DES Hématologie 2012 Nouveaux agents dans les lymphomes folliculaires Gilles SALLES
Même si l imuno imuno-chimiothérapie a conduit à des progrès, des besoins demeurent
Nouveaux agents en développement Anticorps Nus Nouveaux anti-cd20 dirigés contre d autres Ag Couplés à une toxine Radioimmunuthérapie Autres immunothérapies Signalisation Ciblage de l apoptose Angiogénèse micro-environnement
GA101: First type II, glycoengineered monoclonal anti-cd20 antibody Increased direct cell death Type II epitope binding Increased ADCC Glycoengineering for higher affinity to FcγRIIIA Effector cell B cell GA101 Complement CD20 FcγRIIIa Lower CDC activity Type II epitope binding Umana P, et al. Blood 2006; 108:Abstract 229. Umana P, et al. Ann Oncol 2008; 19 (Suppl 4):Abstract 098.
GAUGUIN inhl Phase II: Study design GA101 (400 mg) x 9 (n = 18) Relapsed/refractory inhl (n = 40) Randomization GA101 (1,600/800 mg) x 9 (n = 22) Schedule Arm 1: GA101 d1 and d8 cycle 1, d1 of cycles 2 8, 3-weekly cycles GA101 (400 mg for all doses) Arm 2: GA101 (1,600 mg d1, d8 cycle 1; 800 mg d1 cycles 2 8) Primary endpoint: Secondary endpoints: End of treatment response, assessed 4 weeks after the last infusion (planned 25 weeks after treatment start) Safety, pharmacokinetics, best overall response and PFS
GAUGUIN inhl Phase II: Best overall response, FL patients Response, n (%) 400/400 mg (n = 14) 1,600/800 mg (n = 20) Responders 5 (36%) 12 (60%) Complete response/ complete response unconfirmed 1 (7%) 4 (20%) Partial response 4 (29%) 8 (40%) Stable disease 6 (43%) 5 (25%) Progressive disease 3 (21%) 3 (15%) Salles, ASH 2011
GAUGUIN inhl Phase II: Progression-free survival in FL patients Progression-free survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 400/400 mg: Median 6.0 mo (range 1.0 23.0 mo) HR: 0.77 (95% CI 0.34 1.77) 1,600/800 mg: median 11.8 mo (range 1.8 22.8 mo) 0 3 6 9 12 15 18 21 24 27 Patients at risk, n Study (month) 400/400 mg 1,600/800 mg 14 20 10 17 5 15 5 14 4 9 4 8 4 7 2 5 0 0 0 0 Median observation time 23.1 months.
BO21003 Phase II study schema First head to head trial against rituximab monotherapy Relapsed CD20+ indolent NHL (N=180) RO5072759 1000 mg Weekly x 4 Rituximab 375mg/m 2 Weekly x 4 CR PR SD GA101 extended treatment (1000mg once every 2 months, up to 2 years) Rituximab extended treatment (375 mg/m2 once every 2 months, up to 2 years) Randomization
GA101 versus Rituximab Best overall response by IRF in FL patients Response, n (%) Rituximab (n = 75) GA101 (n = 74) Overall response rate (ORR) 35 (46.7) 45 (60.8) CR/CRu 15 (20.0) 20 (27.0) PR 20 (26.7) 25 (33.8) Difference in ORR, % [95% CI] 14.1 [ 2.5; 30.8] p-value (one-sided, chi-squared test) 0.04 IRF, independent review facility Sehn, ASH 2011
GAUDI: Study design Relapsed/refractory FL (n = 56) G-CHOP (n = 28) G-FC (n = 28) Randomization Randomization GA101 1,600/800 mg + CHOP x 6 8 (n = 14) GA101 400 mg + CHOP x 6 8 (n = 14) GA101 400 mg + FC x 4 6 (n = 14) GA101 1,600/800 mg + FC x 4 6 (n = 14) CR/PR CR/PR GA101 q3m x 2 years GA101 q3m x 2 years GA101 q3m x 2 years GA101 q3m x 2 years Induction Maintenance GA101 1,600/800 mg (up to 9 doses) GA101 400 mg (up to 9 doses) 1,600 mg on day 1 and day 8 of cycle 1 800 mg on day 1 of cycles 2 6/8 400 mg on day 1 and day 8 of cycle 1 and day 1 of cycles 2 6/8 GA101 at the induction dose (400 or 800 mg) every 3 months for 2 years As determined by investigator for each patient, based on prior therapy; G-CHOP, GA101 plus CHOP chemotherapy; G-FC, GA101 plus FC chemotherapy; All cycles in combination with CHOP d1 q21d or FC d1 q28d chemotherapy
GAUDI: Hematologic AEs (induction period) Patients, n (%) All grades Grade 3 4 G-CHOP 1,600/800 mg (n = 14) 400 mg (n = 14) Total (n = 28) 1,600/800 mg (n = 14) 400 mg (n = 14) Total (n = 28) Neutropenia 8 (57) 4 (29) 12 (43) 7 (50) 4 (29) 11 (39) Febrile neutropenia 1 (7) 0 1 (4) 1 (7) 0 1 (4) Thrombocytopenia 1 (7) 0 1 (4) 1 (7) 0 1 (4) Anemia 3 (21) 3 (21) 6 (21) 0 1 (7) 1 (4) Leukopenia 1 (7) 0 1 (4) 1 (7) 0 1 (4) G-FC 1,600/800 mg (n = 14) 400 mg (n = 14) Total (n = 28) 1,600/800 mg (n = 14) 400 mg (n = 14) Total (n = 28) Neutropenia 5 (36) 9 (64) 14 (50) 5 (36) 9 (64) 14 (50) Febrile neutropenia 2 (14) 0 2 (7) 2 (14) 0 2 (7) Thrombocytopenia 4 (29) 3 (21) 7 (25) 4 (29) 3 (21) 7 (25) Anemia 1 (7) 2 (14) 3 (11) 0 2 (14) 2 (7) Leukopenia 1 (7) 0 1 (4) 1 (7) 0 1 (4)
Safety: Study treatment early discontinuations and deaths (induction period) Early discontinuation Patients, n (%) G-CHOP (n = 28) G-FC (n = 28) Due to AEs 0 5 (18) Insufficient response 0 1 (4) Deaths 0 2 (7) No difference observed in exposure between the two treatment doses studied AEs leading to discontinuation: 400/400 mg, neutropenia (n = 2); 1,600/800 mg, neutropenia (n = 1), rash (n = 1), infection (n = 1) Deaths occurred in the 1,600/800 mg cohort as follows: progressive disease (n = 1); underlying Parkinson s disease (n = 1). Neither was considered to be treatment-related
Efficacy: End of induction response rates Patients, n (%) Response G-CHOP (n = 28) G-FC (n = 28) Overall response 27 (96.4) 26 (92.9) Complete response 11 (39.3) 14 (50.0) Partial response 16 (57.1) 12 (42.9) Stable disease 1 (3.6) 0 Progressive disease 0 1 (3.6) No response assessment 0 1 (3.6)
EORTC 20981and GAUDI comparison: Efficacy Arm ORR (%) Difference (%) Overall response G-CHOP (n = 28) 96.4 R-CHOP (n = 234) 87.2 Matched data adjusted for FLIPI Difference (%) 9.2 7.9 Complete response G-CHOP (n = 28) 39.3 R-CHOP (n = 234) 29.5 9.8 9.7
GA101 : la suite? Deux essais randonmisés en cours GADOLIN study of GA101 + bendamustine vs. bendamustine in rituximab-refractory inhl GALLIUM study of GA101 + chemotherapy followed by GA101 maintenance vs. rituximab + chemotherapy followed by rituximab maintenance in first-line inhl Et l étude GALEN (GA101 Lenalidomide)
Autres cibles pour Ac nus? Cheson B and Leonard J, NEJM 2008
Immunoconjugués ou ABC (antibody drug conjugate) LINKER drogue Anti-CD22 Acetyl-butyrate Chalicheamicin Anti-CD19 SPDB DM4 (Maytnasine) Anti-CD79a di peptide MMAE Anti-CD22 di peptide MMAE Anti-CD33 (gemtuzumab) SGN-35 (brentuximab vetodin) Chalicheamicin MMAE
Response Rates - CMC-544 monotherapy Best Responses in subjects treated at 1.8 mg/m2 Responses were seen at 0.8 mg/m2 and at higher doses (MTD 1.8 mg/m2) ORR=41% for 49 patients treated at the MTD For the 43 patients enrolled onto the expandedmtdcohort, duration of response ranged from 63 to 644 days for patients with FL (n=18) and from 34 to 685 days for patients with DLBCL (n =25) J Clin Oncol 28: 2010 (April 20) :2085-2093
Combination therapy (rituximab + CMC-544) ORR : 81% CR+Cru : 52% Survival Distribution Function 1.00 0.75 0.50 0.25 0 Refractory Follicular (n = 38) DLBCL Refractory (n = 28) Months Follicular DLBCL (n = 40) 0 5 10 15 20 25 30 35 1 yr PFS rate Median (months) Follicular 80% (0.62,0.90) Not reached DLBCL 56% (0.38, 0.71) 15.1 (6.80, ---) Refractory Not reached 1.7 (1.00,3.70)
Comment développer ces ADC? En association avec la chimiothérapie (doses, toxicités, ) En consolidation? A la place de la chimiothérapie Autres combinaisons???
Inhibiteur de BCL2
Fostamatinib Phase I/II 22% de réponse Diarrhées, tox hémato, fatigue, HTA
Inhibiteur de la Bruton Kinase ASCO 2010, Advani, résumé 8012 - Ce composé, le PCI-32765, inhibe BTK de manière irréversible - voie orale à doses croissantes depuis 1,25 mg/kg/jour, en continu pendant 28 jours puis avec 7 jours d interruption - 47 patients, lourdement pré-traités. - Toxicité de grade > 3 = 38% des patients, - sans toxicité hématologique notable - sans atteinte de la dose toxique limitante. Réponses = 69% des patients atteints de leucémie lymphoïde chronique (LLC) = 25 à 30% des patients atteints de lymphomes indolents (folliculaires en majorité).
La voie mtor
Quelques questions sur les futurs essais (1) Phase I/II: attention à la sélection des patients - file d attente? - patients ayant besoin d un traitement - les différentes histologies Critère principal de jugement - réponse clinique + scanner - PET scanner - PFS? Autres?
Quelques questions sur les futurs essais (2) Pour continuer le développement du produit: - quelles combinaisons (tox innatendues ou croisées?) - quelles comparaisons (absence de standart) - avec chimiothérapie ou sans chimiothérapie - pour obtenir quoi: - augmentation du taux de réponse? - augmentation de la PFS? - amélioration de la survie?