TDM of Targeted Therapies in Oncology: where do we stand? Dr. Joseph Ciccolini SMARTc - Pharmacokinetics Unit AMU/APHM Inserm U1068 CRCM

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1 TDM of Targeted Therapies in Oncology: where do we stand? Dr. Joseph Ciccolini SMARTc - Pharmacokinetics Unit AMU/APHM Inserm U1068 CRCM

2 Disclosures Roche Merck Serono Novartis

3 How to improve clinical outcome? Rise of personalized medicine! (a.k.a bioguided/precision/individualized/4p/ etc ) «Thou shalt not give ozimertinib until clone with T790M mutation shows» «Thou shalt not give vemurafenib if V600E is not found» «Thou shalt not give crizotinib if ALK is not translocated»..

4 How to improve clinical outcome? Beyond testing tumors.. Time for testing patients? Prof. Merrill J. Egorin, UPMC PA USA ( ) «Check the PK, you stupid!»

5 An emerging novel biomarker in oncology? Dissolution Solubility (L) (etc ) bile Blood Compartment Absorption Bioavailability (F) - K a Metabolism Liver Clearance (Clh) Distribution Distribution Volume (Vd) Elimination Renal Clearance (Clr, t 1/2, Kel) Total Clearance = Clh + Clr «A-D-M-E»

6 An emerging novel biomarker in oncology?

7 TDM: What do we know? Imatinib Gefinitinib Erlotinib Sorafenib Sunitinib Dasatinib Lapatinib Pazopanib Vandetanib Crizotinib Bosutinib Regorafenib Cabozantinib Afatinib Ibrutinib Vemurafenib Dabrafinib Everolimus

8 Does the clinic make better than TDM? Relationships between toxicity and efficacy so why should we bother in measuring drugs?

9 Does the clinic make better than TDM? Essai CRESTO (mrcc) : Ajustement de la dose de sunitinib pour obtenir une toxicité grade I-II >10j sur 1 cycle Relationships between toxicity and efficacy so why should we bother in measuring drug levels?

10 Does the clinic make better than TDM? but Relationships between toxicity and efficacy so why should we bother in measuring drug levels?!!!!

11 Does the clinic make better than TDM? Adherence & pill fatigue Marin D. et al. JCO 2010

12 Does the clinic make better than TDM? Stop-and-go can be deleterious!

13 Fact 1: PK Variability is not an hoax! Ex: Drug-drug interactions Herbrink M. et al. 2015

14 Fact 1: PK Variability is not an hoax! Ex: Food intake Koch KM. et al. JCO. 2009

15 Ex: Drug-drug interactions Fact 1: PK Variability is not an hoax!

16 Ex: Food intake Fact 1: PK Variability is not an hoax!

17 Fact 1: PK Variability is not an hoax! Ex: comorbidities (liver impairment) Herbrink M. et al. 2015

18 Fact 2: DOSE/EXPO Relationships are not clear-cut Ex: Imatinib High PK variability makes dosing little relevant! drug levels must be checked! Demetri GD. et al. 2009

19 Fact 2: DOSE/EXPO Relationships are not clear-cut Ex: Sorafenib High PK variability makes dosing little relevant! drug levels must be checked! Hornecker et al. 2012

20 Fact 2: DOSE/EXPO Relationships are not clear-cut Ex: Sorafenib Sorafenib exposure decreases over time (probably due to self-induction of ABCG2)

21 Fact 3: PK/PD Relationships are reasonnably well defined for a number of TKI s Common Name Indication Starting Dose Endpoint PK Target Reco Crizotinib NSCLC 250 mg bid Efficacy Trough Levels > 233 ng/ml switch to 400 mg bid Dasatinib CML 100 mg Safety Trough Levels < 1,5 ng/ml reduce by 20 mg step Erlotinib NSCLC 150 mg Efficacy Trough Levels > 500 ng/ml increase by 25 mg step Gefitinib NSCLC 250 mg Efficacy Trough Levels > 200 ng/ml x2 dosing Imatinib CML 400 mg Efficacy Trough Levels > 1000 ng/ml increase by 200 mg step - GIST 400 mg Efficacy Trough Levels > 1100 ng/ml increase by 200 mg step Nilotinib CML 400 mg Efficacy Trough Levels > 761 ng/ml increase by 150 mg step Pazopanib RCC 800 mg Efficacy Trough Levels > ng/ml increase by 400 mg step Sunitinib RCC 50 mg (4/2) Efficacy Trough Levels > 50 ng/ml increase by 12,5 mg step - RCC 50 mg (4/2) Toxicity Trough Levels < 100 ng/ml decrease by 12,5 mg step Sunitinib GIST 37,5 mg Efficacy Trough Levels > 37,5-50 ng/ml increase by 12,5 mg step - GIST 37,5 mg Toxicity Trough Levels < ng/ml decrease by 12,5 mg step Vemurafenib Melanoma 960 mg bid Efficacy Css ng/ml change by 240 mg step

22 Fact 3: PK/PD Relationships are reasonnably well defined for a number of TKI s Imatinib A Cmin > ng/ml is associated with MMoR (CML) A Cmin > 1200 ng/ml is associated with MMoR (GIST) Tailored dose if Cmin is not in the ng/ml range! Overexpression of efflux transport could require frequent control to confirm that exposure level is maintained throughout time.

23 Survie globale (proportion) Fact 3: PK/PD Relationships are reasonnably well defined for a number of TKI s Sunitinib 1,0 0,8 AUC > 1,973 ng/ml-h (n = 23) AUC 1,973 ng/ml-h (n = 29) 0,6 0,4 0,2 0 p = 0, Temps depuis le début du traitement (mois)

24 Fact 3: PK/PD Relationships are reasonnably well defined for a number of TKI s Sunitinib A Cmin of ng/ml of combined sunitinib + SU12662 associated with efficacy. is Phosphorylation of FLT3 could be associated with the duration time above 100 ng/ml. A Cmin > 100 ng/ml is associated with thrombocytopenia. A Cmin > 180 ng/ml is associated with prolonged QT.

25 Fact 4: Approved Dosing is not necessarily optimal dosing!

26 Fact 4: Approved Dosing is not necessarily optimal dosing! Change in practices takes years!

27 Ready to perform TDM? Standard dosing?

28 Personalized dosing Ready to perform TDM?

29 Ready to perform TDM? Analyse PK/PD Correction posologique Heparinate Li tube LC-MS/MS analysis; B140 (= 32,2 ), weekly analysis in most centers Developing Therapeutic Drug Monitoring with adaptive dosing strategies

30 TDM & simulation of sampling times Sampling and logistic issues in clinical routine practice: how to deal with samples collected between Tmax and Tmin?

31 TDM & simulation of sampling times Pharmacometrics (i.e., PK model) helps to simulate drug levels at T24H Cp Cp Target Conc. X X X Target Conc. X X? Last intake 24h Last intake 24h 29h15 h

32 Sunitinib + SU12662 (ng/ml) TDM & simulation of sampling times 3h 100 T2,5h T24h (simulated) 50 T24h (simulated) T24h Population No-tox patient: concerns about possible lack of efficacy: painful when off! Cycle 3: No-tox No more pain when off! Cycle 5: No-Tox No pain Efficacy (Recist)

33 TDM & simulation of sampling times Empirical, then PK-guided cut in sorafenib dosing (800 mg/d 200 mg 1/3 d) ng/ml Cmin concentration could be a target!

34 Beyond TDM: Adaptive dosing

35 Take-Home message: Can we make it? Computer-aided dosing algorithms. Why others can make it?

36 Take-Home message: Can we make it? STOP THROWING DICE!

37 Thanks for listening!