Development of the Weight-Tiered Q3W Regimen of Amivantamab in Combination With Carboplatin-Pemetrexed in EGFR-Mutated Non-Small Cell Lung Cancer.

Amivantamab, a bispecific antibody targeting epidermal growth factor and mesenchymal-epithelial transition receptors, was initially approved under accelerated approval as a monotherapy for second-line treatment of non-small cell lung cancer (NSCLC) with exon 20 insertion mutations. Subsequently, amivantamab in combination with carboplatin-pemetrexed demonstrated prolonged progression-free survival compared to chemotherapy alone in the first-line treatment of NSCLC with exon 20 insertion mutations and the second-line treatment of NSCLC with exon 19 deletion or exon 21 L858R substitution mutations. To enable the combination with chemotherapy, the amivantamab regimen was changed from every 2 weeks (Q2W) to every 3 weeks (Q3W); both are weight-tiered with a cutoff at 80 kg. Here we present the population pharmacokinetics (PK) and exposure-response (E-R) analysis supporting this dose regimen change. The population PK analysis demonstrated that the Q3W regimen achieved comparable trough concentrations as the approved Q2W regimen as well as between the two weight tiers. After accounting for confounding covariates, the E-R relationship for PFS was flat in both indications. The safety profile of the Q3W regimen was generally manageable, despite trends of a positive E-R relationship for adverse effects related to the mechanism of action. Besides weight, dose adjustment for other covariates was not warranted. These analyses supported the registration of the weight-tiered Q3W regimen for amivantamab in combination with carboplatin-pemetrexed in the new indications. This work demonstrates how the use of fit-for-purpose pharmacometrics analyses can support dose regimen changes without extensive dose selection clinical studies.