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

Abstract

Purpose: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy.

Patients and methods: Patients with EGFR-mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C_trough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC_D1-D15). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point.

Results: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C_trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC_D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively.

Conclusion: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Trial registration: ClinicalTrials.gov NCT05388669.

FIG 1.

CONSORT diagram of patient disposition. AE, adverse event.

FIG 2.

(A) Objective response forest plot, (B) PFS, and (C) OS. The efficacy population included all patients who had undergone random assignment. (A) The shaded area indicates 95% CIs for the relative risk in all patients; the subgroup analyses were not part of the hypothesis testing and results are reported without adjustment for multiplicity. (B, C) The dashed lines indicate the median PFS and OS, respectively, in the two groups, and the tick marks indicate censoring of data. ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

FIG 3.

IRRs and infusion-related AEs. The safety population included all patients who had undergone random assignment and received at least one dose of any trial treatment. AE, adverse event; IRR, infusion-related reaction.

FIG 4.

Patient-reported convenience of the subcutaneous injection and intravenous infusion. Item 6 of the modified TASQ asked, “How convenient is it for you to have your [IV infusion/SC injection]?” The modified TASQ was completed by patients after treatment administration in cycle-1 (baseline), cycle-3, and at EOT. EOT data could have been collected after administration of the last dose. ^aC1D2 for patients who received IV amivantamab because of split dosing. C, cycle; D, day; EOT, end of treatment; IV, intravenous; SC, subcutaneous; TASQ, Therapy Administration Satisfaction Questionnaire.

FIG A1.

PALOMA-3 study design. ^aCycle 1 for intravenous amivantamab-lazertinib: Days 1, 2 (Day 2 applies to intravenous split dose only), 8, 15, and 22; Cycle 1 for subcutaneous amivantamab-lazertinib: Days 1, 8, 15, and 22; after Cycle 1 for all: Days 1, 15 (28-day cycles). Subcutaneous amivantamab is coformulated with recombinant human hyaluronidase. ^bAssessed by using modified TASQ. AUC, area under the concentration-time curve; C_trough, observed serum concentration of amivantamab at steady state; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion mutation; NSCLC, non–small cell lung cancer; R, random assignment; TASQ, Therapy Administration Satisfaction Questionnaire.

FIG A2.

Time to amivantamab discontinuation. The dashed lines indicate the median time to amivantamab discontinuation in the two groups, and the tick marks indicate censoring of data.

FIG A3.

(A) Observed concentration-time profiles, (B) C_trough, and (C) AUC_D1-D15 of amivantamab. To capture the peak concentration of intravenous amivantamab, two samples were analyzed soon after the end of infusion (at 10 minutes and 2 hours after intravenous infusion). The upper and lower end of the boxes indicate the 25th and 75th quartiles, respectively, the triangles indicate the means, the horizontal lines within the boxes indicate the medians, and the error bars indicate 95% CIs. AUC, area under the concentration-time curve; AUC_D1-D15, AUC between Cycle 2 Day 1 and Day 15; C, Cycle; C_trough, observed serum concentration of amivantamab at steady state; D, Day.

FIG A4.

Best percentage change from baseline in target lesions: (A) subcutaneous group and (B) intravenous group. Target lesions were measured as the sum of the longest diameters. The number of patients with measurable disease at baseline was 206 in the subcutaneous group and 212 in the intravenous group; 190 and 195 patients, respectively, had postbaseline tumor assessments. SoD, sum of diameters.

FIG A5.

DoR: (A) among confirmed responders and (B) among all responders. The efficacy population included all patients who had undergone random assignment. Included in this analysis were the 55 (confirmed) and 62 (including unconfirmed) responders (of the 206 patients with measurable disease at baseline by RECIST, v1.1) in the subcutaneous group and the 57 (confirmed) and 69 (including unconfirmed) responders (of 212 patients) in the intravenous group, respectively. Tick marks indicate censoring of data. DoR, response duration; NE, not estimable.

FIG A6.

Incidence of IRRs by treatment cycle. IRR was counted only once per time frame per patient, and the event experienced by the patient with the worst toxicity was used. AE, adverse event; IRR, infusion-related reaction.