(T-139) Population Pharmacokinetics and Exposure-response Analyses of Amivantamab Administered in Combination with Lazertinib as First-Line Treatment in Patients With EGFR-Mutated Non-Small Cell Lung Cancer

Jessie (Jie) Zhou, NA – Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC; Dandan Luo, NA – Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC; Yaming Su, NA – Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC; Jaydeep Mehta, NA – Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC; Pamela Clemens, NA – Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC; Joshua Bauml, NA – US Clinical Oncology, Janssen Research & Development, LLC; Sandeep Kumar, NA – US Clinical Oncology, Janssen Research & Development, LLC; Nahor Haddish-Berhane, NA – Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC; Mahesh Samtani, NA – Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC

Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecific antibody directed against EGFR and cMET. Amivantamab in combination with lazertinib was 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) [1]. The goals of the analyses were to characterize the PK of amivantamab in patients with NSCLC and explore amivantamab exposure-efficacy/safety relationships in the primary efficacy population in MARIPOSA.

The PPK analyses of amivantamab were based on available data from MARIPOSA and supportive studies 61186372EDI1001 (CHRYSALIS) and 73841937NSC1001 (CHRYSALIS-2). A total of 27,053 measurable serum amivantamab concentrations from 1,327 participants with at least 1 postdose concentration were included in the PPK analyses. A previous PPK model based on the monotherapy data of amivantamab in CHRYSALIS was used as a starting point for base model development, and further refined using pooled data from multiple studies including monotherapy and combination therapy of amivantamab and lazertinib. Covariate relationships were identified using exploratory graphical evaluations on base model parameters and then tested in the stepwise covariate model. The E-R analyses included PK, efficacy and safety data from 408 participants received amivantamab and lazertinib in MARIPOSA Arm A.

The observed amivantamab serum concentration-time data were adequately described by a 2-compartment model with parallel linear and nonlinear elimination. The PPK model included covariate effects of body weight, albumin level, sex and age on CL, body weight and sex on V1.

No clinically meaningful differences in amivantamab PK were observed based on weight, age, albumin, race, ethnicity, hepatic and renal function. Amivantamab serum exposure was comparable when administered in combination with lazertinib or as monotherapy. Female participants appeared to have 20% to 30% higher exposures than males based on AUC0-14days.ss and Ceoi.ss, respectively.

E-R analyses showed there was no apparent E-R relationship between amivantamab exposure and PFS, supporting adequate exposure of amivantamab in participants at the studied dose. PFS was similar in different body weight or gender subgroups.

There were no apparent E-R relationships across the examined safety endpoints including infusion related reactions, rash, venous thromboembolic (events), pneumonitis/interstitial lung disease, hypoalbuminemia, diarrhea, and paresthesia. Paronychia and stomatitis appeared to show a mild increase of occurrence rate with increasing exposure, consistent with EGFR inhibition.

Overall, the PPK and E-R analyses supported the proposed amivantamab dosing regimen of 1050 and 1400 mg IV QW for 4 weeks and Q2W thereafter for body weight < 80 kg and ≥80 kg, respectively. No dose adjustment is recommended based on the investigated covariates from PPK and E-R analyses.

Citations: [1] Investigator’s Brochure: Amivantamab (JNJ-61186372), Edition 11.0. Janssen Research & Development, LLC (07 Jul 2022).