(T-012) popPK & ER analysis of amivantamab in combination with chemotherapy for the treatment of patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure

Corey Bishop, Ph.D. – Associate Director, Johnson & Johnson; Jie Zhou, Ph.D. – Dist Sci Kin Com Pharma, Johnson & Johnson; Alex Yu, Ph.D. – Associate Director, Johnson & Johnson; Dongfen Yuan, Ph.D. – Associate Director, Johnson & Johnson; Jaydeep Mehta, Ph.D. – Associate Director, Johnson & Johnson; Pamela Clemens, Ph.D. – Senior Director, Johnson & Johnson; Nahor Haddish-Berhane, Ph.D. – Senior Director, Johnson & Johnson; Yaming Su, Ph.D. – Director, Johnson & Johnson; Joshua Bauml, M.D. – Global Medical Head, Johnson & Johnson; Julie Man, Ph.D. – Project Management Leader, Johnson & Johnson; Mahesh Samtani, Ph.D. – Senior Director Group Leader, Johnson & Johnson

Objectives: The objectives of the popPK and ER analyses of the Mariposa-2 (M2) study were to: 1) characterize the popPK of amivantamab (ami) for non-small cell lung cancer (NSCLC) patients who received ami, carboplatin and pemetrexed (ACP) based on a prior model; 2) evaluate the impact of potential covariates including demographic characteristics and chemotherapy on ami PK; 3) explore and quantify the relationship between the efficacy and safety endpoints and ami exposure in NSCLC patients who received ACP.

Methods: The popPK analysis included 1,106 ami PK concentrations from 123 participants in M2. The prior model (2-compartment (V1 and V2) with parallel linear (CL) and Michaelis-Menten clearance (Vmax and Km)) was used for external validation (MAXEVAL=0 in NONMEM v7.4.3).
Exposure subgroup analyses were accomplished via univariate and multivariate forest plots. The ER analysis for efficacy focused on progression-free survival (PFS) and were evaluated via stratified Kaplan-Meier plots. Covariates were explored graphically or using Cox proportional hazard modeling. ER analyses for safety endpoints were evaluated using quartiles (R >3.6.2).

Results: Model diagnostic plots and VPCs demonstrated that the model adequately described the PK data collected in M2. Baseline body weight (BW), sex, albumin, and age were covariates on CL, sex on V1, and BW was a covariate for V1 and V2. According to forest plots, chemo had no impact on ami PK exposures. No apparent ER relationship for PFS was observed across exposure tertiles for all exposure metrics. There were no apparent relationships between ami exposure and paronychia, rash, nausea, nor constipation. Incidence rates of hypoalbuminemia slightly increased with PK exposures, but were generally limited to grade 1 or 2.

Conclusions: Based on individual post hoc PK parameters, ami steady-state exposures following the BW tiered regimen were comparable in subgroups by age, albumin, race, renal function, hepatic impairment, EGFR mutation type, brain metastases, or ECOG performance status. Although females appeared to have ~30% higher PK exposures than males, PFS was similar between males and females. Findings suggest optimal exposures have been achieved at the selected regimen and no dose adjustment is warranted.

Citations: Haddish-Berhane, et al. Determination and Confirmation of Recommended Ph2 Dose of Amivantamab in Epidermal Growth Factor Receptor Exon 20 Insertion Non-Small Cell Lung Cancer; 2023.