PMID- 37496366
OWN - NLM
STAT- MEDLINE
DCOM- 20230920
LR  - 20230921
IS  - 2163-8306 (Electronic)
IS  - 2163-8306 (Linking)
VI  - 12
IP  - 9
DP  - 2023 Sep
TI  - Exposure-safety and exposure-efficacy analyses for tisotumab vedotin for patients 
      with locally advanced or metastatic solid tumors.
PG  - 1262-1273
LID - 10.1002/psp4.13007 [doi]
AB  - The antibody-drug conjugate (ADC) tisotumab vedotin (TV) received accelerated 
      approval from the US Food and Drug Administration for treatment of adults with 
      recurrent or metastatic cervical cancer (r/mCC) with disease progression on or 
      after chemotherapy. A population pharmacokinetic (PK) model, developed using 
      dosing data from four clinical TV studies, was used to estimate individual 
      exposure and explore safety and efficacy exposure-response (ER) relationships. 
      Because PK analysis showed no appreciable accumulation of TV and monomethyl 
      auristatin E (MMAE) with repeated dosing, cycle 1 exposure metrics and predicted 
      average concentrations from time zero until end of the cycle in which an event 
      occurred (C(avgLast) ) were used for ER analyses. The probability of achieving 
      objective response increased significantly as the ADC cycle 1 maximum serum 
      concentration (C(max) ) increased. The probability of treatment-related adverse 
      events (AEs) leading to dose modification increased significantly as ADC cycle 1 
      area under the concentration-time curve (AUC) increased. Number of grade 2+ 
      ocular AEs increased significantly as ADC cycle 1 AUC, C(max) , and ADC 
      C(avgLast) increased. MMAE cycle 1 AUC predicted risk of serious 
      treatment-related AEs. The relationship between ADC exposure and efficacy end 
      points suggests ADC treatment was associated with clinically meaningful response 
      across the observed exposures; greater exposure was associated with increased 
      efficacy. The relationship between ADC and MMAE exposure and safety end points 
      suggests increased exposure was associated with increased AE risk. These results 
      align with clinical findings showing TV 2 mg/kg (</=200 mg for patients >/=100 kg) 
      every 3 weeks is efficacious and tolerable for patients with r/mCC.
CI  - (c) 2023 Genmab US Inc. and Seagen, Inc. CPT: Pharmacometrics & Systems 
      Pharmacology published by Wiley Periodicals LLC on behalf of American Society for 
      Clinical Pharmacology and Therapeutics.
FAU - Passey, Chaitali
AU  - Passey C
AD  - Genmab US, Inc., Princeton, New Jersey, USA.
FAU - Voellinger, Jenna
AU  - Voellinger J
AD  - Seagen Inc., Bothell, Washington, USA.
FAU - Gibiansky, Leonid
AU  - Gibiansky L
AUID- ORCID: 0000-0001-6005-7760
AD  - QuantPharm LLC, North Potomac, Maryland, USA.
FAU - Gunawan, Rudy
AU  - Gunawan R
AD  - Seagen Inc., Bothell, Washington, USA.
FAU - Nicacio, Leonardo
AU  - Nicacio L
AD  - Seagen Inc., Bothell, Washington, USA.
FAU - Soumaoro, Ibrahima
AU  - Soumaoro I
AD  - Genmab US, Inc., Princeton, New Jersey, USA.
FAU - Hanley, William D
AU  - Hanley WD
AD  - Seagen Inc., Bothell, Washington, USA.
FAU - Winter, Helen
AU  - Winter H
AD  - Gilead Sciences, Inc., Foster City, California, USA.
FAU - Gupta, Manish
AU  - Gupta M
AD  - Genmab US, Inc., Princeton, New Jersey, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02001623
SI  - ClinicalTrials.gov/NCT02552121
SI  - ClinicalTrials.gov/NCT03438396
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230726
PL  - United States
TA  - CPT Pharmacometrics Syst Pharmacol
JT  - CPT: pharmacometrics & systems pharmacology
JID - 101580011
RN  - T41737F88A (tisotumab vedotin)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Immunoconjugates)
SB  - IM
MH  - Adult
MH  - Humans
MH  - *Neoplasm Recurrence, Local
MH  - Antibodies, Monoclonal, Humanized/adverse effects
MH  - *Immunoconjugates/adverse effects
PMC - PMC10508544
COIS- L.G. is a paid consultant to Genmab A/S and Seagen Inc. C.P., I.S., and M.G. are 
      employees of Genmab and may own stock. J.V., R.G., L.N., and W.D.H. are employees 
      of Seagen Inc. and may own stock. H.W. was an employee at Seagen Inc. during 
      development of this manuscript and is now an employee at Gilead Sciences, Inc.
EDAT- 2023/07/27 06:42
MHDA- 2023/09/20 06:42
PMCR- 2023/07/26
CRDT- 2023/07/27 02:33
PHST- 2023/06/07 00:00 [revised]
PHST- 2023/05/05 00:00 [received]
PHST- 2023/06/16 00:00 [accepted]
PHST- 2023/09/20 06:42 [medline]
PHST- 2023/07/27 06:42 [pubmed]
PHST- 2023/07/27 02:33 [entrez]
PHST- 2023/07/26 00:00 [pmc-release]
AID - PSP413007 [pii]
AID - 10.1002/psp4.13007 [doi]
PST - ppublish
SO  - CPT Pharmacometrics Syst Pharmacol. 2023 Sep;12(9):1262-1273. doi: 
      10.1002/psp4.13007. Epub 2023 Jul 26.