33 hammel pascal 20200111 hammel bgdo

1

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

2




Albumin

Nab‐paclitaxel

Gp60 (albumin receptor)

Caveolin

SPARC

Legends

PAC cell

Fibroblasticcell

Endothelial cell

ECM(collagen)

Trancytosis

Stromalconcentration

Vascular lumen


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


3





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

4




Why (single) immunotherapy has failed in PDAC

Yarchoan M, NEJM 2107

Courtesy : C. Neuzillet

Why (single) immunotherapy has failed in PDAC

5




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…

6




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

7




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 ?

8




• 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)

9




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

10




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)

11




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…

12




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

13




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

14




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)

15




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

16




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],

17





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


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)

18




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)


*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

19




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

20




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).

21




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

22




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

23




Integrating molecular aspects of PDAC in clinical practiceSummary

85 %?

BRCA

MSI

Fusion genes

Metabolism (no marker)

KRAS

Thank you for your attention

33 hammel pascal 20200111 hammel bgdo

Documents