33 hammel pascal 20200111 hammel bgdo
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Disclosure
• Research funding: Eythec, AstraZeneca, Celgène
• Honorarium : Celgène, Merck Serono, IPSEN, Shire
• Boards : Merck Serono, Celgene, Lilly, Halozyme, AstraZeneca, Shire, Novartis, Rafael
Maréchal, Bachet et al, Gastroenterology 2012Poplin E, J Clin Oncol 2013
Adjuvant settingOS
Probabilité
Mois0.0
00.
25
0.5
00.
75
1.0
0(
)
0 6 12 18 24 30 36 42 48 54 60
hENT1 low/moderate
hENT1 high
p<0.0001
hENT1 ++
hENT1 0/+
Mois
Integrating molecular aspects in clinical practice : famous failures (1)
Metastatic settingOS
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Albumin
Nab‐paclitaxel
Gp60 (albumin receptor)
Caveolin
SPARC
Legends
PAC cell
Fibroblasticcell
Endothelial cell
ECM(collagen)
Trancytosis
Stromalconcentration
Vascular lumen
Integrating molecular aspects in clinical practice : famous failures (2)
Core biopsieHAhigh
Randomization2:1
PEGPH20 + Paclitaxel-Gem (PAG)
Placebo + Paclitaxel-Gem(PG)
D1=D28
D1 D4 D8 D11 D15 D18 D1 D8 D15
D1 D8 D15 D1 D8 D15
Cycle 1 Cycle n+1
Etc…
PEGPH20
Core biopsieHAhigh
Randomization2:1
PEGPH20 + Paclitaxel-Gem (PAG)
Placebo + Paclitaxel-Gem(PG)
D1=D28
D1 D4 D8 D11 D15 D18 D1 D8 D15
D1 D8 D15 D1 D8 D15
Cycle 1 Cycle n+1
Etc…
PEGPH20
Phase III – HALO‐301
Integrating molecular aspects in clinical practice : famous failures (3)
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Integrating molecular aspects in clinical practice : famous failures (2)
Erlotinib
Gemcitabine
Platinum saltsPARP inhibitors
Immunotheraph(PD1‐PDL1)
Grainne O'Kane at 2019 Gastrointestinal Cancer Symposium
30%‐40 % « targetable » abnormalities : 5%‐15% of deficient HR « BRCAness » (platins, PARPi,…) , 10% of Wt‐KRAS (MAPK, BRAF, FGFR1…), other (PIK3CA, ERB, STK11, PTEN, HER2, FGF, MSI…)
Main molecular targets
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Why (single) immunotherapy has failed in PDAC
Yarchoan M, NEJM 2107
Courtesy : C. Neuzillet
Why (single) immunotherapy has failed in PDAC
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Lawrence MS, et al, Nature 2013
Lee DT, Science 2017
Immunotherapy and MSI
Lawrence MS, et al, Nature 2013
Lee DT, Science 2017
Immunotherapy and MSI : moderate enthusiasm…
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
R
• LA or M+ PDAC• HLA‐A2• PS 0‐1• SD/PR/CR with L1
FOLFIRINOX
FOLFIRINOX8 cycles
Phase IIRN=156
Primary endpoint: OS at 12 months
Inclusion after induction FOLFIRINOX
Stratification:‐ center, ‐ stage (LA vs M+),‐ best response to induction chemotherapy (SD vs PR/CR)
TEDOPI (J1)(n=52)
Nivolumab (J1) plus TEDOPI (J2) (n=52)
Control Arm – Arm A
Experimental ArmsArm B
Arm C
FOLFIRI(n=52)
FOLFIRI reintroduction at disease
progression
FOLFIRI reintroduction at disease
progression
1:1:1
TEDOPaM – PRODIGE 63Maintenance immunotherapy with TEDOPI ± nivolumab
(PI C. Neuzillet)
Make PDAC immunosensitive ?
Reprogrammation of PDAC metabolism ?
Fu Y, et al. Mol Cancer 2018
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Eryaspase and PDAC metabolism
• KRAS mutations: 90% of PDAC[a]
• Dysregulation of metabolic pathways,including GLU and ASP
• Enhanced expression of ASNS: predictivefactor for L-asparaginase sensitivity in PDAC[b]
• L-asparaginase: growth inhibitory effects inPDAC cell lines and in xenograft models[c-f]
• Excessive toxicity of other L-asparaginase formulations in early clinical studies in various solid tumors (PDAC, ovarian) and multiple myeloma[g-j]
ASNS
ASNase
AsnProliferationGln + Asp Asn + Glu
Gln
ATP
NH3EIF2AK4
EIF2A
Protein Synthesis
Cancer Cell
ATF4
?necrosis
apoptosis
RED ANSase Sensitivity
BLUE ASNase Resistance
NARSQARS
DDIT3
CASP3
GSH
GLS
GLUL
ROSα-KG
TCA
lactate
pyruvate
Rationale for Therapy with L-Asparaginase in PDAC[l]
a. Almoguera C, et al. Cell. 1988;53:549-554; b. Cui H, et al. Cancer Res. 2007;67:3345-3355; c. Dufour E, et al. Pancreas. 2012;41:940-948; d. Yunis, AA, et al. Int J Cancer. 1977;19:128-135. e. Wu MC, et al. Int J Cancer. 1978;22:728-733. f. Sapra P, et al. Proc Amer Assoc Cancer Res. 2006;66(8 Suppl): Abstract 160; g. Lessner HE, et al. Cancer Treat Rep. 1980:64:1359-1361; h. Hays JL, et al. Mol Clin Oncol. 2013;1:565-569; i. Agrawal NR, et al. Cancer. 2003;98:94-99; j. Bachet JB, et al. Pancreas. 2015;44:1141-1147; k. Bertrand Y, et al. J Clin Oncol. 2015;33(suppl): Abstract 7004; l. Lorenzi P, et al. Blood. 2016;128: Abstract 1266.
ASNS = asparagine synthetase.
Eryaspase (phase II) : a signal ?
Gemcitabine ±eryaspase
(N=46)
FOLFOX± eryaspase
• Metastatic PDAC
• Failed 1st line therapy• PS 0-1
• N = 140 (ASNS 0/1 : 70%, ASNS 2/3 : 30% )
Fo
llow
-up
6 cycles of 4 weeks
Previously treated with FOLFIRINOX
Previously Treated with gemcitabine-
based chemotherapy
December 2019 : 169 patients includedTechnical limitation of drug production and transfusional compatibililty ?
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
• Lipoïc acid analog
• CPI‐613 interfers with mitochondrial metabolism
• Study PANC‐003
Target metabolism : Devimistat (CPI‐613)
pyruvate
citrate
isocitrate
α-ketoglutaratesuccinyl-CoA
oxaloacetate
acetyl-CoA
succinate
fumarate
malate
glucose
glutamate
glutamine
PDH
KGDH
CPI-613CPI-613
LipidsProteinsNucleic Acids
PDH = pyruvate dehydrogenase.
Alistar A, et al. Lancet Oncol 2017
Allstar A, et al. Lancet Oncol. 2017;18:770-778. Alistar A, et al. Lancet Oncol 2017
Target metabolism : Devimistat (CPI‐613)
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Phase 3 : CPI‐613 + mFOLFIRINOX
RANDOMIZE
CPI-613 500 mg/m2
Oxaliplatin 65 mg/m2
Irinotecan 140 mg/m2
5FU 2400 mg/m2
FOLFIRINOX“full dose"
• Metastatic PDAC• ECOG 0/1
N = 500Primary endpoints = ORR & PFS
ClinicalTrials.gov. NCT03504423 and NCT03435289.
• CPI-613 also evaluated combined with gemcitabine-nabP in LAPC/mPCA (phase 1; ongoing)
SM‐88
• SM-88 (tyrosin derivated, mTOR inhibitor, induces CYP3a4) uses the Warburg’s effect associated to oxydative stress
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Circulating tumor cells (CTC)
Median CTC decrease (best response) : 73% (range ‐100%, 242%)
Change of imaging targets at 2 months
Clinical benefit rate (SD and PR) of 47%
Noel MS, et al. J Clin Oncol.2019;37(suppl): Abstract 200.
SM‐88 Phase 2Warburg effect (1930)
APACaP Trial (> 240 patients included)
R
Useful treatment (chemo…)
Useful treatment+ APA (16 weeks)Stratification :‐ centre‐ stadge‐ type of chemo‐ PS‐ Initial level of fatigue
Open study
Total duration (intervention + follow up) : 24 months
Exercices :‐ aerobic‐muscular strengthWith « accompagnying APA »Nutritional care
Target tumor metabolism : adapted physical activity(APA)
œstrogenes et SHBG
insulinoresistanceand insulinosecretion
GF‐1
adiponectin and leptin
Inflammatory syndrome (CRP, SAA) (role in cachexia)
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
APACaP Trial
R
Useful treatment(chemo…)
Useful treatment+ APA (16 weeks)Stratification :‐ centre‐ stadge‐ type of chemo‐ PS‐ Initial level of fatigue
Open study
Total duration (intervention + follow up) : 24 months
Exercices :‐ aerobic‐muscular strengthWith « accompagnying APA »Nutritional care
Target tumor metabolism : adapted physical activity(APA)
6 months after diagnosis 5 y after diagnosis, 2 y after post‐op relapse…
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Gene fusions : TRK and larotectinib
Hong ESMO 2019
‐ Increase in OS since FOLFIRINOX/GemNaP, and trends in supportive care
‐ But limitant toxicities (neuropathy)
‐ The more the OS increases, the more quality of life must be taken into
account
‐ Exemples : tumor with slow evolution, such pNET
Concept of maintenance therapy
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Circulating tumor material
• Aim : ‐ Control tumor burden‐ Increase PFS, OS
• Aims : ‐ keep tumor controlled with minimal treatment‐ limit toxicity‐ increase PFS, OS
• Concept : 1st line cytotoxic chemo until progression • Concept : don’t wait progression but propose a maintenance therapy (chemo, targeted, immuno agents…)
Efficient 1st linechemotherapy
QOL
PDAC and concept of maintenance therapy
1st line 2d line 3d line
1st line Maintenance
therapy
Prog
Tumorcontrolled
50% <25%
80%
Prog3d line
? %
Prog
2d line
? %
ProgReintroduce
1st line Prog
? %
BSCBSC
Prog BSC
BSC BSC BSC
4 m 6‐7 m 8‐10 m 11‐12 m
« Classical » schema
Maintenance schema
Maintenance following efficient 1st line
Prog
BSC
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
1st example of maintenance (non targeted) : PANOPTIMOX study
Randomized phase II (PRODIGE 35‐PANOPTIMOX)FOLFIRINOX until progression (arm A) vs. maintenance with 5‐FU (arm B) or
sequential treatment with gemcitabine/FOLFIRI‐3 (arm C)
Gourley C, et al, J Clin Oncol, 2019, [Epub ahead of print],
Cells death induction and BRCA deficiency (synthetic lethality)
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
PARP inhibitors
Olaparib : PARP inhibitor
Ovarian cancer: 2 positive pivotal phase 3 trials, gBCRA1/2m
SOLO 1 maintenance 1st line ; gBRCAm (Moore K, NEJM 2018)
SOLO 2 maintenance when sensitive relapse ; gBRCAm (Pujade‐Lauraine, Lancet Oncol 2017)
Breast cancer: OlympiAD trial
OlympiAD : locally advanced or metastatic gBRCA1/2m, HER2 nég,
gBRCAm (Robson, NEJM 2017)
gBRCAm : mutation germinale de BRCA Prostate cancer: PROfund and TOPARP‐B trials (Mateo, NEJM 2015)
metastatic, resistant to castration
Germinal mutation BRCA1 or BRCA2(gBRCAm) 4%–7%
Tumors sensitive to platinum salts
Standard 1st line
1) FOLFIRINOX2) gemcitabine + Nab‐paclitaxel
No targeted therapy proven to be efficient in that setting (phase III)
<50% eligible for 2de line
Try to find maintenance molecules for ‘silenced” tumors after induction chemo
POLO study
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Rational for POLO study
phase II olaparib 2
(n=298; PDAC: n=23)
Patients
gBRCAm
Prior gemcitabine
1–8 lines chemo
PFS 4.6 months
ORR 21.7%
Kaufman B et al, J Clin Oncol 2015
Primary objective: significant increase in PFS
Months Since Randomization
Pro
bab
ilit
y o
f P
FS
Kindler HL, et al, J Clin Oncol, 2019;37(suppl): Abstract LBA4; Golan T, et al, N Engl J Med, 2019, [Epub ahead of print],
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Kindler HL, et al, J Clin Oncol, 2019;37(suppl): Abstract LBA4; Golan T, et al, N Engl J Med, 2019, [Epub ahead of print],
Time from randomization (months)
Pro
bab
ilit
y o
f P
FS
2
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
Olaparib
Placebo
Delay to 2de progression : benefit beyond tumor progression
Olaparib(n= 92)
Placebo(n = 62)
PFS2 (median), months 13.2 9.2
HR 0,76
95% CI 0,46, 1,23; P = ,26
PFS‐2 according to investigators : interim analysis, 46% maturity
Kindler HL, et al, J Clin Oncol, 2019;37(suppl): Abstract LBA4; Golan T, et al, N Engl J Med, 2019, [Epub ahead of print],
Olaparib(n=92)
Placebo(n=62)
Median OS 18.9 m 18.1 m
HR 0.91
95% CI 0.56, 1.46; P=0.68
POLO : overall survival (46 % maturity)
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Lack of benefit in OS : why ?
‐ Results not mature
‐ Treatments receveid after progression in patients of
placebo arm :
‐ efficient chemo
‐ olaparib (despite cross‐over not allowed) Patients who received PARPi :
1 olaparib patient (1.1%)
9 placebo patients (14.5%)
Objective response* (BICR)
Kindler HL, et al, J Clin Oncol, 2019;37(suppl): Abstract LBA4; Golan T, et al, N Engl J Med, 2019, [Epub ahead of print],
*Selon RECIST modifié v1,1,†Janvier 15, 2019,
Olaparibn = 78
Placebon= 52
n = 18 n = 6
23,1%
11,5%
2 CR with olaparib
persitent†
Median duration of response
24.9 months
3.7 months
Olaparib
Placebo
Median time to onset of response
5.4 months
3.6 months
Olaparib
Placebo
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
POLO : QoL
Hammel P, et al. Ann Oncol 2019
Stade III-IVgBRCA+
ECOG PS 0-1
Gemcitabine CisplatineVeliparib
GemcitabineCisplatine
Etude pilote
R
N = 17Veliparib
O’Reilly EM, et al, Cancer, 2018;124:1374-1382; ClinicalTrials,gov, NCT01585805,
Phase II randomiséen = 107, objectif 1aire = taux de réponse
Other treatments with PARPi
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Somaticmutations of BRCA in PDAC
Hu C, et al. JAMA 2018
Somatic mutations BRCAness : MAZEPPA study
Induction mFOLFIRINOX
Gene mutation analysis: BRCA, KRAS, EGFR, HER2, ATM, PALB2, RAD51..
BRCAness profile
KRAS-mutated
no BRCAness profile
KRAS wild-type
Arm C FOLFIRI until PD
Arm B Durvalumab
+Selumetinib until PD*
Arm A Olaparib until PD
Patients with controlled disease after 4 months of treatment
Randomization 2:1
Exclusion
FOLFIRI until PD**
No germinal mutation
Germinal mutation
Oncogenetic consultation
Germinal analysis
Inclusion Exclusion
Pre‐study treatment (inclusion criterion)
MAZEPPA Study treatment
The panel includes 36 genes involved in homologous recombination (including the "classical"ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, PALB2, RAD51C, RAD51D, FANCA,NBN, RAD51, RAD54L) and more generally in DNA repair (including POLE and POLD1).
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Other DDR to increase ADN alterationsduring phase G1‐S
Signaling pathways modulatingHRR : PI3K/AKT, RAS, VEGF and AR
Agents ciblant :
Genomic instability
Mutations accumulation
(?)Increase of neo‐antigens‐> T lymphocytes activation
Next step : overcome resistances to PARPi
1‐ Faisability‐ poor tumor material
2‐ After progression/resistance : what to do?
3‐ Cost‐ Reimbursement testing & olaparib‐ indications out of A.M.M.‐ benefit cost/efficacy ?
Current limitations
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Testaye A, Experts Rev Anticancer Therap 2018
New trials(but maintenance ?)
(Immediate) future
Integrating molecular aspects of PDAC in clinical practiceSummary
BRCA
MSI
Fusion genes
Metabolism (no marker)
KRAS
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BGDO Annual Meeting 2020Advances in Pancreaticobiliary Cancers
Genetic & Molecular Biology in pancreatico‐biliary cancers|
Integrating molecular aspects in clinical practice Pascal Hammel
Integrating molecular aspects of PDAC in clinical practiceSummary
85 %?
BRCA
MSI
Fusion genes
Metabolism (no marker)
KRAS
Thank you for your attention