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Pancreatic cancer treatment« Second line and Sequence »Julien TAIEBSorbonne Paris-Cité, Paris Descartes UniversityHopital Européen Georges PompidouInserm U970

DOI enCelgeneMSDServierSanofiLillyPierre fabre

First line therapeutic options in 20195

First line therapeutic options in 20196

Second line optionsL1 optionL2FOLFIRINOX*GEMCITABINE-ABRAXANE *GEMCITABINE*PS0, age 75,bili NPS 0-1,age 75-80,bili NPS 0-2, age 75,bili NNAL-IRI/5FU* U*Oxaliplatin/5FU*GEMCITABINE-ABX orFOLFIRINOX ?FOLFIRINOX ?GEM-CDDPor FOLFIRIor FOLFIRIor GEMOXL3* phase III trialor TaxanesClinical trialsClinical trialsClinical trialsClinical trialsClinical trialsClinical trials ?7

How many patients from L1 phase III trialsare eligible for L2? Dahan L et al, Gut 2010(FFCD0301)68% LV5FU2 Cisplatine arm ; 55% gemcitabine arm Conroy T et al, N Engl J Med 201147% FOLFIRINOX arm ; 50% gemcitabine arm Von Hoff DD et al, N Engl J Med 201338% gemcitabine nab-paclitaxel arm ; 42% gemcitabine armAt least 40% to 50%

L2 and L3 in clinical practice117 patients ; 1997 à 200690 synchronous et 27 MetachronusTreatment lineN patientChemo regimen- 5FU platinum- Gem platinum- Gem mono- OtherORR- PR- SD- PD- NEPFS12399 (85%)53 (45%)24 (21%)1830501(18%)(30%)(51%)(1%)111723222253022-5 - 10%15 - 28%23 - 43%10 - 19%2.922%25%30%22%(2.0 – 3.5)2.3(21%)(32%)(43%)(4%)(1.8 – 3.4)9 (38%)2 (8%)5 (21%)8 (33%)46862.5-16%25%33%25%(1.5 – 4.5)Bachet JB et al, Gastroenterol Clin Biol 2009

Retrospective and phase II studiesOxaliplatin - IrinotecanchemoAuthor, yearL1L2N patientsORR(%)SD(%)PFS(mo)OS(mo)Kozuch, 2001Gem BG-FLIP3424213.910.3Cantore, 2004Gem BCPT11-Ox3010234.15.9Tsavaris, 2005Gem5FU-Ox3023305.15.8Gebbia, 2007Gem B5FU-Ox4214384.06.7Xiong, 2008Gem BCapOX39321-5.8Yoo, 2009Gem BmFOLFOXmFOLFIRI.330317010231,52,13,74,2Assaf, 2011Gem BFOLFIRINOX2219445,48,5Zaniboni, 2012Gem BFOLFIRI508283,25,0Neuzillet, 2012GemoxFOLFIRI638323,06,6Lee, 2013Gem BFOLFIRINOX1828282,88,4Ko, 2013Gem BNal-Iri407432,45,2Zaanan, 2014Gem BFOLFOX270361,74,3

Retrospective and phase II studiesOxaliplatin - IrinotecanchemoAuthor, yearL1L2N patientsORR(%)SD(%)PFS(mo)OS(mo)Kozuch, 2001Gem BG-FLIP3424213.910.3Cantore, 2004Gem BCPT11-Ox3010234.15.9Tsavaris, 2005Gem305.15.8Gebbia, 2007Gem B384.06.7Xiong, 2008Gem B21-5.8Yoo, 2009Gem B10231,52,13,74,2Assaf, 2011Gem B445,48,5Zaniboni, 2012Gem BFOLFIRI508283,25,0Neuzillet, 2012GemoxFOLFIRI638323,06,6Lee, 2013Gem BFOLFIRINOX1828282,88,4Ko, 2013Gem BNal-Iri407432,45,2Zaanan, 2014Gem BFOLFOX270361,74,3Overall30230 to 28% 145FU-Ox ORR: 42CapOX DCR: 3639 to 63% 3mFOLFOX307 PFS:1.5to5.1momFOLFIRI.3310FOLFIRINOX OS: 3.7 22to 10.3 mo195FU-Ox

Is it relevant ? Any randomized data?Phase III trial: 5FU oxaliplatin and BSC vs BSC 46 patients Stopped prematurely because of poor accrual Median 2nd line survival: 4.82 vs 2.30 months(p 0.008) Median Overall Survival: 9.09 vs 7.90 months(p 0.031)Pelzer U et al, Eur J Cancer 2011

Randomized data for L2Author, yeartreatmentnPFS (mo)Oettle et al,J Clin Oncol 20145FU842,05FU Oxali762,9Von Hoff et al,WCGIC 20145FU5FU MM-3981,53983,1OS (mo)HR 0,68p 0,0193,3HR 0,56p 0,0014,25,96,1HR 0,66p 0,010HR 0,67p 0,012MM-3982,7Gill et al,20145FUFOLFOX2.93.1NS9.16.1NSYoo et al,2009FOLFOXFOLFIRI.321.5NS4.23.7NSMainly in the era of gem-based first line treatments4,9

5FU based after Gem-basedin clinical practice?Pointet et al. ASCO GI 2018 (in press)

NAPOLI-1: 1.9 month (45%) increase in median OSwith nal-IRI 5-FU/LVnal-IRI 5-FU/LV combination therapy vs. 5-FU/LVMedian,mo (95% CI)Survival probability (%)10080nal-IRI 5-FU/LV6.1 (4.8–8.9)5-FU/LV4.2 (3.3–5.3)Stratified HR 0.57 (0.41–0.80)60Unstratified HR 0.67 (0.49–0.92)40P 0.0122000369121518Time (months)Number at risknal-IRI 5-FU/LV5-FU/LV117975120800119683411610Survival analysis after 313 deaths on Feb 14th, 2014; Wang-Gillam A, et al. Lancet 2016;387:545; Chen LT, et al.J Clin Oncol 2015;33(S3):abstract 234 (and presentation)

NAPOLI-1: significant OS benefit with nal-IRI 5-FU/LV for thePP population in a pre-specified extended analysisPP population*Median,mo (95% CI)Overall Survival Proportion (%)10080nal-IRI 5-FU/LV8.9 (6.4–10.5)5-FU/LV5.1 (4.0–7.2)Stratified HR 0.47 (0.29–0.77)6040P 0.00182000369121518Time (months)nal-IRI 5-FU/LV666338166005-FU/LV71522510610Number at risk*Per-protocol (PP) population: eligible patients who received 80% dose intensity of the protocoldefined treatment during the first 6 weeks of treatment.Chen LT, et al. J Clin Oncol 2015;33(S3):abstract 234 (and presentation)

NAPOLI-1: survival benefit of nal-IRI 5-FU/LV washomogeneous across most subgroups (II)SexWomenMenBMI Median MedianRegionNorth AmericaAsiaEuropeOtherStage at diagnosisStage IVOtherTime since diagnosis Median MedianTime since metastatic diagnosis Median MedianPrevious lines of metastatic therapy01 2Combination therapynal-IRI 5-FU/LVEvents/patients (n/N)Combination therapy control5-FU/LVEvents/patients (n/N)Hazard ratio fordeath (95% CI)30/4845/6933/5247/670.74 (0.45–1.22)0.60 (0.40–0.91)36/5839/5939/5841/610.68 (0.43–1.07)0.60 /160.79 (0.36–1.75)0.51 (0.28–0.93)0.69 (0.42–1.14)0.58 (0.24–1.38)46/6128/5551/6228/550.63 (0.42–0.94)0.72 (0.42–1.21)38/6237/5538/6042/570.86 (0.55–1.34)0.46 (0.29–0.73)42/6132/5541/5839/600.80 (0.52–1.23)0.50 (0.31–0.81)10/1540/6225/401/1547/6723/370.68 (0.28–1.64)0.66 (0.43–1.00)0.68 (0.38–1.20)0.125Wang-Gillam A, et al. Lancet 2016;387:5450.5Favours nal-IRI 5-FU/LV124Favours 5-FU/LV8

Non metastaticL1L2GEML35FU- NalIRIFOLFOX or TaxanesSynchronousmPDACGEM Nab-Pacli 5FU-NalIRIWith a gem based first line the second line standard is5FU Nal-IriFOLFOX or taxane (if nab-paclitaxel has not been used) can be used later for eligible patientsFOLFOX

And after FOLFIRINOX? Available agents :- gemcitabine- taxanes (docetaxel, paclitaxel)- nab-paclitaxel What are the published data ?

Gemcitabine in L2 After L1 5FU : 63 patients,ORR:10,5%; DCR:40,5%PFS: 2,5 mo; OS:3,8 moRothenberg et al, Ann Oncol 1996 After L1 5FU Cisplatin : 69 patientsORR: 10%; DCR: 38%Dahan L et al, Gut 2010 After L1 FOLFIRINOX : 85 patientsgem monotherapy 82,5% or gem-based 12,5%,OS: 4,4 moisConroy T et al, NEJM 2011

Taxanes in L2Author,yearChemoL1L2N patientsORR(%)SD(%)PFS(mo)OS(mo)Oettle, 2000Gem BPaclitaxel18628-4.0Ignatiadis, 2006Gem BDocetaxel-Gefitinib260192.12.9Saif, 2010Gem BDocetaxel1763124Hosein, 2012Gem Bnab-paclitaxel195321,77,3Soares, 2014Gem B4314593,75,3Ettrick, xaliplatine

What aboutGem and Taxanesin L2?

All patients eligible for L2ORR 17%DCR 58%OS 9 moOS from L1 18 moGrade 3-4 AE 40%

Non metastaticL1GEMSynchronousmPDACGEM Nab-PacliFOLFIRINOXL2L35FU- NalIRI5FU-NalIRIGEM Nab-PacliFOLFOX or TaxanesFOLFOX? After FOLFIRINOX, gem nab-paclitaxel seems to give promising results in good condition patients thoughrandomized data are still lacking Issue : access to nab-paclitaxel L2

European Chart reviewPhysicians recruited from nine European countriesRecruitment from different regions and clinical settings* to ensure a balanced selectionInclusion criteriaCompleted first-line treatment for mPAC between July 2014and January 2016; age 18 years Patient recordGeneral disease information and patient characteristicsDisease characteristics at diagnosisInitial treatment for pancreatic cancerDetails of first/second/third-line treatment*University and general hospitals, cancer and reference centres, office-based specialists.mPAC, metastatic pancreatic adenocarcinomaTaieb et al. ESMO GI 2018Grouped as “North”region

European Chart review 2500 patientsMore than 70% received a second line (but biased)Taieb et al. ESMO GI 2018

European Chart reviewTaieb et al. ESMO GI 2018

Non metastaticL1GEMSynchronousmPDACGEM Nab-PacliL2L35FU- NalIRI5FU-NalIRIFOLFIRINOXGEM Nab-PacliGEM adjFOLFIRINOX?FOLFIRINOX adjGEM Nab-Pacli?GEM Nab-Pacli ?FOLFIRINOX?FOLFOX or TaxanesFOLFOX?

A randomised, open-label phase II study of 1st-linenal-IRI-containing regimens vs. nab-paclitaxel gemcitabine in metastaticpancreatic cancern 50(80 mg/m2 2400/400 mg/m2 Q2W[cycle Q4W];oxaliplatin according to part 1)Study endpoints: HR PFS (1 ), OS, PFS, ORR, CA19-9response, HRQoL, safety and toxicity2-part study:1. Safety run-in of nal-IRI 5-FU/LV oxaliplatin2. Randomised efficacy/safety study ofnal-IRI 5-FU/LV oxaliplatin vs. nab-paclitaxel gemcitabinenal-IRI 5-FU/LV oxaliplatinPatients with previouslyuntreated, metastaticadenocarcinoman 50Rnal-IRI 5-FU/LV(80 mg/m2 2400/400 mg/m2 Q2W [cycleQ4W])(n 150)nab-paclitaxel gemcitabine No prior therapy inmetastatic setting ECOG PS 0 or 1 Aged 18 yearsn 50(125/1000 mg/m2 weekly, 3Q4W)

A randomised, open-label phase II study of 1st-linenal-IRI-containing regimens vs. nab-paclitaxel gemcitabine in metastaticpancreatic cancerFUNGEMAX – PRODIGE 61n 95nal-IRI 5-FU/LV for 2 moNab-paclitaxel gem 2 moIn a predefinedsequential sequenceStudy endpoints: HR PFS (1 ), OS, PFS, ORR, CA19-9response, HRQoL, safety and toxicityPatients with previouslyuntreated, metastaticadenocarcinoman 95Rnal-IRI 5-FU/LV(80 mg/m2 2400/400 mg/m2 Q2W [cycleQ4W])(n 285)nab-paclitaxel gemcitabine No prior therapy inmetastatic setting ECOG PS 0 or 1 Aged 18 years Normal bilirubine leveln 95(125/1000 mg/m2 weekly, 3Q4W)

GRASPANC : design mPDACGemcitabine or FOLFOX Eryaspase(N 95) 2nd line Pretreated withgemcitabine based chemo. orFOLFIRINOX PS0 and 1N 141(70% ASNS 0/1, 30% ASNS 2/3)R2 to 1Gemcitabine or FOLFOX(N 46)Eryaspase : (100 IU/Kg J3 et J17 every 4 w)6 cyclesPrimary Objective:– PFS and OS in pts with no or weak ASNS expression (0/1 in IHC)– Target HR 0.85 for PFS or OS Secondary Objectives : PFS, OS, ORR and tolerability in all patients Hammel P. et al. - ESMO 2017 - Abs. 621PD

GRASPANC : OS in all patients100Chimio EryaspaseN 9590Chimio seuleN 46Survival probability (%)8070OS HR (95% CI)P-value60Median OS (weeks)26.119.050OS rate at 24 weeksOS rate at 52 week46%15%37%3%400.60 (0.40,0.88)0.00930C 5110614222111110weeksC EC95468940Hammel P. et al. - ESMO 2017 - Abs. 621PD8234712558194615321025622519412281

Target Cancer Stemcell (Napabucasin)Target BRCAnessTarget Ras or interaction domains with abolism MetforminL-asparaginaseHydroxychloroquinPhysical activityTGF-b (evofosamide)Notch/DDL4 (demcizumab)Wnt/B-catenin (OMP-54F28)Lysyl-oxidase inhibitors (simtuzumab)Recombinant human hyalorunidase Gvax /CRS207Anti-CLTA4, Anti-PD1/PDL1 CCR2 targeting oranti-TGFb or other co treatmentsAdapted from Neuzillet C, Pharmacol Ther 2015

Conclusion Second line treatment of mPDAC depends of first-line choices (and adjuvant?) The landscape of mPDAC treatment is moving, changing second line possibilities 5FU Nal-IRI has the highest level of evidence currently after a gem based first-linetreatment Gem or Gem nab-paclitaxel are good options after FOLFIRINOX (registration issues?) Sequencial trials are now mandatory to move forward and give patients the best sequenceto improve their OS If not done in first line think about rare subtypes (MSI, BRCA2 ) for specifictreatments/trials.

Thank you for your attention !

ESMO wishes to thank the following company for supporting this . Lee, 2013 Gem B FOLFIRINOX 18 28 28 2,8 8,4 Ko, 2013 Gem B Nal-Iri 40 7 43 2,4 5,2 Zaanan, 2014 Gem B FOLFOX 27 0 36 1,7 4,3. Retrospective and phase II studies Oxaliplatin -