PMID- 36625894
OWN - NLM
STAT- MEDLINE
DCOM- 20230212
LR  - 20230317
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 91
IP  - 2
DP  - 2023 Feb
TI  - Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of 
      nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell 
      carcinoma.
PG  - 179-189
LID - 10.1007/s00280-022-04500-9 [doi]
AB  - PURPOSE: In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 
      2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival 
      (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma 
      (RCC). To support cabozantinib dosing with the combination, this 
      exposure-response analysis characterized the relationship of cabozantinib 
      exposure with clinical endpoints. METHODS: Dose modification was allowed with 
      cabozantinib (holds and reductions) to manage adverse events (AEs). The 
      population pharmacokinetics analysis was updated and used to generate individual 
      predicted cabozantinib exposure measures. Kaplan-Meier plots and time-to-event 
      Cox proportional hazard (CPH) exposure-response models characterized the 
      relationship of cabozantinib exposure with PFS, dose modifications, and selected 
      AEs. RESULTS: Kaplan-Meier plots showed no clear difference in PFS across 
      cabozantinib exposure quartiles. Cabozantinib exposure did not significantly 
      affect the hazard of PFS in the CPH base model nor in the final model. In 
      contrast, baseline albumin and nivolumab clearance had a significant effect on 
      PFS. There was no significant relationship between cabozantinib clearance and 
      risk of dose modification, but a significant relationship was identified between 
      cabozantinib exposure and Grade >/= 1 palmar-plantar-erythrodysesthesia and 
      Grade >/= 3 diarrhea in the exposure-response analysis. CONCLUSION: To optimize 
      individual cabozantinib exposure, these data support the dose modification 
      strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when 
      combined with nivolumab.
CI  - (c) 2023. The Author(s).
FAU - Tran, Benjamin Duy
AU  - Tran BD
AUID- ORCID: 0000-0001-7077-9409
AD  - Exelixis, Inc., 1851 Harbor Bay Parkway, Alameda, CA, USA. btran@exelixis.com.
FAU - Li, Jing
AU  - Li J
AD  - Exelixis, Inc., 1851 Harbor Bay Parkway, Alameda, CA, USA.
FAU - Ly, Neang
AU  - Ly N
AD  - Exelixis, Inc., 1851 Harbor Bay Parkway, Alameda, CA, USA.
FAU - Faggioni, Raffaella
AU  - Faggioni R
AD  - Exelixis, Inc., 1851 Harbor Bay Parkway, Alameda, CA, USA.
FAU - Roskos, Lorin
AU  - Roskos L
AD  - Exelixis, Inc., 1851 Harbor Bay Parkway, Alameda, CA, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03141177
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230110
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Anilides)
RN  - 0 (Antineoplastic Agents)
RN  - 1C39JW444G (cabozantinib)
RN  - 31YO63LBSN (Nivolumab)
RN  - V99T50803M (Sunitinib)
SB  - IM
MH  - Humans
MH  - Anilides
MH  - *Antineoplastic Agents
MH  - *Carcinoma, Renal Cell/drug therapy
MH  - *Kidney Neoplasms/drug therapy
MH  - Nivolumab
MH  - Sunitinib/therapeutic use
PMC - PMC9905187
OTO - NOTNLM
OT  - Cabozantinib
OT  - Exposure-response analysis
OT  - Nivolumab
OT  - Renal cell carcinoma
COIS- All authors are employees and stockholders of Exelixis, Inc.
EDAT- 2023/01/11 06:00
MHDA- 2023/02/10 06:00
PMCR- 2023/01/10
CRDT- 2023/01/10 11:14
PHST- 2022/09/08 00:00 [received]
PHST- 2022/12/18 00:00 [accepted]
PHST- 2023/01/11 06:00 [pubmed]
PHST- 2023/02/10 06:00 [medline]
PHST- 2023/01/10 11:14 [entrez]
PHST- 2023/01/10 00:00 [pmc-release]
AID - 10.1007/s00280-022-04500-9 [pii]
AID - 4500 [pii]
AID - 10.1007/s00280-022-04500-9 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2023 Feb;91(2):179-189. doi: 
      10.1007/s00280-022-04500-9. Epub 2023 Jan 10.