Population Pharmacokinetics and Exposure-response Analyses of Lazertinib in Combination with Amivantamab as First-Line Treatment in Patients With EGFR-Mutated Locally Advanced or Metastatic NSCLC

Objectives: Lazertinib (JNJ-73841937; YH25448) is a mutant-selective irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting both the T790M mutation and activating EGFR mutations while sparing wild-type EGFR. Lazertinib in combination with amivantamab is being investigated in a Phase 3 Study 73841937NSC3003 (MARIPOSA) as a first-line treatment in patients with EGFR-mutated, locally advanced or metastatic non-small cell lung cancer (NSCLC). The objectives of the analyses were to characterize the PK of lazertinib in patients with NSCLC and explore lazertinib exposure response (E-R) relationships in MARIPOSA.Methods: The lazertinib Population PK (PPK) analyses were based on data from MARIPOSA and supportive studies 61186372EDI1001, 73841937NSC1001, YH25448-201(lazertinib monotherapy), and YH25448-301(lazertinib monotherapy). A total of 14,936 measurable lazertinib plasma concentrations from 1,389 participants were included. The PPK model was developed in NONMEM (ICON plc). Covariate relationships were identified using exploratory graphical evaluations and generalized additive modeling and then tested in the stepwise covariate model. The E-R analyses included PK, efficacy, and safety data from 416 participants treated with amivantamab and lazertinib combination therapy in MARIPOSA.Results: The observed lazertinib plasma concentration-time data were adequately described by a 2 compartment model with sequential zero- and first order absorption. The PPK model included covariate effects of body weight, Glutathione S-Transferase Mu 1 (GSTM1) genotype, sex, Japanese population, prior treatment (naïve vs non-naïve) on CL/F, and body weight, sex on V2/F. Patients with GSTM1 non-null genotype had 44% and 34% lower exposure compared to GSTM1 null participants based on AUC0-24h.ss and Cmax.ss, respectively. PFS was similar between GSTM1 non-null and null participants despite the PK difference in these two patient groups. No clinically meaningful differences in lazertinib PK were observed based on age, sex, body weight, race, ethnicity, hepatic function, and renal function. Lazertinib plasma exposure was comparable when administered either in combination with amivantamab or as monotherapy.E-R analyses showed no apparent E-R relationship between lazertinib exposures and PFS, supporting lazertinib dose in MARIPOSA seeking for approval. There were no observed E-R relationships across the examined safety endpoints including rash, pneumonitis/interstitial lung disease, venous thromboembolic events, paronychia, hypoalbuminemia, and diarrhea. Paresthesia and stomatitis appeared to show a mild increase in incidence with increasing exposure.Conclusions: Overall, the findings from PPK and E-R analyses supported the proposed lazertinib oral dosing of 240 mg once daily in combination with amivantamab. No dose adjustment is recommended based on the investigated covariates from PPK, efficacy, and safety E-R analyses.Citations: NA