The OPTIM program and TKI therapeutic drug monitoring Philippe Rousselot Université de Versailles Saint-Quentin-en-Yvelines Université Paris-Saclay Hôpital André Mignot, Hôpitaux de Versailles, France
Two first line randomized studies OPTIM imatinib : 139 pts, completed Imatinib dose adaptation based on pharmacokinetic Aim : To improve efficacy OPTIM dasatinib : 288 pts, analyzed Dasatinib dose adaptation based on pharmacokinetic Aim : To improve tolerance
OPTIM DASATINIB A prospective randomized phase II study evaluating the optimization of the residual plasmatic level of dasatinib (Sprycel ) in patients newly diagnosed with chronic phase Chronic Myelogenous Leukaemia (CP-CML). Philippe Rousselot, Luigina Molica On behalf of the French CML (FiLMC) group And the Canadian CML group
Differences in AEs Rates for Dasatinib and Imatinib : DASISION trial Cortes JE, et al. J Clin Oncol. 2016 Jul 10;34(20):2333-40.
Percent Patients Pleural effusion by exposure to dasatinib in second line 50 45 40 35 30 25 20 15 10 5 0 Pleural Effusion <65 years >65 years Cmin <2.5 ng/ml Cmin 2.5-<5.0 ng/ml Cmin >5.0 ng/ml C Nicaise, EHA 2008
Pleural effusion and Dasatinib
Rational : pharmacokinetic 1000 QD 105 mg QD 140 mg QD Hypothesis : Cmin may be the driver of pleural effusions BMS-354825 (ng/ml) 100 10 Cmax Cmin Toxicity Pleural effusions : DASISION, dasatinib first line 100 mg/d 12 months 10% 24 months 14% 36 months 19% 60 months 28% 1 0 6 12 18 24 Time (hr) Kantarjian H et al. N Engl J Med 2010;362:2260-70 Jabbour E et al. Blood. 2014;123:494-500 Cortes JE, et al. J Clin Oncol. 2016;34:2333-40
Tyrosine kinase inhibitors quantification in plasma using UPLC/MS-MS
Optim dasatinib trial EudraCT number 2008-006854-17 French Canadian joint study Inclusion criteria Philadelphia chromosome positive newly diagnosed ( 3 months) CP-CML Patients not previously treated except with hydroxyurea or imatinib (less than 4 weeks for imatinib) Primary endpoints The cumulative rate of all grade pleural effusion The cumulative rate of serious AEs defined by grade 3-4 fluid retention, all grade pleural effusion, haematological grade 3-4 AEs related to and/or all AE leading to dasatinib discontinuation Secondary endpoints Molecular response, EFS, PFS, overall survival Persistence of major molecular response after dasatinib discontinuation Methods Chest X ray every 3 months (1 year) Cmin and Cmax determined with Tandem Mass Mass Spectrometry BCR-ABL IS in 17 laboratories ((16 in France, 1 in Quebec) Centralized analysis at month12 sent to the reference EUTOS laboratory for France (Saint-Louis, Paris)
OPTIM dasatinib trial design Amendment Adjustment of the Cmin cutoff value from 5nM to 3nM after 30 pts R A1 PK PK PK PK Dasatinib dose adjustment every 2 weeks until optimal Cmin > or = 53 nm A2 Dasatinib 100 mg/d QD CML CP < 3 months Inclusion Dasatinib 100mg/d [C] min PK PK PK PK Not previously treated by TKI < 35 nm B Dasatinib 100 mg/d QD Day 1 Week 1 Month 6 Month 12
Patients characteristics By January 2014 : median follow-up 32 months (14-57) TOTAL B (<3nM) A ( 3nM) A1 A2 Patients Jun 09 Dec 12 287 (288 recruited) 208 79 37 42 Sex ratio M/F 1.3 1.13 1.8 1.2 1.9 Median Age (min-max) 53 (18-90) 49 (18-86) p<0.001 60 (22-90) 60 (39-90) 59 (22-81) Sokal Low (%) 45 47 42 40 43 Sokal Int (%) 34 31 43 42 44 Sokal High (%) 21 22 15 18 13
nm Cmin assessment during 12 months Arm A2 (non adapted) 2 0 p=0.41 NS 1 5 1 0 5 3 0 M 0 M 1 M 2 M 3 M 4 M 5 M 6 M 7 M 8 M 9 M 1 0 M 1 1 M 1 2 CH Versailles / INSERM CIC 1402 Poitiers FR (March, 2015)
nm Cmin assessment during 12 months Arm A1 (adapted) 2 0 p<0.001 1 5 1 0 5 3 0 M 0 M 1 M 2 M 3 M 4 M 5 M 6 M 7 M 8 M 9 M 1 0 M 1 1 M 1 2 CH Versailles / INSERM CIC 1402 Poitiers FR (March, 2015)
Dasatinib treatment in arms A1 and A2 Treatment Arm Mean dose (mg/d) Dose intensity (mg/d) Discontinuation rate Arm A1 (adapted) Arm A2 (non adapted) 51 57 13% 92 96 27%
P e rc e n t w ith p le u ra l e ffu s io n Cumulative incidence of all grades pleural effusions by 36 months All patients : 16.2% 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 M o n th s
P e rc e n t w ith p le u ra l e ffu s io n Cumulative incidence of all grades pleural effusions by 36 months Patients with low Cmin values at D15 (arm B) : 11.4% Patients with high Cmin values at D15 (arms A1 and A2) : 29.6% 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 M o n th s A1 and A2 arms B arm Gray test p=0.006
P e rc e n t w ith p le u ra l e ffu s io n Cumulative incidence of all grades pleural effusions by 36 months Patients with dose adaptation (arm A1) : 11% Patients without dose adaptation (arm A2) : 45% 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 Arm Total Events Competing events A1 38 4 2 A2 42 16 7 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 M o n th s A2 arm A1 arm Gray test p=0.008
P e rc e n t o n d a s a tin ib Patients on dasatinib (A1 versus A2) 1 0 0 P a tie n ts o n d a s a tin ib (A 1 v s A 2 ) 8 4 % 7 5 p = 0,0 2 5 0 5 8 % 2 5 censored for STOP dasatinib study A 1 A 2 Discontinuations 0 0 1 2 2 4 3 6 4 8 6 0 7 2 ALL M o n th s Failure AEs and others STOP dasa A1 A2 A1 A2 A1 A2 A1 A2 n 9 17 0 2 5 13 4 2 % 23 40 0 5 13 30 10 5
nm Cmin assessment during 12 months Arm B 2 0 p=0.17 NS 1 5 1 0 5 3 0 M 0 M 1 M 2 M 3 M 4 M 5 M 6 M 7 M 8 M 9 M 1 0 M 1 1 M 1 2 CH Versailles / INSERM CIC 1402 Poitiers FR (March, 2015)
Cumulative incidence of all grades pleural effusions Influence of Cmin during follow-up (Cmin during follow-up 3nM) Percent pleural effusion 100 80 60 40 20 Cmin 3nM Cmin <3nM 17% 3.5% 0 0 12 24 36 48 Months p=0.007
SAEs and emerging AEs All n=289 B n=208 A1 n=38 A2 n=42 SAE (n) 146 88 14 44 SAE / patient 0.5 0.42 0.36 1.04 Pulmonary Art hypertension Nodal Follicular hyperplasia 2 0.6% 8 2.7% Age (median) Dasa duration (median, mo) Sexe ratio M/F 0 0 2 51 34 1/1 6 1 1 46 24 (20 33) NHL 2 2 0 0 56 31 2/0 Second Malignancies Pulmonary Embolism Coronary VOD Raynaud syndrome 5/3 2 1 0 1 68 14 1/1 3 1% 4 1.3% 2 0 1 71 16 2/1 3 0 1 48 32 4/0 2 2 0 0 49 34 1/1 Cardiac failure 3 3 0 0 55 13 2/1
% re s p o n s e s Overall molecular responses : Month 3 (ITT, not done = failure) ns ns ns ns ns 1 0 0 9 0 8 0 A L L B 7 0 6 0 5 0 4 0 57% p=0.001 A 1 A 2 3 0 2 0 1 0 0 23% 5% 7% 2% > 1 0 % M R 2 M R 3 M R 4 M R 4.5 1% MMR 3 m o n th s
% re s p o n s e s Overall molecular responses : Month 6 (ITT, not done = failure) ns ns ns ns ns 1 0 0 9 0 8 0 7 0 70% A L L B A 1 6 0 5 0 4 0 43% A 2 3 0 2 0 1 0 0 20% 11% 4% > 1 0 % M R 2 M R 3 M R 4 M R 4.5 1% MMR 6 m o n th s
% re s p o n s e s Overall molecular responses : Month 12 (ITT, not done = failure) 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 ns ns ns ns ns 83% 61% 33% 19% 1% > 1 0 % M R 2 M R 3 M R 4 M R 4.5 1% MMR 1 2 m o n th s A L L B A 1 A 2
OPTIM in real life PK 1 PK 2 TKI at Conventional dose TKI at Conventional dose TKI at Conventional dose Optimized dose 1 Optimized dose 1 Optimized dose 2 Optimized dose 1: 70 mg/d Optimized dose 2: 50 mg/d
Conclusions Dasatinib dose optimization is an efficient strategy to overcome the risk of pleural effusion in high risk patients (defined by a Cmin value 3nM) and to reduce the discontinuation rate. The proportion of patients eligible to dasatinib dose optimization is increasing with age (up to 43% over 60y) reflecting the CP-CML population. A personalized dasatinib dose schedule in this high risk population may be close to 50-60 mg/d and remains associated with high levels of molecular responses
Acknowledgments French Investigators Agnès Guerci Franck E Nicolini Gabriel Etienne Laurence Legros Aude Charbonnier Valérie Coiteux Caroline Dartigeas Martine Escoffre-Barbe Lydia Roy Pascale Cony-Makhoul Viviane Dubruille Martine Gardembas Christian Berthou Françoise Huguet Bénédicte Deau Eric Jourdan Loïc Fouillard Sandra Malak Delphine Réa François Guilhot Francois-Xavier Mahon Canadian Investigators Luigina Mollica Mary Lynn Savoie Stephen Couban Sheldon H Rubin Sarit Assouline Robert Delage Pierre Laneuville Amélie Fontaine Marc Lalancette Jean-Luc Dionne Lambert Busque Molecular biology Jean Michel Cayuela The GBMHM group Pharmacology Stéphane Boucher Mathieu Molimard Biostatistics Joelle Guilhot Protocol monitoring Laure Morisset Anaïs Beulaygue CH de Versailles Drug supply and research grant Mohamed Hesham Abderrahim Oukessou Bristol Myers Squibb