PMID- 32659623
OWN - NLM
STAT- MEDLINE
DCOM- 20200828
LR  - 20200828
IS  - 1532-1967 (Electronic)
IS  - 0305-7372 (Linking)
VI  - 89
DP  - 2020 Sep
TI  - Exposure-response modeling of cabozantinib in patients with renal cell carcinoma: 
      Implications for patient care.
PG  - 102062
LID - S0305-7372(20)30100-6 [pii]
LID - 10.1016/j.ctrv.2020.102062 [doi]
AB  - Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the 
      treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 
      60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient 
      variability in drug clearance and exposure that can significantly impact safety 
      and tolerability across a patient population. To optimize cabozantinib exposure 
      (maintaining efficacy and tolerability) for the individual, patients may require 
      treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the 
      pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall 
      survival, progression-free survival and the objective response rate compared with 
      everolimus in patients with advanced RCC who had received previous treatment with 
      a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib 
      (60%) but effective as only 9% discontinued treatment due to adverse events 
      (AEs). In this review, we discuss pharmacometric analyses that evaluated the 
      impact of cabozantinib dose on efficacy and safety outcomes during the METEOR 
      study. Exposure-response models demonstrate that the risk of experiencing adverse 
      events and dose reduction is increased in patients with low cabozantinib 
      clearance versus typical clearance and decreased in patients with high clearance. 
      Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact 
      on efficacy as AEs are more likely to occur in patients with low clearance and 
      higher exposure to cabozantinib. These analyses further support a dose 
      modification strategy to optimize cabozantinib exposure for individual patients.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Castellano, Daniel
AU  - Castellano D
AD  - Hospital Universitario 12 de Octubre, Madrid, Spain. Electronic address: 
      cdanicas@hotmail.com.
FAU - Pablo Maroto, Jose
AU  - Pablo Maroto J
AD  - Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
FAU - Benzaghou, Fawzi
AU  - Benzaghou F
AD  - Ipsen Pharma, Boulogne-Billancourt, France.
FAU - Taguieva, Naila
AU  - Taguieva N
AD  - Ipsen Pharma, Boulogne-Billancourt, France.
FAU - Nguyen, Linh
AU  - Nguyen L
AD  - Exelixis, Inc., Alameda, CA, USA.
FAU - Clary, Douglas O
AU  - Clary DO
AD  - Exelixis, Inc., Alameda, CA, USA.
FAU - Jonasch, Eric
AU  - Jonasch E
AD  - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, TX, USA.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20200624
PL  - Netherlands
TA  - Cancer Treat Rev
JT  - Cancer treatment reviews
JID - 7502030
RN  - 0 (Anilides)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Pyridines)
RN  - 1C39JW444G (cabozantinib)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Anilides/*administration & dosage/adverse effects/pharmacokinetics
MH  - Antineoplastic Agents/administration & dosage/adverse effects/pharmacokinetics
MH  - Carcinoma, Renal Cell/*drug therapy/metabolism
MH  - Clinical Trials, Phase I as Topic
MH  - Clinical Trials, Phase II as Topic
MH  - Clinical Trials, Phase III as Topic
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Kidney Neoplasms/*drug therapy/metabolism
MH  - Models, Statistical
MH  - Progression-Free Survival
MH  - Pyridines/*administration & dosage/adverse effects/pharmacokinetics
MH  - Randomized Controlled Trials as Topic
MH  - Receptor Protein-Tyrosine Kinases/administration & dosage/adverse 
      effects/pharmacokinetics
OTO - NOTNLM
OT  - Cabozantinib
OT  - Dose
OT  - Efficacy
OT  - Exposure-response
OT  - Renal cell carcinoma
OT  - Tolerability
EDAT- 2020/07/14 06:00
MHDA- 2020/08/29 06:00
CRDT- 2020/07/14 06:00
PHST- 2019/12/05 00:00 [received]
PHST- 2020/06/15 00:00 [revised]
PHST- 2020/06/17 00:00 [accepted]
PHST- 2020/07/14 06:00 [pubmed]
PHST- 2020/08/29 06:00 [medline]
PHST- 2020/07/14 06:00 [entrez]
AID - S0305-7372(20)30100-6 [pii]
AID - 10.1016/j.ctrv.2020.102062 [doi]
PST - ppublish
SO  - Cancer Treat Rev. 2020 Sep;89:102062. doi: 10.1016/j.ctrv.2020.102062. Epub 2020 
      Jun 24.