
269 randomized
133 went on to
receive chemoRT
173 dropped out
(mainly due to
progressive dz)
Hammel, J Clin Oncol 2013, 31 (suppl):LBA 4003.
MEDIAN OS 15.2 mos
MEDIAN PFS 9.9 mos
Updated LAP-07 data reveal other differences in patient outcomes
when radiation is given
Patterns of progression
Chemotherapy
(n= 125)
Chemoradiation
(n= 111)
Local progression only
58 (46%)
35 (32%)
Metastatic progression
55 (44%)
67 (60%)
Non-evaluable
12 (10%)
9 (8%)
Median time without treatment
Chemotherapy
(n= 101)
Chemoradiation
(n= 81)
3.2 months
5.2 months
Implications here that better local control, as well as more time off therapy, may translate
into better QoL -- but this assumption not confirmed by patient-reported outcomes (PRO)
Implications/unresolved issues of LAP-07
• Do we conclude from this study that
radiation should or should not be routinely
given to patients with locally advanced
pancreatic cancer?
 Do more effective systemic therapies (FOLFIRINOX,
gemcitabine/nab-paclitaxel) attenuate, or
accentuate, any survival benefit that radiation
might offer?
As chemotherapy improves to better sterilize distant disease,
locoregional control with RT may become more important… but
only up to a point
Beyond this point, chemorx
can control both distant and
locoregional disease 
therefore, importance of RT
would decline
Marks and Prosnitz, Int J Rad Onc Bio Phys, 2000; 48:625-27.
Finding the ‘sweet spot’ where both chemotherapy and radiation
impact overall survival
Locally advanced pancreatic cancer
Could FOLFIRINOX,
or gemcitabine/nabpaclitaxel, be here on
the curve?
Or here?
Gemcitabine/erlotinib
Punglia et al, N Engl J Med 2007;356:2399-405.
Other recent examples in GI oncology demonstrating
this principle that more does not always equal better
• Use of EGFR inhibitors (cetuximab,
panitumumab) in metastatic colorectal cancer
– Expanded KRAS testing shows that we may still be
overtreating some patients with this class of agents
who are unlikely to benefit!
• Adjuvant sorafenib in hepatocellular carcinoma
– No benefit yet identified in patients following
resection, ablation, or embolization
Ciardello, J Clin Oncol 2014 (suppl); 32:5s, abstr 3506;.
Bokemeyer, J Clin Oncol 2014 (suppl); 32:5s, abstr 3505.
Bruix, J Clin Oncol 2014 (suppl) 32:5s, abstr 4006.
Lencioni, J Clin Oncol 2012 (suppl); 30:4, abstr LBA154).