(M-132) Population Pharmacokinetics and Exposure-Response Relationship of Amivantamab in Combination with Carboplatin-Pemetrexed: Analyses from PAPILLON Supporting the Weight-Tiered Q3W Regimen

Wangda Zhou, PhD – Associate Director, Janssen Research & Development; Lu Zhang, Pharm D – Senior Scientist, Janssen Research & Development; Trishala Agrawal, MD – Senior Medical Director, Janssen Research & Development; Pritam Kambuj, MD – Senior Director, Janssen Research & Development; Honeylet Wortman-Vayn, BS – Director, Janssen Research & Development; Mahadi Baig, MD – Executive Medical Director, Janssen Research & Development; Jaydeep Mehta, PhD – Associate Director, Janssen Research & Development; Pamela Clemens, PhD – Senior Director, Janssen Research & Development; Nahor Haddish-Berhane, PhD – Senior Director, Janssen Research & Development; Yaming Su, PhD – Director, Janssen Research & Development; Mahesh Samtani, PhD – Senior Director, Janssen Research & Development

Objectives: AMI was initially approved as a monotherapy for second-line treatment of NSCLC patients with EGFR exon 20 insertion (exon20ins) mutations whose disease has progressed on or after platinum-based chemotherapy based on CHRYSALIS study. The approved regimen is a weight-tiered Q2W IV regimen in a 28-day cycle with a cutoff of 80 kg [1].

PAPILLON is a Phase 3 study demonstrating a significant prolongation of progression free survival (PFS) of AMI in combination with CP (ACP) compared to CP alone for the first-line treatment of NSCLC patients with EGFR exon20ins mutations. To align with the regimen of chemotherapy and to ensure equivalent therapeutic exposure, AMI was adjusted to Q3W in a 21-day cycle at a slightly higher dose for each weight tier. Both Q2W and Q3W regimens applied QW loading doses in Cycle 1. Here we present the popPK and E-R analyses from PAPILLON study supporting the weight-tiered Q3W IV regimen.

Methods: The previous popPK model supporting the Q2W monotherapy regimen was updated based on pooled PK data of monotherapy and combination with CP from CHRYSALIS and PAPILLON studies. PK simulation was conducted to compare Q2W and Q3W regimens and to support subgroup analysis of PK exposures.
The E-R analysis for efficacy included PAPILLON participants who received ACP. The analysis focused on the primary endpoint PFS, using Kaplan-Meier plots and log-rank test. Impact of covariates were explored graphically and using Cox-PH modeling.

Results: The updated popPK model was a 2-compartment model with parallel linear and Michaelis-Menten elimination. Baseline weight, age, albumin, and sex were identified as statistically significant PK covariates. Coadministration with CP had no impact on AMI PK. PK simulation demonstrated that AMI trough concentrations at the end of the QW loading phase and at steady state for the Q3W regimen were generally comparable to the approved Q2W regimen and between the two weight tiers. The 17% and 27% lower exposures in 60 to 70 kg and 70 to 80 kg subgroups were not clinically meaningful as these subgroups had similar PFS, supporting the 80 kg weight cutoff. AMI exposures were comparable across age and albumin subgroups.

A weak trend of positive E-R relationship for trough concentration at the end of the QW loading doses and PFS was observed, however, was insignificant in multivariable Cox-PH modeling after accounting for brain metastases and sex. The insignificant (flat) E-R relationship for PFS suggested that the Q3W regimen provided adequate exposure for efficacy. Males appeared to have 24% lower steady state exposure and shorter PFS than females, but the E-R relationship in males was flat, therefore no dose adjustment is warranted for males.

Conclusions: The popPK and E-R efficacy analyses adequately supported the weight-tiered Q3W IV regimen of AMI in combination with CP for the first-line treatment of NSCLC patients with EGFR exon20ins mutations.

Citations: [1] Haddish-Berhane N, Su Y, Russu A, Thayu M, Knoblauch RE, Mehta J, Xie J, Gibbs E, Sun YN, Zhou H. Determination and Confirmation of Recommended Ph2 Dose of Amivantamab in Epidermal Growth Factor Receptor Exon 20 Insertion Non-Small Cell Lung Cancer. Clin Pharmacol Ther. 2024 Mar;115(3):468-477. doi: 10.1002/cpt.3064.