Determination and Confirmation of Recommended Ph2 Dose of Amivantamab in Epidermal Growth Factor Receptor Exon 20 Insertion Non-Small Cell Lung Cancer.

Amivantamab has demonstrated durable responses with a tolerable safety profile in NSCLC with EGFR exon 20 insertions (Ex20ins) who progressed after prior platinum chemotherapy. Data supporting the amivantamab recommended phase 2 dose (RP2D) in this patient population are presented. Pharmacokinetic (PK) analysis and population PK (PopPK) modeling were conducted using serum concentration data obtained following amivantamab intravenous administration (140-1750 mg). Pharmacodynamics (PD) were evaluated using depletion of soluble EGFR and MET (mesenchymal-epithelial transition factor). Exposure-response (ER) analyses were performed using the primary efficacy endpoint of objective response rate in patients with EGFR Ex20ins. ER relationship for safety was explored for adverse events of clinical interest. Amivantamab exhibited linear PK at 350 to 1750 mg dose levels following administration, with no maximum tolerated dose identified. A 2-compartment PopPK model with linear clearance adequately described the observed PK. Body weight was a covariate of clearance and volume of distribution in the central compartment. PopPK modeling showed that a weight-based, 2-tier (<80 kg and ≥80 kg) dosing strategy reduces PK variability and provides comparable exposure across 2 weight groups, with 87% of patients achieving exposures above the target threshold. The final confirmed RP2D of amivantamab was 1050 mg for <80 kg (1400 mg for ≥80 kg) weekly in Cycle 1 (28 days) and every 2 weeks thereafter. No significant exposure-efficacy or safety correlation was observed. In conclusion, the amivantamab RP2D is supported by PK, PD, safety, and efficacy analyses. ER analyses confirmed that the current regimen provides durable efficacy with tolerable safety.