1628TiP - Precision medicine for advanced pancreas cancer: Early lessons learned from negotiating the pitfalls of a molecular therapeutics trial in a poor pr...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Pancreatic Cancer
Pathology/Molecular Biology
Presenter Lorraine Chantrill
Citation Annals of Oncology (2014) 25 (suppl_4): iv546-iv563. 10.1093/annonc/mdu358
Authors L. Chantrill1, A. Johns1, C. Watson1, S. Mead1, A. Gill2, N. Pavlakis3, P. Grimison4, G.R. Asghari5, B. Li6, A. Chou1, S. Simpson1, M. Martyn-Smith1, A. Nagrial1, V. Chin1, L. Sebastian7, S. Yip8, K. Sjoquist9, S. Grimmond10, R.J. Simes8, A. Biankin11
  • 1Kinghorn Cancer Centre, Garvan Institute of Medical Research, 2010 - Darlinghurst/AU
  • 2Anatomical Pathology, Royal North Shore Hospital, St Leonards/AU
  • 3Medical Oncology, Royal North Shore Hospital, AU-2065 - St Leonards/AU
  • 4Medical Oncology, Chris O'Brien Lifehouse, Sydney/AU
  • 5Medical Oncology, Bankstown-Lidcombe Hospital, AU-2200 - Bankstown/AU
  • 6Department Of Medical Oncology, Royal North Shore Hospital, Sydney/AU
  • 7Clinical Trials Centre, University of Sydney, Sydney/AU
  • 8Nhmrc Clinical Trials Centre, University of Sydney, 2050 - Sydney/AU
  • 9Agitg, NHMRC Clinical Trials Centre, 1450 - Sydney/AU
  • 10Institute Of Cancer Sciences, University of Glasgow, Glasgow/GB
  • 11Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow/GB

Abstract

Background

The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was designed to exploit results from whole genome sequencing of pancreatic cancer collected under the auspices of the ICGC in Australia. Results showed that small subsets of patients had actionable changes in their tumor genome that could be druggable with currently available therapies. 93% of cases analyzed harbored a KRAS mutation, KRAS wildtype phenotype may enrich for susceptibility to EGFR inhibition. Her2 positivity occurs in 2% and may confer sensitivity to Her inhibition. Tumors displaying defects in the DNA damage repair pathway (∼5%) respond to DNA damaging chemotherapy.

Trial design

The IMPaCT trial is a randomized phase 2 study of first line molecularly guided therapy against standard therapy with gemcitabine in advanced pancreas cancer. We screen potential patients for the three molecular targets: Her2 amplification: trastuzumab+gemcitabine; KRAS wildtype: erlotinib+gemcitabine; and DNA damage: mitomycin C+5-fluorouracil chemotherapy. If a patient's tumour has one of these signals, they consent to be randomized to precision treatment tailored for them or standard therapy with gemcitabine. For analysis, the precision treatment arm will be considered as a whole and compared to the standard therapy arm. In our initial cohort of patients who underwent resection with curative intent, 70% recurred. Recurrence occurred on average 16m after initial surgery. Collection of tissue commenced in 2009. The first site to open was in June 2013 by which time, only 6 patients for whom we had complete sequence data and actionable mutations were still alive, so we changed the trial to screen de novo metastatic patients. Using the WGS data, we constructed a custom sequencing panel for DNA extracted from FFPE core biopsies to screen for mutations in KRAS, BRCA2, BRCA1, PALB2 and ATM. Her2 screening is undertaken with IHC and FISH. We have screened 49 cases, and found 10 with relevant molecular targets, 5 of whom were eligible. The average time from biopsy to delivery of results is 23d, an amendment has allowed patients to commence standard therapy whilst waiting for the results of molecular analysis. The IMPaCT trial is breaking new ground in the treatment of pancreas cancer.

Disclosure

All authors have declared no conflicts of interest.