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Update on Pancreatic CancerFarshid Dayyani, MD, PhDAssociate Clinical Professor, Departmentof Medicine, UC Irvine School of MedicineFebruary 2nd, 2018

Overview Current Systemic Treatments Adjuvant Chemotherapy in resected PDAC Neoadjuvant Treatment Metastatic Disease New Developments

Principles of MultidisciplinaryTreatment Based on Resectability

Q: Which Patients Need Chemotherapy?A: All Patients!!! Resectable: Before ( neoadjuvant) OR after surgery (adjuvant) Borderline resectable / locally advanced Neoadjuvant, followed by surgery if resectable Metastatic Combo or single agent based on patient’s statusImportant: Discuss Goals of Chemotherapy (potentiallycurable vs life extending vs palliative) ahead of time

Chemotherapy Side Effects Q: If the patient is symptomatic from the cancer (abdominal pain, anorexia,nausea/vomiting, weight loss etc), and the chemo shrinks the tumor, what willhappen?A: The patient actually starts feeling better!!! First symptom to improve isusually the pain.Main side effects NumbnessTinglingCytopenia

Adjuvant ChemotherapyComparison of adjuvant gemcitabine and capecitabine withgemcitabine monotherapy in patients with resected pancreatic cancer(ESPAC-4): a multicentre, open-label, randomised, phase 3 trialProf John P Neoptolemos, MD, Prof Daniel H Palmer, PhD, Prof Paula Ghaneh, MD, Eftychia E Psarelli, MSc, Juan W Valle, MD,Christopher M Halloran, MD, Olusola Faluyi, MD, Derek A O'Reilly, MD, Prof David Cunningham, MD, Prof Jonathan Wadsley, MD,Suzanne Darby, MD, Prof Tim Meyer, MD, Roopinder Gillmore, MD, Alan Anthoney, MD, Pehr Lind, MD, Bengt Glimelius, MD, StephenFalk, MD, Prof Jakob R Izbicki, MD, Gary William Middleton, MD, Sebastian Cummins, MD, Paul J Ross, MD, Harpreet Wasan, MD, AlecMcDonald, MD, Tom Crosby, MD, Yuk Ting Ma, MD, Kinnari Patel, MD, David Sherriff, FRCR, Rubin Soomal, MD, David Borg, MD,Sharmila Sothi, MD, Prof Pascal Hammel, MD, Thilo Hackert, MD, Richard Jackson, PhD, Prof Markus W Büchler, MDThe LancetVolume 389, Issue 10073, Pages 1011-1024 (March 2017)DOI: 10.1016/S0140-6736(16)32409-6Copyright 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CCBY-NC-ND license Terms and Conditions

ESPAC-4Copyright 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CCBY-NC-ND license Terms and Conditions

(Phase III)(Phase II)1 Endpoint: TTF2 Endpoint: DCR in pts whocompleted induction

LAPACT Trial N 101 pts includedN 60 (59%) completed inductionN 93 evaluable; DCR 82% (n 33 PR)N 14 (13.9%) underwent surgery (R0, n 4;R1, n 6; R2, n 1; 3 missing)

Recurrent/MetastaticmOS: 11.1mo vs 6.8moORR: 31.6% vs 9.4%N Engl J Med 2011;364:1817-25.

Recurrent/Metastatic- 1st LinemOS: 11.1mo vs 6.8moORR: 31.6% vs 9.4%N Engl J Med 2011;364:1817-25.

Recurrent/Metastatic- 1st LinemOS: 8.5mo vs 6.7moORR: 23% vs 7%N Engl J Med 2013;369:1691-703.

Recurrent/Metastatic- 2nd LineProportion of Surviving PtsNAPOLI-1: Nanoliposomal Irinotecan 5-FU/LV vs 5-FU/LV—OS1.00.90.80.70.60.50.40.30.20.10Nal-IRI 5-FU/LV5-FU/LVmOS: 6.2mo vs 4.2moORR: 16% vs 1%03691215Wang-Gillam A, et al. Lancet. 2016;387:545-557.Slide credit: clinicaloptions.com

New Directions in the Treatment ofPancreatic CancerInvestigational Agents for Advanced Pancreatic CancerClinicalTrials.gov.Slide credit: clinicaloptions.com

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Primary Efficacy Endpoint: PFS (Stages 1 & 2)

Secondary Endpoint: Progression-Free Survival HA-High (Combined Stages 1 & 2)

This Trial is currently available at UC Irvine(UCI 15-94)

New Trials for Pancreatic Cancer at UCI UCI-17-103: Irinotecan liposomal injection (lip-IRI)-containingRegimens in Patients with Previously Untreated, MetastaticPancreatic Adenocarcinoma UCI-17-109: Durvalumab /- Treme in combination withGemcitabine and Abraxane in First Line Pancreatic DuctalAdenocarcinoma UCI-15-94: PEGPH20 in combination with Gemcitabine andAbraxane in First Line Pancreatic Ductal Adenocarcinoma withHyaluronan-HighClinicalTrials.gov.Slide credit: clinicaloptions.com

SummaryImproving options for all treatment settings “Chemo for everybody” Adjuvant: Gem-Cap x 6 months LAPC: no randomized phase 3 trial (yet); gemcitabine/nab-paclitaxel (LAPACT phase II) and FOLFIRINOX have shown activity Metastatic: 2 first-line regimens, FOLFIRINOX and gemcitabine/nabpaclitaxel, have demonstrated survival benefit (vs gemcitabinealone) in phase III studies Second-line/salvage treatment benefit with nanoliposomalirinotecan and 5-FU after gemcitabine-based therapyNovel therapeutics Active area of research Multiple ongoing randomized phase II/III trials at UCI

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