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
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 rate 1,2 – 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
Gemcitabine Registration Study in Pancreatic Cancer R i t ti St d i P ti C Gemcitabine 5-FU N = 63 N = 63 p- value Clinical benefit response † Clinical benefit response 24% 24% 5% 5% 0.002 0.002 Survival — — 0.002 — Median survival, months ed a su a , o t s 5.7 5 4.4 1-year survival 18% 2% — Partial response 5.4% 0 — 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
Randomised phase III trials in pancreatic cancer (median overall survival in months) Gem Gem + X p value Gem ± exatecan (Abou-Alfa, JCO 2006) 6.2 6.7 NS Gem ± CPT 11 (Rocha Lima, JCO 2006) Gem ± CPT-11 (Rocha-Lima JCO 2006) 6 6 6.6 6 3 6.3 NS NS Gem ± pemetrexed (Oettle, Ann Oncol 2006) 6.3 6.2 NS Gem ± 5-FU bolus (Berlin, JCO 2002) 5.4 6.7 NS Gem ± capecitabine (Herrmann, JCO 2007) Gem ± capecitabine (Herrmann JCO 2007) 7 3 7.3 8 4 8.4 NS NS Gem ± 5-FU/LV (Riess, JCO 2005) 6.2 5.9 NS Gem ± capecitabine (Cunningham, ECCO 2005) 6.0 7.4 0.026 (preliminary results) Gem ± cisplatin (Heinemann, JCO 2006) Gem ± cisplatin (Heinemann JCO 2006) 6.0 6 0 7 5 7.5 NS NS Gem ± oxaliplatin (Louvet, JCO 2005) 7.1 9.0 NS Gem ± oxaliplatin (Poplin, ASCO 2006) 4.9 5.9 NS
Some key molecular abnormalities in Pancreatic Cancer i P ti C Oncogene Relevance 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 Sonic Hedg Sonic Hedgehog ehog ehog � Cr � Cr Crucial r Crucial r ucial role in ucial role in le in embry le in embry embryological signaling embryological signaling logical signaling logical signaling � Ev Evolving r olving role in le in pancr pancreas cancer eas cancer AU AURKA � Encodes Aur Encodes Aurora-A k -A kinase nase � Overam � Overam amplif amplif plifica plifica icatio icatio ion - chromosomal insta ion chromosomal insta mosomal instabili mosomal instabili ility ility ty ty Suppressor Relevance CDKN2A/p16 CDKN2A/p16 � Normal function induces cell c Normal function induces cell cycle ar e arrest st � Ear E E arly ev l l event t t t –en –enhances h h ances eff f ff ffec ect t of K t f 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
Pancreatic Cancer: Other Molecular Targets Other Molecular Targets Growth Factor Ligand (EGF, VEGF) ECM Integrin Integrin Homodimer Y Y ras FAK Y Y Y Y Src raf EGF Receptor PI3K Pro-MMP MEK MEK Akt Akt ERK Nucleus Nucleus Regulation of Gene Transcription
Gemcitabine vs MMPI: NCIC.PA1 y Advanced/Metastatic Pancreas Cancer 100 GEM = 6.67m (5.75-8.02) GEM N=350 BAY = 3.74m (2.79-4.57) 80 HR = 0.565 (0.44-0.73) ( ) No prior chemotherapy No prior chemotherapy Pe r cen t age P= 0.0001 60 BAY Stratification 40 Prior RT PS 0-1 vs 2 20 Measurable disease 0 0.0 3.0 6.0 9.0 12.0 15.0 18.0 138 77 40 22 9 5 3 Arm A - BAY 12-9566 Arm A BAY 12 9566 Arm B Gemcitabine Arm B - Gemcitabine 139 139 110 110 76 76 46 46 25 25 11 11 6 6 Time (Months) 800mg bid po cycle 1 - weekly 7 of 8 weeks # At Risk(Bay 12-9566) cycle 2 on - weekly 3 of 4 weeks # At Risk(Gemcitabine) Bay 12-9566 Gemcitabine • Survival of untreated metastatic disease is short. • Salvage of patients with crossover not possible. • Gemcitabine needs to be included in all treatments.
Angiogenesis: CALGB 80303 Gemcitabine +/ Bevacizumab Gemcitabine +/- Bevacizumab GEM + GEM BEVACIZUMAB ALONE HR p (n=302) (n=300) Median 5.8 6.1 1.03 0.78 survival (mos) ( ) PFS (months) 4.9 4.7 1.0 0.99 Response (%) 1.0 0.8 Bevacizumab Proportion Surviving g 0 Placebo 0.6 CR + PR 11 10 0.4 0.2 SD 36 31 0.0 0 5 10 15 20 25 Months from Study Entry Phase II : 8.7 mos median survival; 5.8 mos PFS 67% tumor control rate (PR+SD) Kindler HL et al. J Clin Oncol
NCIC. PA.3 Study Schema Patient Population R R � Adenocarcinoma of Gemcitabine pancreas A � No prior + N N chemotherapy chemotherapy E lotinib 100/ 150 mg Erlotinib 100/ 150 mg � Measurable or non- D measurable disease O � EGFR status not an eligibility criterion M Gemcitabine I Stratification + + Z � Center Placebo � PS (0/ 1 vs 2) E � Stage of disease (L (Loc Adv / Metastatic) Ad / M t t ti )
Overall Survival for All Patients 100 100 HR = 0.81* 80 95% CI (0.67, 0.97) centage 60 P = 0 025 P = 0.025 er P 40 80 20 0 0 5 10 15 Time (Months) 60 ercentage Gemcitabine + Erlotinib Median = 6.4 months e P P 40 40 1 Year Survival = 24% Gemcitabine + Placebo 20 20 Median = 5.9 months 1 Year Survival = 17% 0 0 0 6 12 18 24 Time (Months)
PA.3 Rash vs Survival 100 Hazard Ratio = 0.71 p< 0.0001 80 Grade 2 60 e g ta Grade 1 Grade 1 nt e erc Grade 0 P 40 20 0 0 0 5 10 15 20 Time (Months) Grade 0 Grade 1 Grade >2 N= 79 N= 79 N= 108 N= 108 N= 103 N= 103 Median Survival 5.29 5.75 10.51 1 year Survival 16% 11% 43%
NCIC PA 3: K-ras EGFR & Survival NCIC PA.3: K-ras, EGFR & Survival � N � N= 569; 146 adequate specimens (26%) 569 146 d t i (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%) K-ras Mut (79%) 6 0 mths 6.0 mths 7 4 mths 7.4 mths 1.07 1 07 0 78 0.78 EGFR Pos (47%) EGFR Pos (47%) 5.2 mths 5 2 mths 5 2 mths 5.2 mths 0 90 0.90 0 32 0.32 EGFR Neg (53%) 8.4 mths 6.7 mths 0.60 0.08
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 signaling pathways that were found in 67- i li h h f d i 6 100% 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
Drug Development Drug Development – the future the future � This is not CML or GIST. � Targeting individual pathways such as EGFR, hedgehog less likely to be successful than hedgehog less likely to be successful than focussing on downstream effects. � Multiple agents likely to be needed. M l i l lik l b d d � Therapy needs to be individualized � We need to link biology and genomics with therapy to move forward. therapy to move forward.
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