MetAction actionable targets in cancer metastasis from bed to bench to byte to bedside

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1 MetAction actionable targets in cancer metastasis from bed to bench to byte to bedside Kjersti Flatmark MD PhD Departments of Tumor Biology and Gastroenterological Surgery, Oslo University Hospital PIs: Gunhild Mælandsmo and Anne-Lise Børresen Dale CoPIs: Anne Hansen Ree and Kjersti Flatmark

2 The MetAction management team RCN Strategic Cancer Program 2011: Program for Publicly-initiated Clinical Cancer Studies Support projects that will increase the understanding and thereby enhance the basis for effective decision-making within cancer treatment and care Personalized cancer therapy based on genetic aberrations approved as strategic area One of the three projects that was funded was MetAction Gunhild M. Mælandsmo Department of Tumor Biology, OUH Anne Hansen Ree Department of Oncology, AUH Department of Tumor Biology, OUH Anne-Lise Børresen-Dale Department of Genetics, OUH Kjersti Flatmark Department of Gastroenterological Surgery, OUH Department of Tumor Biology, OUH

3 What is personalized cancer therapy? - inter patient heterogeneity

4 What is personalized cancer therapy? - inter tumor heterogeneity RCN call: Personalizing cancer therapy to target specific molecular aberrations in individual tumors Actionable targets Predictive biomarkers Are we doing this today?

5 What is personalized cancer therapy? - inter tumor heterogeneity Metastastic colorectal cancer Maximize efficacy Avoid unnessesary treatment

6 Personalized cancer therapy - inter tumor heterogeneity Current practice: One size fits all Tumor entity Organ Histologic subgroup Personalized therapy: The right treatment to the right patient at the right time Based on actionable target identification

7 Actionable targets in metastatic lesions - intra tumor heterogeneity

8 Actionable targets in metastatic lesions - intra tumor heterogeneity Current practice: Analysis of primary tumor Identify actionable targets in the metastatic lesion(s) to be treated

9 So to summarize Basing treatment on actionable target identification in the metastatic tumor to be treated should Benefit the patients Improved efficacy Avoid side effects from drugs that will not be efficacious Benefit society Help use drug money on the patients that will actually benefit from treatment

10 Planned activities in MetAction Activity 1 Plan and conduct n-of-1 clinical trial: Actionable Target Identification in Metastatic Cancer for Palliative Systemic Therapy Activity 2 Explorative study multilevel characterization of metastases test screening technology for n-of-1 trial identify and investigate novel actionable targets metastatic melanoma (MM), breast (BC) and colorectal carcinoma (CRC) Activity 3 Integrated computational analyses develop and test pipeline for analysis of screening data for N-of-1 trial perform integrative analysis of data from multilevel characterization of metastatic cancer develop tool for identification of optimal target-drug combinations

11 Planned activities in MetAction Activity 1 Plan and conduct n-of-1 clinical trial: Actionable Target Identification in Metastatic Cancer for Palliative Systemic Therapy Activity 2 Explorative study multilevel characterization of metastases test screening technology for n-of-1 trial identify and investigate novel actionable targets metastatic melanoma (MM), breast (BC) and colorectal carcinoma (CRC) Activity 3 Integrated computational analyses develop and test pipeline for analysis of screening data for N-of-1 trial perform integrative analysis of data from multilevel characterization of metastatic cancer develop tool for identification of optimal target-drug combinations

12 n-of-1 trial: Actionable Target Identification in Metastatic Cancer for Palliative Systemic Therapy Anne Hansen Ree Principal Investigator Department of Oncology AHUS Svein Dueland Principal Investigator Department of Oncology OUS Kjersti Flatmark National Coordinator Dep Gastroenterological Surgery OUS

13 Challenges in clinical implementation of personalized cancer therapy Global challenges Technology Biology Drugs availability of targeted drugs that show clinical efficacy related to the presence or absence of a biomarker Bioinformatics Local challenges that have to be solved Program logistics organize sample collection, transport and processing, timely analysis and interpretation of results to allow treatment start as rapidly as possible Create and educate the multidiciplinary teams that will interpret molecular findings and determine the best therapeutic intervention Data transfer, storage, processing and interpretation Economy (additional radiology, biopsies, drugs)

14 Why a clinical trial? Feasibility assessment and logistics development as an important objective Are we able to perform medium scale actionable target identification in Norway today? Can we interpret the results from such analyses? Can we implement relevant treatment? Will regulatory authorities approve such a trial? Small clinical trial 50 patients will be screened for actionable targets Two centres, Oslo University Hospital and Akershus University Hospital Metastatic disease from any solid primary tumor Disease progression on at least one standard systemic treatment regimen and no alternative standard therapy Biopsy of progressing metastatic lesion for biomarker assessment must be possible

15 MetAction N-of-1 trial Study flow chart

16 Identification of actionable targets Time line: 2-3 weeks from inclusion to treatment start Radiological identification of progressing metastatic tumor Radiology-guided core biopsy Molecular analysis Merkle E M; Radiographics 2006

17 Identification of actionable targets Screening: IonTorrent Cancer Hot Spot Panel Rapid sample processing 50 genes Sequencing depth: 2000x

18 Identification of actionable targets Screening: IonTorrent Cancer Hot Spot Panel Rapid sample processing 50 genes Sequencing depth: 2000x Actionable target validation by Section for Molecular Pathology More time consuming analyses Selected targets, validation of positive findings Tumor board evaluation Clinician, radiologist, pathologist, molecular biologist, bioinfomatician Drugs

19 Drugs and actionable targets Drug Target(s) Biomarker Validation assay cetuximab EGFR KRAS wildtype gene sequencing panitumumab EGFR KRAS wildtype gene sequencing gefitinib EGFR EGFR mutations gene sequencing erlotinib EGFR EGFR mutations gene sequencing crizotinib ALK ALK rearrangement FISH traztuzumab HER-2 HER-2 expression, ERBB2 amplification IHC, FISH lapatinib HER-2 HER-2 expression, ERBB2 amplification IHC, FISH imatinib KIT, BCR/ABL, PDGFR KIT expression, BCR/ABL translocation IHC, PCR dasatinib BCR/ABL, SRC BCR/ABL translocation PCR nilotinib BCR/ABL BCR/ABL translocation PCR vemurafenib BRAF BRAF mutation gene sequencing sunitinib PDGFR, VEGFR, KIT KIT mutation (exon 9) PCR temsirolimus mtor TSC1 or TSC2 mutation/deletion PCR everolimus mtor TSC1 or TSC2 mutation/deletion PCR ruxolitinib JAK2 JAK2 mutation PCR vandetanib RET RET mutation PCR

20 Study design n-of-1 Controversial trial design in oncology Primary end point Compare progression-free survival on study treatment (B) to be compared with PFS last standard treatment (A) If B 1.3 x A, study treatment is considered efficacious Several secondary end points

21 Project status n-of-1 trial Protocol has been approved by REK NMA Screening analysis by IonTorrent has been established 50 CRC, MM, BC metastases are being analyzed Bioinformatics processing of sequencing data Validation assays Mock -patient testrun First patient included q1 2014?

22 The MetAction project group Project employees: CLINICAL TEAM: Kjetil Boye (MD, study oncologist, OUS) Daniel Heinrich (MD, study oncologist, AHUS) Janne-Merete Torset Øien (study nurse, OUS) Christin Johansen (study nurse, AHUS) LAB TEAM: Veronika Skarpeteig (technician) Merete Thune Wiiger (technician) Einar Rødland (postdoc, bioinformatics) Olga Østrup (postdoc, molecular biology) Vegar Dagenborg (MD, PhD student) Project collaborators: COLORECTAL CANCER: MELANOMA: BREAST CANCER: Bjørn Edwin (OUS) Kathrine Røe (AHUS) Vivi Ann Flørenes (OUS) Jürgen Geisler (AHUS) Øystein Fodstad (OUS) Hans Petter Gullestad (OUS) Birgit Engsæter (OUS) Vessela Kristensen (AHUS) Olav Engebråten (OUS) Bjørn Naume (OUS) PATHOLOGY: RADIOLOGY: BIOINFORMATICS: CLINICAL TRIALS UNIT: Hege Russnes (OUS) Inger Nina Farstad (OUS) Solveig Norheim Andersen (AHUS) Lars Julsrud (OUS) Stein Harald Holmedal (AHUS) Ole Christian Lingjærde (OUS) Eiving Hovig (OUS) Svein Dueland (OUS) Kirsten Thorin Hagene (OUS) Steinar Aamdal (OUS)