Efficacy of SC vs IV Amivantamab + Lazertinib in NSCLC

Amivantamab (ami) plus lazertinib (laz) has demonstrated significant antitumor activity in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC). Subcutaneous (SC) administration of ami takes ≤7 minutes and is associated with low rates of infusion-related reactions (IRR).

In PALOMA-3 trial (NCT05388669), Natasha B. Leighl and the team aimed to evaluate the pharmacokinetics (PK), efficacy, and safety of SC ami + laz compared to intravenous (IV) ami + laz in patients with EGFR Ex19del or L858R-mutated advanced NSCLC who had disease progression on osimertinib and platinum-based chemotherapy.

They performed an inclusive analysis comparing the pharmacokinetics, efficacy, and safety of SC ami at 1600 mg (2240 mg for patients ≥80 kg) administered weekly for the first 4 weeks, then every 2 weeks, vs IV ami at the approved dose of 1050 mg (1400 mg for patients ≥80 kg). Lazertinib was orally dosed at 240 mg daily.

Co-primary pharmacokinetic noninferiority endpoints included trough concentration (C_trough) on Cycle [C] 2 Day [D] 1 or C4D1) and C2 area under the curve (AUC_D1-D15). Key secondary endpoints comprised objective response rate (ORR) and progression-free survival (PFS), with overall survival (OS) as a predefined exploratory endpoint. Prophylactic anticoagulation was recommended for the first 4 months (mo) of treatment.

About 418 patients were randomized (SC, n = 206; IV, n = 212); 416 received ≥1 dose. The median age was 61 years; 67% were female, and 61% were Asian, with a median of 2 prior lines. At a median follow-up of 7.0 months, PALOMA-3 met both co-primary endpoints. Geometric mean ratios (GMRs) comparing SC ami+laz vs IV for C_trough were 1.15 (90% CI, 1.04–1.26) for C2D1 and 1.43 (90% CI, 1.27–1.61) for C4D1. GMR for C2 AUCD1-D15 was 1.03 (90% CI, 0.98–1.09). ORR was 30.1% (95% CI, 24–37) in the SC arm and 32.5% (95% CI, 26–39) for IV (relative risk, 0.92; P = 0.001), meeting noninferiority criteria. The median duration of response (DoR) was longer for SC ami+laz vs IV (median, 11.2 vs 8.3 mo among confirmed responders).

A favorable PFS trend was observed for SC ami+laz over IV (median, 6.1 vs 4.3 months; HR, 0.84; P = 0.20). OS was notably longer for SC ami+laz vs IV (HR, 0.62; 95% CI, 0.42–0.92; nominal P = 0.017). At 12 months, 65% were alive in the SC arm vs 51% for IV. IRRs were ~5-fold lower in the SC arm: 13% vs 66% for IV, primarily grade 1-2 (0.5% vs 4% grade ≥3, respectively). Overall, 81% received prophylactic anticoagulants, with VTE reported by 9% in the SC arm vs 14% for IV. Across both arms, VTE incidence was 10% for patients who received prophylactic anticoagulants vs 21% for patients who did not. Severe bleeding risk was low among all patients receiving anticoagulants (1% grade ≥3).

The study concluded that SC ami demonstrated non-inferior PK and ORR compared to IV administration. Surprisingly, patients receiving SC amivantamab experienced longer DoR, PFS, and OS suggesting a potential impact of route or formulation on outcomes in EGFR-mutated advanced NSCLC. Additionally, SC administration was associated with improved safety, including lower rates of infusion-related reactions and VTE. Implementation of prophylactic anticoagulation was deemed safe and effective in reducing VTE risk.

The trial was sponsored by Janssen Research & Development, LLC.

Source: https://meetings.asco.org/abstracts-presentations/232405

Clinical Trial: https://clinicaltrials.gov/study/NCT05388669

Leighl N B, Akamatsu H, Lim S M, et al. (2024). “Subcutaneous amivantamab vs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial.” Presented at ASCO 2024. J Clin Oncol 42, 2024 (suppl 17; abstr LBA8505), 10.1200/JCO.2024.42.17_suppl.LBA8505