SLIDE 1
Putting drug development into Putting drug development into practice for Pancreatic Cancer:
Malcolm J . Moore MD
Head, Division of Medical Oncology and Hematology
Putting drug development into Putting drug development into - - PowerPoint PPT Presentation
Putting drug development into Putting drug development into - - PowerPoint PPT Presentation
Putting drug development into Putting drug development into practice for Pancreatic Cancer: Malcolm J . Moore MD Head, Division of Medical Oncology and Hematology My Mentors My Mentors Pancreatic Cancer Ductal Adenocarcinom a
SLIDE 2
SLIDE 3
Pancreatic Cancer – Ductal Adenocarcinom a
SLIDE 4
Pancreatic cancer: a major therapeutic challenge a major therapeutic challenge
Major health burden
j
– fourth leading cause of cancer death in Canada
Affects over 3000 Canadians annually
– Affects over 3000 Canadians annually
Fatal disease with 98% mortality rate1,2
– overall survival rate is among the shortest of any
solid tumour
Poor prognosis
– usually locally advanced or metastatic at diagnosis
y y g
– most patients unsuitable for surgery
SLIDE 5
Gemcitabine R i t ti St d i P ti C Registration Study in Pancreatic Cancer
Gemcitabine N = 63 5-FU N = 63 p-value
Clinical benefit response† 24% 5% 0.002 Clinical benefit response 24% 5% 0.002 Survival Median survival, months — 5.7 — 4.4 0.002 — ed a su a ,
- t s
5 1-year survival 18% 2% — Partial response 5.4% — Stable disease 39% 19% — Time to progression, months 2.3 0.9 0.0002
† Composite of measurements of pain (analgesic consumption and pain intensity), KPS and weight Burris HA, Moore MJ, Andersen J, et al. J Clin Oncol. 1997;15:2403-2413
SLIDE 6
Randomised phase III trials in pancreatic
Gem Gem + X p value
cancer (median overall survival in months)
Gem ± CPT-11 (Rocha-Lima JCO 2006) 6 6 6 3 NS Gem ± exatecan (Abou-Alfa, JCO 2006) 6.2 6.7 NS Gem ± pemetrexed (Oettle, Ann Oncol 2006) 6.3 6.2 NS Gem ± CPT 11 (Rocha Lima, JCO 2006) 6.6 6.3 NS Gem ± 5-FU bolus (Berlin, JCO 2002) 5.4 6.7 NS Gem ± capecitabine (Herrmann JCO 2007) 7 3 8 4 NS Gem ± cisplatin (Heinemann JCO 2006) 6 0 7 5 NS Gem ± capecitabine (Cunningham, ECCO 2005) 6.0 7.4 0.026 Gem ± capecitabine (Herrmann, JCO 2007) 7.3 8.4 NS Gem ± 5-FU/LV (Riess, JCO 2005) 6.2 5.9 NS
(preliminary results)
Gem ± cisplatin (Heinemann, JCO 2006) 6.0 7.5 NS Gem ± oxaliplatin (Louvet, JCO 2005) 7.1 9.0 NS Gem ± oxaliplatin (Poplin, ASCO 2006) 4.9 5.9 NS
SLIDE 7
Some key molecular abnormalities i P ti C
Oncogene Relevance
in Pancreatic Cancer
K-r K-ras
Noted in 75% to 90% of
Noted in 75% to 90% of cases cases
‘Signa
‘Signatur ture’ def ’ defect of ct of pancr pancreatic cancer ic cancer Sonic Hedg Sonic Hedgehog ehog
Cr
Crucial r ucial role in le in embry embryological signaling logical signaling Sonic Hedg Sonic Hedgehog ehog
Cr
Crucial r ucial role in le in embry embryological signaling logical signaling
Ev
Evolving r
- lving role in
le in pancr pancreas cancer eas cancer AU AURKA
Encodes Aur
Encodes Aurora-A k
- A kinase
nase
Overam
amplif plifica icatio ion - chromosomal insta mosomal instabili ility ty
Overam
amplif plifica icatio ion chromosomal insta mosomal instabili ility ty Suppressor Relevance CDKN2A/p16 CDKN2A/p16
Normal function induces cell c
Normal function induces cell cycle ar e arrest st E l E l t t h f h ff t f K
Ear
arly ev event t –en –enhances ances eff ffec ect t of K f K-r
- ras
as SMAD4 SMAD4
Encodes
Encodes tr transcription anscription factor actor; ; lost in 50% cases lost in 50% cases
Ma
May also potentia y also potentiate K-r e K-ras phenotype phenotype p53 p53
Role in
le in cell c cell cycle ar e arrest and st and apoptosis poptosis
Loss
Loss contrib contributes to tes to chromosomal insta mosomal instabil ility ity
SLIDE 8
Pancreatic Cancer: Other Molecular Targets
Growth Factor Ligand (EGF, VEGF)
Other Molecular Targets
ECM Integrin
Y Y Y Y
ras FAK Integrin Homodimer
Y Y
Src raf MEK PI3K Akt Pro-MMP EGF Receptor ERK MEK Akt Nucleus Nucleus Regulation of Gene Transcription
SLIDE 9
Gemcitabine vs MMPI: NCIC.PA1
Advanced/Metastatic Pancreas Cancer N=350
No prior chemotherapy
y
80 100
GEM = 6.67m (5.75-8.02) BAY = 3.74m (2.79-4.57) HR = 0.565 (0.44-0.73)
GEM
Stratification Prior RT
No prior chemotherapy Pe r cen t age 40 60
( ) P= 0.0001
BAY
Arm A BAY 12 9566 Arm B Gemcitabine PS 0-1 vs 2
Measurable disease 20 0.0
138 139
3.0
77 110
6.0
40 76
9.0
22 46
12.0
9 25
15.0
5 11
18.0
3 6
Arm A - BAY 12-9566 800mg bid po Arm B - Gemcitabine cycle 1 - weekly 7 of 8 weeks cycle 2 on - weekly 3 of 4 weeks
Bay 12-9566 Gemcitabine
Time (Months)
# At Risk(Bay 12-9566) # At Risk(Gemcitabine)
139 110 76 46 25 11 6
- Survival of untreated metastatic disease is short.
- Salvage of patients with crossover not possible.
- Gemcitabine needs to be included in all treatments.
SLIDE 10
Angiogenesis: CALGB 80303 Gemcitabine +/- Bevacizumab Gemcitabine +/ Bevacizumab
GEM + GEM BEVACIZUMAB (n=302) ALONE (n=300) HR p Median survival (mos) 5.8 6.1 1.03 0.78 ( ) PFS (months) 4.9 4.7 1.0 0.99 Response (%)
0.8 1.0g Bevacizumab
CR + PR 11 10 SD 36 31
5 10 15 20 25Months from Study Entry
0.0 0.2 0.4 0.6Proportion Surviving Placebo
Kindler HL et al. J Clin Oncol
Phase II : 8.7 mos median survival; 5.8 mos PFS 67% tumor control rate (PR+SD)
SLIDE 11
- NCIC. PA.3 Study Schema
Patient Population
R
Adenocarcinoma of
pancreas
No prior
chemotherapy
R A N
Gemcitabine
+
E lotinib 100/ 150 mg
chemotherapy
Measurable or non-
measurable disease
EGFR status not an
N D O
Erlotinib 100/ 150 mg
eligibility criterion
Stratification
M I
Gemcitabine
+
Center PS (0/ 1 vs 2) Stage of disease
(L Ad / M t t ti )
Z E
+
Placebo
(Loc Adv / Metastatic)
SLIDE 12
Overall Survival for All Patients
100 HR = 0.81* 95% CI (0.67, 0.97) P = 0 025
centage 60 80 100
80 P = 0.025
P er 20 40 Time (Months) 5 10 15
P ercentage 40 60
Gemcitabine + Erlotinib Median = 6.4 months
P e 20 40
1 Year Survival = 24% Gemcitabine + Placebo
20
Median = 5.9 months 1 Year Survival = 17%
Time (Months) 6 12 18 24
SLIDE 13
PA.3 Rash vs Survival
80 100
Hazard Ratio = 0.71 p< 0.0001
ta g e 60
Grade 2 Grade 1
P erc e nt 40
Grade 0 Grade 1
20 Time (Months) 5 10 15 20
Grade 0 N= 79 Grade 1 N= 108 Grade >2 N= 103 N= 79 N= 108 N= 103 Median Survival 5.29 5.75 10.51 1 year Survival 16% 11% 43%
SLIDE 14
NCIC PA 3: K-ras EGFR & Survival NCIC PA.3: K-ras, EGFR & Survival
N
569 146 d t i (26%)
N= 569; 146 adequate specimens (26%) Gem + Erlotinib Gem + Placebo HR P K-ras WT (21%) 6.1 mths 4.5 mths 0.66 0.34 K-ras Mut (79%) 6 0 mths 7 4 mths 1 07 0 78 K-ras Mut (79%) 6.0 mths 7.4 mths 1.07 0.78 EGFR Pos (47%) 5 2 mths 5 2 mths 0 90 0 32 EGFR Pos (47%) 5.2 mths 5.2 mths 0.90 0.32 EGFR Neg (53%) 8.4 mths 6.7 mths 0.60 0.08
SLIDE 15
Going forward Understanding the genetics Understanding the genetics.
Sequencing of over 20,000 protein coding
q g , p g genes in 24 pancreatic cancers.
Average number of genetic mutations was 63 Average number of genetic mutations was 63. Clustered into abnormalities in 12 core
i li h h f d i 6 signaling pathways that were found in 67- 100% of cases.
However, marked heterogeneity in individual
tumors both in which pathways affected and what the mutations in those pathways were.
Jones et al, Science 2008
SLIDE 16
SLIDE 17