biostudies-literatureUnknown112(2)Gupta NMobocertinib 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.Clinical pharmacology and therapeutics327-334https://www.ebi.ac.uk/biostudies/studies/S-EPMC9540490biostudies-literatureMobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure-Response Analyses of a Pivotal Phase I/II Study.PMC9540490Witjes HHanley MJMehta MDiderichsen PMLargajolli ALin JGupta NZhang SfalseMobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure-Response Analyses of a Pivotal Phase I/II Study.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.2022-01-01T00:00:00Z2022 Aug2024-10-16T04:36:43.554Z2024-10-16T04:36:43.554ZS-EPMC95404903546700910.1002/cpt.2622