PMID- 35467009
OWN - NLM
STAT- MEDLINE
DCOM- 20220720
LR  - 20221015
IS  - 1532-6535 (Electronic)
IS  - 0009-9236 (Print)
IS  - 0009-9236 (Linking)
VI  - 112
IP  - 2
DP  - 2022 Aug
TI  - Mobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 
      Insertions: Exposure-Response Analyses of a Pivotal Phase I/II Study.
PG  - 327-334
LID - 10.1002/cpt.2622 [doi]
AB  - Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of 
      patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC) 
      with epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20ins) 
      mutations previously treated with platinum-based chemotherapy. These 
      exposure-response analyses assessed potential relationships between exposure and 
      efficacy or safety outcomes in platinum-pretreated patients with 
      EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily (q.d.) in 
      a pivotal phase I/II study. A statistically significant relationship between the 
      independent review committee-assessed objective response rate and molar sum 
      exposure to mobocertinib and its active metabolites (AP32960 and AP32914) was not 
      discernable using a longitudinal model of clinical response driven by normalized 
      dynamic molar sum exposure or a static model of best clinical response based on 
      time-averaged molar sum exposure. However, the longitudinal model suggested a 
      trend for decreased probability of response with the change in mobocertinib molar 
      sum exposure between the 160- and 120-mg doses (odds ratio: 0.78; 95% confidence 
      interval: 0.55-1.10; P = 0.156). Time-averaged molar sum exposure was a 
      significant predictor of the rate of grade >/= 3 treatment-emergent adverse events 
      (AEs). Taken together, these exposure-efficacy and exposure-safety results 
      support a favorable benefit-risk profile for the approved mobocertinib 160-mg 
      q.d. dose and dose modification guidelines for patients experiencing AEs.
CI  - (c) 2022 Takeda Pharmaceuticals. Clinical Pharmacology & Therapeutics published by 
      Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Gupta, Neeraj
AU  - Gupta N
AD  - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA.
FAU - Largajolli, Anna
AU  - Largajolli A
AD  - Certara, Princeton, New Jersey, USA.
FAU - Witjes, Han
AU  - Witjes H
AD  - Certara, Princeton, New Jersey, USA.
FAU - Diderichsen, Paul M
AU  - Diderichsen PM
AD  - Certara, Princeton, New Jersey, USA.
FAU - Zhang, Steven
AU  - Zhang S
AD  - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA.
FAU - Hanley, Michael J
AU  - Hanley MJ
AD  - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA.
FAU - Lin, Jianchang
AU  - Lin J
AD  - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA.
FAU - Mehta, Minal
AU  - Mehta M
AD  - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220529
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology
MH  - ErbB Receptors/genetics
MH  - Exons
MH  - Genes, erbB-1
MH  - Humans
MH  - *Lung Neoplasms/drug therapy/genetics/pathology
MH  - Mutation
MH  - Protein Kinase Inhibitors/adverse effects
PMC - PMC9540490
COIS- N.G.: Employment (Takeda); A.L.: Employee of Certara, a consulting firm under 
      contract with Takeda; H.W.: Employee of Certara, a consulting firm under contract 
      with Takeda; P.M.D.: Employee of Certara, a consulting firm under contract with 
      Takeda; S.Z.: Employment (Takeda); M.J.H.: Employment (Takeda); J.L.: Employment 
      (Takeda); M.M.: Employment (Takeda).
EDAT- 2022/04/26 06:00
MHDA- 2022/07/22 06:00
PMCR- 2022/05/29
CRDT- 2022/04/25 08:57
PHST- 2021/12/23 00:00 [received]
PHST- 2022/04/18 00:00 [accepted]
PHST- 2022/04/26 06:00 [pubmed]
PHST- 2022/07/22 06:00 [medline]
PHST- 2022/04/25 08:57 [entrez]
PHST- 2022/05/29 00:00 [pmc-release]
AID - CPT2622 [pii]
AID - 10.1002/cpt.2622 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 2022 Aug;112(2):327-334. doi: 10.1002/cpt.2622. Epub 2022 
      May 29.