Thérapeutiques Ciblées Généralités et spécificités en oncogériatrie

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1 Thérapeutiques Ciblées Généralités et spécificités en oncogériatrie r. Éric RAYMOND Service InterHospitalier de Cancérologie Bichat-Beaujon Hôpital Beaujon, Clichy ARIS DIDEROT University aris 7 eric.raymond@bjn.aphp.fr Modèles simplifiés de signalisation cellulaire THERAIES CIBLEES MULTI-CIBLEE CHIMIO Voie de signalisation prédominante Réseaux de signalisation interconnectés 1

2 Ligand Binding and Dimerization hosphorylation and Transactivation AT AD Hackel et al, Amundadottir et al, Vincent et al, Cell signaling activation CETUXIMAB ANITUMUMAB KIT GEFITINIB ERLOTINIB TYROSINE KINASE RECETORS VEGF-Trap EGFR DGFR VEGFR LAATINIB HKI-272 EKB-569 CI-1033 IMATINIB DASATINIB AEE788 ZD6474 BMS SUNITINIB SORAFENIB AMG 706 CEDIRANIB AG VATALANIB GW BAY XL820 XL999 CHIR-258 BEVACIZUMAB RAS RAF MAK RAS/MAK ATHWAY I3K I3k p85 p110 TEN I2 I3k/AKT/mTOR ATHWAY CELL MEMBRANE I3 AKT mtor RAAMYCIN TEMSIROLIMUS EVEROLIMUS A

3 Cell Signaling Inhibitors Novel Anticancer Agents in Cancer Therapy Faivre et al. Nat Rev Drug Disc, 2006 inib versus imab Anticorps: spécificité : peux d effets off-targets etites molécules: multi-cibles: nombreux effets off-targets 3

4 Antibodies versus Small Molecules Small molecules (may) get in T T Nucleus T Antibodies stay out Cancer cell Antibodies in oncology Good points Excellent for proof of principal (speed up the proof of concept and validation in clinical trials) : Specificity No metabolic/pharmacokinetic problems High drug exposure & long half-life Half-life depending on the type of immunoglobulin No drug interaction and biliary-renal excretion Distribute easily into the blood stream Limited side effects: target specific side effects +/- allergic reactions no overlapping toxicity with chemotherapy 4

5 Antibodies in oncology Bad points Specificity limits the spectrum of activity: Requirement for combinations with partners Chemotherapy Radiotherapy Small molecule targeted therapy Convenience is limited by requirement of repeated intravenous infusions Sustained exposure may not be desirable in case of toxicity They can t get into the cells which may limit number of targets to growth factors, tyrosine kinases, and cell surface molecules Small molecules Good points Broader specificity with multiple targets enlarging the spectrum of activity (AT mimetic) They not always require to be combined They can act against multiple tumor types Often orally available, thus more convenient for protracted target inhibition Distribute easily into tissue and they can get into cancer cells to hit a broader number of targets including cytoplasmic and nuclear targets 5

6 Small molecules Bad points Xenobiotics may be hard for proof of concept and validation in clinical trials (multiple cellular effects not always associated with efficacy): No specificity (or dose dependent) Metabolic/pharmacokinetic problems Depend on the chemical structure Variable biodisponibility/metabolism/catabolism Sometimes important drug-drug interactions Broad number of (sometimes unexpected) side effects: target specific side effects Off-target side effects sometimes overlapping with chemotherapy Main indications for validated targets in cancer HER2 (trastuzumab, lapatinib in breast cancer) EGFR (cetuximab, panitumumab in colon and head and neck; gefitinib, erlotinib in lung,.) KIT/DGFR (GIST and imatinib) VEGF/VEGFR (angiogenesis) Bevacizumab (breast, colon, lung, renal, glioblastoma, ovarian ) Sunitinib (SU11248) (renal cell carcinoma, GIST, endocrine ) Sorafenib (renal cell carcinoma, hepatocellular carcinoma, thyroid ) Regorafenib (colon) azopanib (renal) ALK (poumon NC) RAF (melanoma) mtor: Temsirolimus & everolimus (renal cell carcinoma, endocrine, breast, ) 6

7 Inhibiteurs de (Multiples) Récepteurs Tyrosine Kinases Lexemple du sunitinib Novel aradigm : Multi-targeted therapy Multiple targeted cells Cancer cells Endothelial cells Angiogenesis ericytes Fibroblasts Multiple molecular targets HER VEGF/VEGFR Receptor tyrosine kinases DGF/DGFR KIT/MET/RET Serine/threonine kinases Others kinases Faivre et al. Sem Oncol,

8 17/02/13 FOLKMAN: 1971 The Angiogenic Switch and Antiangiogenic Therapy Angiogenic Switch Somatic Mutation Small Avascular Tumor Tumor Secretion of roangiogenic Factors Stimulates Angiogenesis Rapid Tumor Growth and Metastasis Angiogenic Inhibitors May Reverse this rocess CO2, hypoxia COX 2, NO src, HER2/neu, ras 53, VHL oxidative stress 8

9 Les cibles de la thérapie anticancéreuses ne se limitent pas aux cellules tumorales Faivre et al. Nat Rev Drug Disc, 2007 VEGFs/VEGFRs sont des cibles essentielles de l angiogenèse Faivre et al. Nat Rev Drug Disc,

10 17/02/13 VEGF DGF SCF lasma Membrane Extracellular Ligandbinding Domain VEGFR 1, 2, 3 DGFR, KIT Tyrosine Kinase Domain EXRESSED IN CANCER CELLS ROLIFERATION EXRESSED IN ENDOTHELIAL CELLS ANGIOGENESIS Mécanisme(S!) d action du sunitinib Faivre et al. Nat Rev Drug Disc,

11 Bloquer l angiogenèse peut entraîner des régressions tumorales majeures SU11248 Faivre et al, J Clin Oncol, 2005 Effets cytotoxiques et antiangiogéniques complexes Faivre et al. Nat Rev Drug Disc,

12 Effets vasculaires du sunitinib Faivre et al. Nat Rev Drug Disc, 2007 Tumor Blood erfusion arameters on CT-Scan rior Sunitinib After Sunitinib Decrease from baseline (%) Range Nb of pts evaluable 4 Blood Flow 58.8% ( ) Blood Volume 68.4% ( ) Faivre et al, ASCO

13 25 A hase III, Randomized, Double-Blind, Trial of Sunitinib vs lacebo in atients with rogressive, Well-Differentiated, Malignant ancreatic Islet Cell Tumours: Study A Study design Key eligibility criteria Well-differentiated, malignant pancreatic endocrine tumour Disease progression in past 12 months Not amenable to treatment with curative intent Balanced by region Europe, Asia, Americas/Australia N=340 (planned) R A N D O M I S A T I O N 1:1 Sunitinib 37.5 mg/day orally, continuous daily dosing lacebo Disease progression rimary endpoint: FS Secondary endpoints: OS, ORR, TTR, duration of response, safety, patientreported outcomes Crossover Open-label sunitinib protocol (NCT or NCT ) Note: After 171 patients had been randomised to a study arm, the DSMC recommended to close the trial due to more deaths and serious AEs in the placebo group. atients in both arms became candidates for open-label sunitinib in trial NCT or NCT patients from the placebo arm crossed over to sunitinib at disease progression before study termination and a further 21 received sunitinib after study termination. ORR = objective response rate; TTR = time to tumour response Raymond E et al. N Engl J Med 2011;364: FS (primary endpoint) roportion of patients Median FS Sunitinib 11.4 months (95% CI: ) lacebo 5.5 months (95% CI: ) HR=0.418 (95% CI: ) < Time, months Number at risk Sunitinib lacebo HR = hazard ratio Raymond E et al. N Engl J Med 2011;364:

14 27 hase III Trial of Sunitinib in ancreatic NET: All-causality AEs in the Safety opulation All-grade AEs in 20% of patients in either arm, n (%) Sunitinib (n=83) lacebo (n=82) Diarrhoea 49 (59) 32 (39) Nausea 37 (45) 24 (29) Asthenia 28 (34) 22 (27) Vomiting 28 (34) 25 (30) Fatigue 27 (32) 22 (27) Hair colour changes 24 (29) 1 (1) Neutropenia 24 (29) 3 (4) Abdominal pain 23 (28) 26 (32) Hypertension 22 (26) 4 (5) Hand foot syndrome 19 (23) 2 (2) Anorexia 18 (22) 17 (21) Stomatitis 18 (22) 2 (2) Taste disturbances 17 (20) 4 (5) Epistaxis 17 (20) 4 (5) Raymond E, et al. N Eng J Med 2011;364: Toxicité des antiangiogéniques 14

15 17/02/13 Asthénie : un effet secondaire FREQUENT Sunitinib : SUTENT 58% (Gr 3/4: 9%) Sorafenib : NEXAVAR 24% (Gr 3/4: 2.5%) Toxicité cutanée: Lésions bulleuses douloureuses des mains et des pieds Lateral inter-phalange junctions Metatarsi and plantar areas eri ungueal lesions Recovery of Skin Toxicity Faivre et al, JCO 2006: 25 15

16 LE CIBLAGE DE l EGFR et de mtor K-Ras mutation (pancreatic, gastric and colon cancer) RAS TKR Receptor activation Erb-R, DGF/KIT-R, IGF-R (many tumor types) Gene amplification (head and neck, ovarian cancer) or mutation (gastrointestinal, brain cancer) p110 I3K Gene mutation p85 (colon, ovarian cancer) Gene amplification (breast, ovarian, colon cancer) or protein overexpression (ovarian, breast cancer) RAA AKT mtor # TSC1-2 RHEB TEN Loss of function via gene mutation, deletion or promoter methylation (colon cancer, endometrial cancer, glioblastoma thyroid, hepatocellular carcinoma Cowden syndrome) Gene mutation (TSC syndrome) RAAMYCIN DERIVATIVES Gene amplification (breast, ovarian cancer) S6K1 4E-B1 eif4e Gene amplification (breast cancer) or protein overexpression (squamous cell and adenocarcinoma) 16

17 Etude OUS, CRC 1ère ligne : Survie sans progression KRAS WT KRAS muté Kaplan-Meier Estimate FOLFOX ERBITUX + FOLFOX rogression-free time (months) FOLFOX ERBITUX + FOLFOX rogression-free time (months) Log Rank p = 0,016 Log Rank p = 0,0192 KRAS wt: HR=0.57 mfs ERBITUX+FOLFOX: 7.7 months mfs FOLFOX: 7.2 months KRAS mt HR=1.83 mfs ERBITUX+FOLFOX: 5.5 months mfs FOLFOX: 8.6 months C. Bokemeyer et al., ASCO 2008, A 4000 Etude CRYSTAL, CRC 1ère ligne : Survie sans progression selon statut KRAS KRAS WT KRAS muté 1.0 FS 1an: 25% vs 43 % Kaplan-Meier Estimate B:FOLFIRI A:ERBITUX+FOLFIRI Kaplan-Meier Estimate A:ERBITUX+FOLFIRI B:FOLFIRI rogression-free time (months) rogression-free time (months) Log Rank p :0.017 Log Rank p :0.47 KRAS wt HR=0.68 mfs Erbitux+Folfiri: 9.9 mo mfs Folfiri: 8.7 mo KRAS mt HR=1.07 mfs Erbitux+Folfiri: 7.6 mo mfs Folfiri: 8.1 mo E. Van Cutsem et al., ASCO 2008, A 2 17

18 Dérivés de la rapamycine RAAMYCIN Raymond et al, J Clin Oncol, 2004 Faivre et al. NRDD

19 Spécificité chez le sujet âgé Des médicaments ayant une meilleure tolérance hématologique et digestive eu de problèmes de réanimation aigue De multiples problèmes de tolérance chronique et cardiovasculaire Des problèmes d observance et des interactions médicamenteuses pour les molécules orales chez les patients recevant d autres traitements (polymédications) Tenir compte du terrain pour la prescription Tenir compte du terrain et des co-morbidités Ex. Éviter les anti-angiogéniques chez les patients ayant une pathologie cardiaque ischémique récente et/ou mal contrôlée Ex. Éviter les anti-angiogéniques chez les patients présentant une pathologie vasculaire cérébrale Éviter de traiter des patients ayant un mauvais état général (asthénie) Tenir compte des capacités d observance du patient 19

20 Tolérance révenir et traiter les effets cutanés chroniques (tous) révenir et traiter les diarrhées chroniques Surveiller l apparition et traiter l hypertension artérielle (anti-vegf/ VEGFR) Surveiller la fonction cardiaque (anti- VEGF/VEGFR) Surveiller la thyroïde (asthénie) Asthénie Liée au cancer Liée aux co-morbidités (diabète, anémie, dénutrition, hypothyroïdie, ) Liée aux traitements Conséquences dans les actes de la vie quotidienne 20

21 Éviter les interactions médicamenteuses Capacité de déglutition, dysphagie, asialie pour les médicaments par voie orale Inducteurs et inhibiteurs de cytochromes p450 Anticoagulants oraux +++ sychotropes Observance Tenir compte de la longue liste de prescription Vérifier la prise de médicaments (questions indirectes, effets indésirables mineures traduisant l exposition, ) 21

22 Conclusions Thérapie ciblées un fort potentiel thérapeutique chez les personnes âgées compte tenu de la faible toxicité mais un coût élevé Des toxicités différentes de la chimiothérapie: moins graves mais chroniques Non hématologique (HTA, acné, mucite, diarrhée,..) Une efficacité à priori identique chez les sujets âgés et les sujets plus jeunes Des risques liés à l observance, aux interactions médicamenteuses et aux Co morbidités fréquentes sur ce terrain 22