(S-005) Amivantamab population pharmacokinetics analyses of PALOMA studies supporting the bridging from intravenous formulation to subcutaneous formulation in epidermal growth factor receptor-mutated non-small cell lung cancer

Dongfen Yuan – Janssen Research & Development; Ali Alhadab – Janssen Research & Development; Lu Zhang – Janssen Research & Development; Chunying Gao – Janssen Research & Development; Mahadi Baig – Janssen Research & Development; Mohamed Gamil – Janssen Research & Development; Jie Zhang – Janssen Research & Development; Peter Hellemans – Janssen Research & Development; Anna Mitselos – Janssen Research & Development; Jaydeep Mehta – Janssen Research & Development; Pamela Clemens – Janssen Research & Development; Nahor Haddish-Berhane – Janssen Research & Development; Yaming Su – Janssen Research & Development; Mahesh Samtani – Janssen Research & Development

Objectives: Amivantamab IV was approved for the treatment of EGFR-mutated NSCLC as a single agent (Q2W), in combination with lazertinib (Q2W), and in combination with chemotherapy (Q3W). Amivantamab IV requires split doses over 2 days for the 1st infusion and a prolonged infusion time to mitigate infusion-related reactions. Amivantamab SC was developed to reduce administration time and administration-related reactions and to enhance the treatment experience for patients and healthcare providers. The objective of the popPK analyses was to characterize the PK of amivantamab IV and SC and to support the IV to SC PK bridging of the Q2W and Q3W regimens.

Methods: The amivantamab SC program consists of 3 studies: (1) PALOMA [1], a dose escalation study to determine the SC RP2Ds for Q2W, Q3W, and Q4W regimens; (2) PALOMA-2 [2], a multi-cohort study to evaluate the safety and efficacy of SC RP2Ds in combination with chemotherapy or lazertinib in respective patient populations of approved IV indications; (3) PALOMA-3 [3], the pivotal study to demonstrate SC to IV PK non-inferiority of the Q2W regimen in combination with lazertinib. The previously developed popPK model for amivantamab IV [4] was updated using combined IV and SC PK data from the PALOMA studies.
In PALOMA-3, the primary PK endpoints for the non-inferiority test were C2D1 Ctrough (EU), C4D1 Ctrough (US), and Cycle 2 AUCD1-D15 (both EU and US); the secondary PK endpoint was Cycle 4 AUCD1-D15. The final model was used to simulate C4D1 Ctrough and Cycle 4 AUCD1-D15 for participants who were evaluable for Cycle 2 AUCD1-D15 and therefore obtained reliable PK parameter estimates. To increase the sample size for C4D1 Ctrough, in addition to observed data, a hybrid approach was taken where the observed values were combined with model-simulated values for participants who were unevaluable for C4D1 Ctrough.
Trial simulation was performed in the PALOMA-3 population to demonstrate SC to IV PK non-inferiority for the Q2W and Q3W regimens. Forest plots were generated to support PK subgroup analysis.

Results: The final model adequately described the PK of amivantamab IV and SC. PALOMA-3 study demonstrated SC to IV PK non-inferiority for the Q2W regimen for all PK endpoints. The SC/IV geometric mean ratio for C4D1 Ctrough derived from both the hybrid approach and trial simulation were close to the observed value [5], lending credibility to the trial simulation results of SC to IV PK non-inferiority for the Q3W regimen. PK similarity of amivantamab across different populations supported the extrapolation of the PK non-inferiority results from the PALOMA-3 population to other populations with approved IV indications. Consistent with approved IV regimens, amivantamab SC had comparable exposure across subgroups of sex, race, age, albumin, renal function, and hepatic function for the Q2W and Q3W regimens, and therefore no dose adjustment is warranted.

Conclusions: The popPK analyses corroborated the SC to IV PK non-inferiority at the Q2W regimen observed in PALOMA-3 study [5]. Trial simulation further confirmed SC to IV PK non-inferiority at the selected Q3W regimen. Therefore, amivantamab SC at the selected Q2W and Q3W regimens are projected to maintain the efficacy comparable to that of approved IV regimens.

Citations: [1] PALOMA ClinicalTrials.gov identifier: NCT04606381
[2] PALOMA-2 ClinicalTrials.gov identifier: NCT01740427
[3] PALOMA-3 ClinicalTrials.gov identifier: NCT05388669
[4] Dongfen Yuan et al. Population Pharmacokinetics and Exposure-Response Relationship of Amivantamab in Combination with Carboplatin-Pemetrexed: Analyses from PAPILLON Supporting the Weight-Tiered Q3W Regimen. ACOP 2024, November 11 2024, Phoenix, Arizona
[5] Natasha B. Leighl et al. Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study. JCO 42, 3593-3605(2024). DOI:10.1200/JCO.24.01001

Keywords: IV to SC bridging, trial simulation, noninferiority