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Immunothérapie & thérapies ciblées :

les avancées en digestif

Cancer du pancréas – A.Lambert

Liens d’intérêt

Déplacement GRDig : MerckRéunions scientifiques :

AstrazenecaTesaroServierBayerJanssenPfizerMerck

Four presentations at diagnosis

Setting Metastatic Locallyadvanced

Borderline resectable

Upfrontresectable

Incidence 50-60% 25-40% 5-8% 10-15%

Treatments’ goals

Palliative Palliative if no surgery

Curative Curative

• Quality of life

• Survival• Quality of life

• R0resectability

• Survival• DFS

• Survival • R0resectability

• Survival• Quality of life

• Completionof treatment

Four presentations at diagnosis

Setting Metastatic Locallyadvanced

Borderline resectable

Upfrontresectable

Incidence 50-60% 25-40% 5-8% 10-15%

Treatments’ goals

Palliative Palliative if no surgery

Curative Curative

• Quality of life

• Survival• Quality of life

• R0 resectability

• Survival• DFS

• Survival • R0 resectability

• Survival• Quality of life

• Completionof treatment

Four presentations at diagnosis

Setting Metastatic

Incidence 50-60%

Treatments’ goals

Palliative

• Quality of life

• Survival

Les thérapies cibléesNombreux échecs

JAK 1&2 inhibitor

Hurwitz HI, Van Cutsem E, Bendell JC, et al. Two randomized, placebo-controlled phase3 studies of ruxolitinib (Rux) + capecitabine (C) in patients (pts) with advanced/metastatic pancreatic cancer (mPC) after failure/ intolerance of first-line chemotherapy: JANUS 1 (J1) & JANUS 2 (J2). J Clin Oncol 2017; 35(suppl 4S): abstract 343

Voies de signalisation• IMPACT

• 93 patients inclus• 73 screenés• 22 cibles identifiées

• KRAS 14• HER2 5• BRCA2 2• ATM 1

• Zéro patient traité !• AEG• Refus• Décès

Chantrill LA, Nagrial AM, Watson C, et al. Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial. Clin Cancer Res 2015; 21: 2029–2037

• Voie RAS – MAPK / PI3K–AKT -> EchecTipifarnib : farnesyltransferase inhibitorVan Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004; 22: 1430–1438.

Et le stroma ?

PEGPH20 recombinant pegylated hyaluronidase enzyme

Phase Ib prometteuseHingorani SR, Zheng L, Bullock AJ, et al. HALO 202: randomized phase II study of PEGPH20 plus Nab-Paclitaxel/gemcitabine versus Nab- Paclitaxel/gemcitabine in patients withuntreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol 2018; 36: 359–366.

Phase II délétèreRamesh K. Ramanathan, Shannon L, et al. Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313. J Clin Oncol 2019 37:13, 1062-1069

Voie Hedgehog -> vismodegib

Phase I/II -> négatif sur OS et PFSCatenacci DVT, Junttila MR, Karrison T, et al. Randomized Phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastaticpancreatic cancer. J Clin Oncol 2015; 33: 4284–4292.

-> Phase III en cours

Erlotinib

Etude positive !Phase III : gemcitabine +/- erlotinibGain de survie de 12 jours

Moore MJ, Goldstein D, Hamm J, et al. (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advan- ced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25: 1960–6

BRCA

BRCA

PFS : (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P=0.004)

The POLO study: maintenance Olaparib for Germline BRCA-Mutated

3315 patients screened for inclusion: 7.5% had a germline BRCA mutation.154 pts randomized after >16 weeks of first-line platinum-based chemotherapy(FOLFIRINOX 84%)

Placebo Olaparib pTotal randomized 62 92 -

Response rate 11.5% 23.1% 0.0001

Median PFS 3.8 mths 7.4 mths 0.004

Median Overall Survival 18.1 mths 18.9 mths 0.68

Golan T, et al. N Engl J Med 2019;381:317-27

Et l’immunothérapie ?

immunothérapie

Anti CTLA4 – ipilimumab -> pas de bénéficeRoyal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (Anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010; 33: 828–833

Anti CTLA4 - tremelimumab -> pas de bénéficeSharma P, Dirix L, De Vos F, et al. Efficacy and tolerability of tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma. J Clin Oncol 2018; 36(Suppl.): abstract 470.

Association ipilimumab + durvalumab (Anti PDL1) -> pas de bénéficeO’Reilly E, Oh D, Dhani N, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal AdenocarcinomaA Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5(10):1431-1438. doi:10.1001/jamaoncol.2019.1588

immunothérapie

Anti CTLA4 – ipilimumab -> pas de bénéficeRoyal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (Anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010; 33: 828–833

Anti CTLA4 - tremelimumab -> pas de bénéficeSharma P, Dirix L, De Vos F, et al. Efficacy and tolerability of tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma. J Clin Oncol 2018; 36(Suppl.): abstract 470.

Association ipilimumab + durvalumab (Anti PDL1) -> pas de bénéficeO’Reilly E, Oh D, Dhani N, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal AdenocarcinomaA Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5(10):1431-1438. doi:10.1001/jamaoncol.2019.1588

Nab-paclitaxel-gemcitabine +/- durvalumab et tremelimumab10 patients en 1ère ligneDCR 100%PFS 7.9 moisRenouf D, Dhani N, Kavan P, et al. The Canadian cancer trials group PA. 7 trial: results from the safety run in of a randomized phase II study of gemcitabine (GEM) and nab- paclitaxel (Nab-P) versus s Gemcitabine, Nab- Paclitaxel, Durvalumab and Tremelimumab as 1st Line Therapy in Metastatic Pancreatic Adenocarcinoma. J Clin Oncol 2018; 36(4 Suppl.): 349–349

dMMR / MSI -> anti PD 1

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357: 409–413.

• 86 patients (8 pancréas)• 12 types de cancers différents• dMMR confirmé• L2 et plus• Blocage anti PD1

pembrolizumab : RC 21% (2 pancréas) RP 53% SD 77% (6 pancréas)

-> 1% des cancers du pancréasHu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res 2018; 24: 1326–1336

Les perspectives

Vaccins

GV1001 phase III -> pas de beneficeMiddleton G, Silcocks P, Cox T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol 2014; 15: 829–840

G17DT -> prometteur chez les répondeursYutani S, Komatsu N, Yoshitomi M, et al. A phase II study of a personalized peptide vaccination for chemotherapy-resistant advanced pancreatic cancer patients. Oncol Rep 2013; 30: 1094–1100

GVAX -> stoppéNewLink Genetics Announces Results from Phase 3 IMPRESS trial of algenpantucel-L for patients with resected pancreatic cancer, https://globenewswire.com/ news-release/2016/05/09/837878/0/en/ NewLink-Genetics-Announces-Results-from- Phase-3-IMPRESS-Trial-of-Algenpantucel-L-for- Patients-with-Resected-Pancreatic-Cancer.html.

GVAX + ipilimumab -> prometteurLe DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013; 36: 382–389.

OSE2101 - Tedopam

CAR T Cells ?

Possible activité dans le pancréasPotentialisation avec immunothérapie ?

Beatty GL, O’Hara MH, Lacey SF, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology2018; 155: 29–32

Cellules souches

Inhibiteurs de cellules : potentialisation de la chimiothérapie ?Phase Ib/II : napabucasin (BBI-608) + nab-paclitaxel–gemcitabine en situation métastatique.

71 patients en ITTDCR 55 (77%)CR 1 (1.4%)PR 26 (37%)A phase III en cours (NCT02231723)

Bekaii-Saab TS, Starodub A, El-Rayes BF, et al. A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with gemcitabine (gem) and nab-paclitaxel(nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts). J Clin Oncol 2017; 35(15 Suppl.): 4106–4106

NTRK

Taux de réponse : 75% (95% [CI], 61 to 85)1 pancréas : PR

NTRK

Réponse sur 54 patients : PR 31 (57%; 95% CI 43·2–70·8) CR 7%

Traitement personnalisé

Traitement personnalisé

1856 patients1082 (58%) ayant reçu un rapport d’analyse moléculaireCible pour 282 (26%) d’entre euxDonnées présentes pour 189 patients avec cible activable

Median OS : 2·58 years [95% CI 2·39 to not reached] vs 1·51 years [1·33–1·87]; HR 0·42 [95% CI 0·26–0·68], p=0·0004;

Merci