This document discusses the potential role of pharmacometrics in optimizing immunotherapy drug regimens. It notes that immunotherapy drugs are extremely expensive, have limited efficacy, and lack validated biomarkers. Their pharmacokinetic-pharmacodynamic relationships are also not clear. Combination regimens are common but scheduling matters, and many combination studies have failed due to a lack of rationale and pharmacokinetic support. The document argues that pharmacometrics could help design combination regimens, optimize dosing levels, and determine when dose adjustments or delays may be needed based on individual drug exposure levels. Measuring drug concentrations could help move immunotherapy treatments towards more precision medicine approaches.

1. Dr. Joseph Ciccolini
SMARTc - Pharmacokinetics Unit AMU/APHM
Inserm U1068 CRCM
ANY ROOM FOR
PHARMACOMETRICS
IN THE ERA OF IMMUNOTHERAPY?

2. • Roche
2018 Disclosures
• Merck Serono
• Novartis
• Lilly
• Ipsen
• Pierre Fabre

3. WHAT ABOUT IMMUNO-ONCOLOGY DRUGS?

4.  It is utterly complex
WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?
Dempke WCM et al., EJC 2017
 
What we once thought What it actually looks like (as of today)

5. WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?
 They are overpriced
5-fluorouracil
Metastatic colorectal cancer
Approved: 1960’s
Yearly cost per patient:
2017: < 110 €
Ipilimumab
Metastatic Melanoma
Approved: 2010’s
Yearly cost per patient:
2017: > 120 000 €

6. WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?
 They are overpriced
5-fluorouracil
Metastatic colorectal cancer
Approved: 1960’s
Yearly cost per patient:
2017: < 110 €
Ipilimumab
Metastatic Melanoma
Approved: 2010’s
Yearly cost per patient:
2017: > 120 000 €

7. WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?
 Their efficacy is limited to a subset of patients in a limited number of cancers

8.  There is no robust biomarker validated yet.
WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?

9. Where is exactly the site of action (i.e., with anti-PD1)?
Infiltrated
T cells ?
Circulating
T cells ?
Both?
WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?
 PK/PD relationships are not clear-cut.
Lymph
Node?

10.  PK/PD relationships are not clear-cut.
WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?
What is the right metrics?
µg/ml
AUC
Trough levels
should ensure
maximal target
engagement
24/7 !
Peak concentration?
Binding-site Barrier
issues?
?

11. Durvalumab in lung cancer
 PK variability is massive.
WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?

12.  Combinatorial regimen is the future
WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?

13.  Since 2017, most combo studies are negative
WHAT DO WE KNOW ABOUT IMMUNO-ONCOLOGY DRUGS?

14. Anti-angiogenics
Targeted therapies
Radiation Therapy
Cytotoxics
Time to use Pharmacometrics?

15. Immune Check-Point
Inhibitors
Chemotherapy
Targeted Therapies
Anti-Angiogenics
Radiation Therapy
MTD
Metro-
nomics
Chemo
Switch
The curse of multi-dimensionality

16. Immune Check-Point
Inhibitors
Chemotherapy Targeted TherapiesAnti-Angiogenics RadioTherapy
Immune Check-Point
Inhibitors
Chemotherapy Targeted TherapiesAnti-Angiogenics RadioTherapy
Immune Check-Point
Inhibitors
ChemotherapyTargeted Therapies Anti-AngiogenicsRadioTherapy
Immune Check-Point
Inhibitors Chemotherapy Targeted TherapiesAnti-Angiogenics RadioTherapy
(…)
The curse of multi-dimensionality

17. D.R.U.G.S.
D.U.R.G.S.
D.R.U.S.G.
(…)
Number of possible combinations: 5!= 120
Chemo
Radiation therapy
Anti-VEGF
I.C.I
Targeted therapy
The curse of multi-dimensionality

18. Several different treatments used at different possible dose levels and various scheduling lead to
millions of different combinations to be tested !
The curse of multi-dimensionality

19. M.U.C.H.M.O.R.E.D.R.U.G.S
(…)
Number of possible combinations: 13! = 36 590 400
M.U.C.H.M.O.R.E.D.R.U.S.G
U.M.C.H.M.O.R.E.D.R.U.S.G
Phased VS. Concomitant VS. Sequential VS. Dosing VS. Which drugs ???
The curse of multi-dimensionality

20. Combining anti CDK4/6 with anti PD-L1 is sound…. but scheduling matters!
The curse of multi-dimensionality

21. Combining anti OX-40 with anti PD-1 is sound…. but scheduling matters!
The curse of multi-dimensionality

22. Poor rationale and lack of PK/PD support make studies fail!
Time to use pharmacometrics?

23. Poor rationale and lack of PK/PD support make studies fail!
Time to use pharmacometrics?

24. Poor rationale and lack of PK/PD support make studies fail!
Time to use pharmacometrics?

25. Time to use pharmacometrics?

26. Models to optimize combo designs?

27. Models to optimize combo designs?

28. Models to optimize combo designs?
Algorithm for decision-making when using radiation therapy with immuno-oncology drugs

29. Room for pharmacokinetically-guided dosing?
 Mixed: linear + non-linear PK.
 Mean population PK parameters published.
 Large inter-patient variability (causes largely unknown).
 Possible intra-patient variability (TMDD).
 Narrow therapeutic window?
 Identified target exposures and clear PK/PD relationships?
 Rapid and simple bioanalytical methods made available?

30.  ELISA-based methods
 Mass Spec Methods
Room for pharmacokinetically-guided dosing?

31.  Clinical trials patients and real-life patients are not always the same.
 Approved dosing is not necessarily optimal dosing!
 Dose-finding studies during Phase I are often designed using outdated protocols.
Room for pharmacokinetically-guided dosing?
 Fast-Track approval reduces the knowledge we have regarding new drugs.

32. How flat are PK/PD relationships?

33. There is a major confounding factor in the « flat » PK/PD relationships with nivolumab
Nivolumab in cancer patients
Even very low doses of
nivolumab do the job..
So why should we bother?
Room for pharmacokinetically-guided dosing?

34.  Nivolumab (Opdivo®) in NSCLC
EXPOSURE (TROUGH LEVELS) DOES MATTER!
Is PK the forgotten biomarker?

35.  Nivolumab (Opdivo®) in lung cancer
Beside PK variability, differences in dosing can lead
to differences in efficacy
Is dosing an actionnable item?

36.  Pembrolizmab (Keytruda®) in lung cancer
Beside PK variability, differences in dosing can lead
to differences in efficacy
Is dosing an actionnable item?

37.  Ipilimumab (Yervoy®) in melanoma
EXPOSURE (TROUGH LEVELS) DOES MATTER!
(MORE THAN DOSING: PK VARIABILITY BLURS THE PICTURE!)
Exposure matters!

38.  Ipilimumab (Yervoy®) in melanoma
EXPOSURE (TROUGH LEVELS) DOES MATTER!
Exposure matters!

39. DOES EXPOSURE REALLY MATTER?
Target Mediated Drug Disposition (TMDD)
Tumor burden and antigenic mass both increase Mab’s clearance!
Is the truth out there?

40. DOES EXPOSURE REALLY MATTER?
Low drug levels make
big tumors!
No! Big tumors make
low drug levels!
Target Mediated Drug Disposition (TMDD)
measured
LOW
measured
HIGH
Is the truth out there?

41. DOES EXPOSURE REALLY MATTER?
Target Mediated Drug Disposition (TMDD)
Is PK really the forgotten biomarker?
She is young and
gorgeous!
No! She is old and ugly!

42. Nivolumab
3 mg/kg Q2W 240 mg Q2W 480 mg Q4W
Pembrolizumab
200 mg Q3W2 mg/kg Q3W
Flat-dosing may lead
to trough levels largely
exceeding the threshold
associated with efficacy
Is this « Precision medicine »?

43. Nivolumab
3 mg/kg Q2W 240 mg Q2W 480 mg Q4W
Pembrolizumab
TDM TO HELP CUTTING THE DOSING AND/OR DELAYING THE NEXT COURSE?
200 mg Q3W2 mg/kg Q3W
Flat-dosing may lead
to trough levels largely
exceeding the threshold
associated with efficacy
Is this « Precision medicine »?

44. Nivolumab
3 mg/kg Q2W 240 mg Q2W 480 mg Q4W
Pembrolizumab
TDM TO HELP CUTTING THE DOSING AND/OR DELAYING THE NEXT COURSE?
200 mg Q3W2 mg/kg Q3W
Flat-dosing may lead
to trough levels largely
exceeding the threshold
associated with efficacy
Is this « Precision medicine »?

45. Time to use pharmacometrics?
TDM TO HELP CUTTING THE DOSING AND/OR DELAYING THE NEXT COURSE?

46. Bayesian
Estimation
Individual PK parameters known
Mean population PK parameters
in the data base
New patient
Individual PK
parameters unknown
CtSparse
sampling
Simulations
Time to use pharmacometrics?

47. Dr. Joseph Ciccolini
SMARTc - Pharmacokinetics Unit AMU/APHM
Inserm U1068 CRCM
ANY ROOM FOR
PHARMACOMETRICS
IN THE ERA OF IMMUNOTHERAPY?

48. Time to use pharmacometrics?
50 €
80 000 €

49. …..STOP THROWING DICE !
Take-Home message: Can we make it?
MEASURE DRUG LEVELS…..

50. Thanks for listening!