Co Contempo porary Treatment Appr pproache ches s for r - PowerPoint PPT Presentation

Co Contempo porary Treatment Appr pproache ches s for r Patients s with h Pancr ncreatic c Ca Cance ncer r Philip A Philip, MD, PhD, FRCP Kathryn Cramer Endowed Chair in Cancer Research Professor of Oncology and Pharmacology Leader, GI and Neuroendocrine Oncology Karmanos Cancer Institute Wayne State University Detroit, Michigan

Sequencing therapy in metastatic disease First-line treatment • “Younger older” patients • Patients who have received prior neoadjuvant therapy Later-line treatment (Nal-IRI)

Sequencing therapy in metastatic disease First-line treatment • “Younger older” patients • Patients who have received prior neoadjuvant therapy Later-line treatment (Nal-IRI)

Co Contempo porary Treatment Appr pproache ches s for r Patients s with h Pancr ncreatic c Ca Cance ncer r Philip A Philip, MD, PhD, FRCP Kathryn Cramer Endowed Chair in Cancer Research Professor of Oncology and Pharmacology Leader, GI and Neuroendocrine Oncology Karmanos Cancer Institute Wayne State University Detroit, Michigan

Disclosures Advisory Committee ASLAN Pharmaceuticals, BioLineRx, Caris Life Sciences, Celgene Corporation, Eisai Inc, Erytech Pharma, Halozyme Inc, Ipsen Biopharmaceuticals Inc, Merck, TriSalus Life Sciences Consulting Agreements AbbVie Inc, Merck, Rafael Pharmaceuticals Inc, TriSalus Life Sciences Contracted Research Astellas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, BeiGene, BioLineRx, Boston Biomedical Inc, Bristol-Myers Squibb Company, Caris Life Sciences, Celgene Corporation, Halozyme Inc, Incyte Corporation, Lilly, Novartis, Novocure, QED Therapeutics, Rafael Pharmaceuticals Inc, Roche Laboratories Inc, Taiho Oncology Inc Data and Safety Monitoring ASLAN Pharmaceuticals, Blueprint Medicines, Erytech Pharma, Board/Committee Lexicon Pharmaceuticals Inc Speakers Bureau Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Celgene Corporation, Ipsen Biopharmaceuticals Inc, Merck

In Incr cremen emental imp mprovemen ement in systemi emic c ther erapies es that are e largel ely y based sed on cy cytotoxic c drugs gs 1 year 6 mon Gemcitabine 1 Gemcitabine Gemcitabine nab -Paclitaxel 3 FOLFIRINOX 4 POLO 5 Erlotinib 2 1. Burris HA 3 rd , et al. J Clin Oncol. 1997;15(6):2403-2413. 1 2. Moore MJ, et al. J Clin Oncol. 2007;25(15):1960-1966. 3. Von Hoff DD, et al. N Engl J Med. 2013;369(18):1691-1703. 4. Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825; 5. Golan et al, NEJM, 2019.

Me Metastatic Pancrea eatic Cancer: er: AS ASCO Cl Clinical P Practice G e Guidel eline Up e Update In Initial As Asses essmen ent • The goals of care • Include discussion of an advance directive • Patient preferences • Support systems should be discussed with every patient with metastatic pancreatic cancer and his or her caregivers Sohal D et al. J Clin Oncology, 2018, 36(24):2545-2556

Me Metastatic Pancrea eatic Cancer: er: AS ASCO Cl Clinical P Practice G e Guidel eline Up e Update Tr Treatment recommendations • ECOG PS 0-1 • ECOG PS of 2, • Favorable comorbidity profile or FOLFIRINOX A comorbidity profile that precludes more • Patient preference • Gem aggressive regimens and who wish to • Support system for aggressive medical pursue cancer-directed therapy . therapy • ECOG PS >3 • ECOG PS 0-1 or • Favorable comorbidity profile Gem Supportive with poorly controlled comorbid • • Patient preference Nab- care conditions despite ongoing active paclitaxel • Support system for a relatively medical care aggressive medical therapy Sohal D et al. J Clin Oncology, 2018, 36(24):2545-2556

Se Second-Line Line Oxalipla aliplatin tin-Ba Based R Regi gimens: Con Confl flicting R g Results F From om P Phase I III T Trials CONKO-003 PANCREOX Patients (N = 268) PD on Gem Therapy (n = 160) Previous Gem Therapy (n = 108) OFF 5-FU/LV mFOLFOX6 5-FU/LV Treatment (n = 76) (n = 84) (n = 54) (n = 54) 5.9 months 3.3 months 6.1 months 9.9 months OS, median HR 0.66 (95% CI, 0.48 – 0.91) HR 1.78 (95% CI, 1.08 – 2.93) P = .01 P = .02 2.9 months 2.0 months 3.1 months 2.9 months PFS, median HR 0.68 (95% CI, 0.50 – 0.94) HR 1.00 (95% CI, 0.66 – 1.53) P = .02 P = .99 Oettle H, et al. J Clin Oncol . 2014;32(23):2423-2429. Gill S, et al. J Clin Oncol . 2016;34(32):3914-3920.

Phase 3 trial of Nano-liposomal irinotecan + 5-FU/LV as 2 nd -line therapy for metastatic pancreatic cancer (NAPOLI-1) Primary endpoint: OS Secondary endpoints: PFS, ORR, CA19-9 response, safety Nal-IRI (120 mg/m 2 Q3W) n=151 • Metastatic pancreatic cancer 5-FU/LV R • Received prior (2000 mg/m 2 over 24 h / 200 mg/m 2 weekly Q6W) gemcitabine-based n=149 therapy • N=417 Nal-IRI + 5-FU/LV (80 mg/m 2 + 2400 mg/m 2 over 46 h / 400 mg/m 2 Q2W) n=117 Stratification: Albumin, KPS, ethnicity Wang-Gillam et al. Lancet 2016;387:536

NAP NAPOLI LI-1: 1: Stu tudy y outcome me Grade 3 or 4 Toxicity Nano-liri-5FU/LCV 5FU/LCV Diarrhea 13 % 4% Vomiting 11% 3% Appetite 4% 2% Fatigue 14% 4% Neutropenia 27% 1% Wang-Gillam A, et al. Lancet 2016; Update Wang-Gillam, et al, JCO, 2016, 34:abstract 417

NA NAPOX: X: movin mo ing Na Nal-Ir Iri to to the front nt line Nal-Iri/5FU/LV/Oxaliplatin Cohort A Phase III Nal-Iri 50 mg/m 2 70/2400/400/60 5FU 2,400 mg/m 2 Oxaliplatin 60 mg/m 2 Q 2 weeks Cohort B R N = 750, Overall Survival 5 0/2400/400/60 Dose exploration Gemcitabine/ Nab-paclitaxel & Cohort C No grade 3 or higher standard 50/2400/400/85 expansion fatigue or neuropathy NCT04083235 Cohort D 55/2400/400/70 Wainberg et al, ESMO GI, 2019

PR PRODIGE 24/CC CCTG PA.6: Ph Phas ase III ad adjuvan ant trial al in res resec ected ed pa pancr ncreatic c c cance ncer Modified FOLFIRINOX R Oxaliplatin 85 mg/m 2 A Irinotecan 180 (150) mg/m 2 5FU 2,400 mg/m 2 N X 12 cycles Primary endpoint = DFS D O CT scans Q 3 months M I Gemcitabine Z Stratification, by Standard dose Center • E CA 19-9 • X 6 cycles pN status • Resection margin • Conroy T, et al. N Engl J Med 2018; 379:2395-2406

Di Disease-fr free ee surviv vival al an and over erall all surviv vival al wer ere e sig ignific ifican antly ly im improved ed wit ith modified ified FOLFIR IRIN INOX Disease-free Survival Overall Survival Conroy T, et al. N Engl J Med 2018; 379:2395-2406

AP APACT: Pha Phase se III, Ope pen-La Label, Ra Randomized Tri rial of Adjuvant t nab -Pa nab Paclitaxel plus Gemcitabine vs Gemcitabine fo for Resected Pa Pancreatic Adenocarcinoma Arm A nab -Paclitaxel 125 mg/m 2 qw 3/4 + Randomized 1:1 Gemcitabine 1000 mg/m 2 qw 3/4 Resected PDAC × 6 cycles R0/R1; ECOG PS 0 or 1; CA19-9 < 100 Arm B Gemcitabine 1000 mg/m 2 qw 3/4 × 6 cycles 866 patients; 179 sites; 21 countries Patients were randomized no later than 12 weeks post surgery • Stratification factors: R0 vs R1; LN+ vs LN−; North America, Europe and Australia vs Asia Pacific • Tempero et al, Abstract #4000, ASCO, 2019

APACT did not meet the primary endpoint but demonstrated significant improvement in OS Tempero et al, Abstract #4000, ASCO, 2019

Evolution of adjuvant therapies in pancreatic cancer: Ev me median overall survival time mes in mon months Observe 19 RTOG 20.5 ESPAC1 21.6 CONKO1 22.8 ESPAC3 23.6 EORTC 24.5 S1 ESPAC4 28.0 Nab-pacli/gem IMPRESS 30.4 FOLFIRINOX CONKO5 28.0 JASPAC1 46.5 40.5 APACT PRODIGE 54.4

It Is a Challenge to Give Enough Combination Chemo After Surgery! PRODIGE [a] ESPAC-4 [b] Gemcitabine/ FOLFIRINOX Gemcitabine Capecitabine Gemcitabine Completed all 66.4 79.0 54 65 cycles Relative dose intensity of 48.7% 91.4% - - > 0.70 a. Conroy T, et al. N Engl J Med. 2018;379:2395-2406; b. Neoptolemos JP, et al. Lancet. 2017:389:1011-1024

More Patients Will Receive Effective Systemic Therapy With the Neoadjuvant Approach 100 Newly diagnosed Surgery resectable NeoAdj 80 Chemo R2+ R0/R1 15 50 Progression Adjuvant 85 chemo Surgery 15 Relapsed 35 50 Complete Adjuvant adjuvant chemo ≤ 50% receive chemo. 100% receive chemo. > 15% futile surgery 15% spared futile surgery

S-1505: picking a winner neoadjuvant regimen for resectable disease N = 150 R R mFOLFIRINOX E E S mFOLFIRINOX 12 weeks S S U 12 weeks E T R R C A Primary endpoint is survival at 20 months G T G E Gemcitabine A I R Gemcitabine Nab-paclitaxel B N Y Nab-paclitaxel 12 weeks L G 12 weeks E Off study if, Toxicity Unresectability

Role of Multimodality Therapy: The Literature Helps, But Also Confusing!

Conclusions • FOLFIRINOX and gemcitabine/nab-paclitaxel are appropriate regimens for first line therapy with comparable efficacy • Careful patient assessment and discussion is very important • Nal-Iri/5FU/LCV improves survival in patients after gemcitabine based therapy • Current development of Nal-Iri in frontline therapy • mFOLFIRINOX is preferred adjuvant treatment, other options include gemcitabine/capecitabine, gemcitabine/nab-paclitaxel, or gemcitabine • Neoadjuvant therapy is preferred in patients with potentially resectable pancreatic cancer