Pancreatic Ductal Adenocarcinoma (PDAC) The Clinical Problem and Current Drug Treatment Duncan Jodrell Professor of Cancer Therapeutics CRUK Cambridge Institute Li Ka Shing Centre, University of Cambridge
The clinical problem • The 10 th most common cancer, but the 4 th most common killer • Using current trends in outcome, PDAC is projected to become the 2nd most common cancer killer by 2030 • Why? – Presents late: • Non specific symptoms; weight loss, epigastric pain • only 10-20% of patients suitable for operation at presentation (usually those presenting with obstructive jaundice) – Considered to be relatively resistant to chemotherapy (average survival < 12 months, following a diagnosis of metastatic disease) – Debilitating effects often preclude aggressive treatment: • Pain, anorexia, biliary obstruction, duodenal obstruction, cachexia
Patients present “late”, often with extensive metastatic and rapidly progressing disease 7/11/13 17/01/14 ~ 2 month interval between scans
Summary overview of survival and resection percentages of different groups of patients with pancreatic cancer. Gillen S, Schuster T, Meyer zum Büschenfelde C, Friess H, et al. (2010) Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages. PLoS Med 7(4): e1000267. doi:10.1371/journal.pmed.1000267 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000267
Established treatments for advanced disease • Gemcitabine ( Burris et al, JCO, 1997 ) – Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU treated patients (P = .0022) – The median survival durations were 5.65 and 4.41 months for gemcitabine treated and 5-FU treated patients, respectively (P = .0025). – The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. • Gemcitabine plus erlotinib • Gemcitabine plus capecitabine • Gemcitabine plus nab-paclitaxel (2013) • Not to mention multiple, negative GEM plus X Phase III trials! • FOLFIRINOX (2013)
Gemcitabine plus erlotinib (Moore et al, 2007 ) 569 patients HR was 0.82 for survival (p=0.038) This translates into a median survival advantage of 0.33 months Q: can molecular phenotyping or genotyping identify the small number of patients who benefit from erlotinib ? e.g. “EGF addicted” tumours
Gemcitabine plus capecitabine (Cunningham et al, 2009 ) 533 patients HR (survival) = 0.86 (p=0.08) compared to gemcitabine alone 935 patients were included in a meta-analysis of 3 studies, confirming the HR of 0.86 (p=0.02) On this basis, GEMCAP became the standard of care in the UK
Gemcitabine/nab-paclitaxel (Abraxane TM) (Von Hoff et al, 2013 ) The positive outcome of the Phase III (MPACT) study was presented at ASCO 2013 861 patients HR was 0.72, leading to an improvement in overall survival of 1.8 months
FOLFIRINOX (Conroy et al, 2013 ) 342 patients HR of 0.57, leading to a survival advantage of 4.3 months 2 weekly regimen: Oxaliplatin (85 mg m -2 ) Irinotecan (180 mg m -2 ) Folinic acid (400 mg m -2 ) Bolus 5FU (400 mg m -2 ) Infusional 5FU (2400 mg m -2 over 46 hours) ….. plus G -CSF (filgastrim) s.c. in 43%
Gemcitabine Control Experimental Arm GEM CAP Response: 12% Response: 19% Median PFS: 3.9 months Median PFS: 5.3 months OS: 6.2 months OS: 7.1 months FOLFIRINOX Response: 9% Response: 32% Median PFS: 3.3 months Median PFS: 6.4 months OS: 6.8 months OS: 11.1 months GEM/nab-paclitaxel Response: 7% Response: 23% Median PFS: 3.7 months Median PFS: 5.5 months OS: 6.7 months OS: 8.5 months
Is FOLFIRINOX just too toxic? mFOLFIRINOX 2 weekly regimen: Oxaliplatin (85 mg m -2 ) Irinotecan ( 135 mg m -2 ) Folinic acid (400 mg m -2 ) Omit Bolus 5FU (400 mg m -2 ) Infusional 5FU (2400 mg m -2 over 46 hours) ….. plus G -CSF prophylactically
FOLFIRINOX or gemcitabine/nab-paclitaxel? What will the community decide? According to clinicaltrials.gov (2014): FOLIRINOX plus x 3 studies Gem/nab-p plus x 12 studies
Summary overview of survival and resection percentages of different groups of patients with pancreatic cancer. Gillen S, Schuster T, Meyer zum Büschenfelde C, Friess H, et al. (2010) Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages. PLoS Med 7(4): e1000267. doi:10.1371/journal.pmed.1000267 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000267
Whipple’s Procedure Removal of: the distal half of the stomach (antrectomy), the gall bladder and its cystic duct (cholecystectomy), the common bile duct (choledochectomy), the head of the pancreas, the duodenum, the proximal jejunum, and the regional lymph nodes. Reconstruction consists of: attaching the pancreas to the jejunum (pancreaticojejunostomy) to allow digestive juices to flow into the gastrointestinal tract attaching the hepatic duct to the jejunum (hepaticojejunostomy) to allow bile respectively to flow into the gastrointestinal tract attaching the stomach to the jejunum (gastrojejunostomy) to allow food to pass through.
Adjuvant chemotherapy studies: • ESPAC-1 : demonstrated that bolus 5FU/folinic acid (FUFA) is active adjuvant therapy – The 5-year survival rate was 21% among patients who received chemotherapy and 8% among patients who did not receive chemotherapy (P=0.009). (Neoptolemos et al, NEJM, 2004 ). • ESPAC-3 : demonstrated that gemcitabine and FUFA are equivalent as adjuvant therapy • ESPAC-4 ( ongoing (in ampullary, completed recruitment in adeno) NIHR trial ) – GEMCAP vs GEM as adjuvant therapy – In advanced disease, GEMCAP is associated with an increased response rate (19% vs 12%) and survival (HR 0.86) • APACT: Gem/nab-paclitaxel versus Gem alone (Celgene sponsored study) – Andrew Biankin = translational lead, Jeff Evans = UK clinical lead • What about FOLFIRINOX or mFOLFIRINOX? Is anyone asking the question? – Krankenhaus Nordwest – Neoadjuvant/adjuvant FOLFIRINOX versus adjuvant gemcitabine (SoC)
Summary overview of survival and resection percentages of different groups of patients with pancreatic cancer. Gillen S, Schuster T, Meyer zum Büschenfelde C, Friess H, et al. (2010) Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages. PLoS Med 7(4): e1000267. doi:10.1371/journal.pmed.1000267 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000267
Summary overview of survival and resection percentages of different groups of patients with pancreatic cancer. PRICKLE if mFOLFIRINOX mFOLFIRINOX borderline or Gem SIEGE trial (GemNab-P) ± chemoRT Gem mFOLFIRINOX 2 nd Line APACT Gem vs GemNab-P Clinical Trials Capecitabine
How does nanoparticle albumin – bound (nab)- paclitaxel potentiate gemcitabine activity? PDAC is a stromal-rich tumour and it expresses high levels of secreted protein acidic and rich in cysteine (SPARC) One hypothesis was that SPARC may act as an albumin-binding protein, sequestering the nab-paclitaxel, to concentrate the drug intra-tumourally SPARC expression was therefore suggested to be a potential predictive biomarker for nab-paclitaxel activity (Von Hoff, J. Clin Oncol. 2011) … but subsequently, review of the MPACT Phase III data discounted this (Hidalgo, World GI, 2014)markers
Gemcitabine metabolism CDA = Cytidine deaminase dCK = deoxycytidine kinase UMP-CMPK = cytidine monophosphate kinase Variability in CDA activity and CDA polymorphisms have both been associated with CDA variability in response and toxicity following gemcitabine dFdU administration Inactive Gemcitabine (dFdC) dFdCTP dCK, UMP-CMPK1,2 Active - Incorporated into DNA
Reverse translation: We use the KPC model of pancreatic ductal adenocarcinoma in many of our studies STOP Kras LSL.G12D G12D * Kras I II III IVa IVb p53 LSL·R172H STOP KPC R172H * AUG p53 I II III IV V VI VII VIII IX X XI PdxCre Pdx Pro. Cre tg Hingorani et al, Cancer Cell. 2005; 7(5):469-83.
KRAS (92%) and TP53 (50%) are the most common mutations in the TCGA database Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets Agnieszka K. Witkiewicz, et al. Nature Communications 6, 6744 doi:10.1038/ncomms7744
KPC mice develop pre-malignant (PanIN) and malignant (adenocarcinoma) lesions identical to human PDAC Mouse Human Human Mouse PanIN1b PanIN1a PanIN3 PanIN2 Met PDA
Nab-paclitaxel plus gemcitabine was more active than either single agent alone in the KPC model Frese et al. Cancer Discovery, 2012
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