Subcutaneous Amivantamab Noninferior to IV Administration in EGFR-Mutated NSCLC

Subcutaneous Amivantamab Noninferior to IV Administration in EGFR-Mutated NSCLC

Subcutaneous amivantamab (Rybrevant) was noninferior to intravenous (IV) administration of the therapy with regards to pharmacokinetics and objective response rate (ORR) in patients with refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC), as demonstrated by primary results from the phase 3 PALOMA-3 trial (NCT05388669) presented at the 2024 ASCO Annual Meeting.

Further, data from the trial also demonstrated improvements in other end points, such as duration of response (DOR), as well as progression-free (PFS) and overall survival (OS).

“Compared to the IV arm, we saw a numerically longer duration of response and PFS and a significant improvement in overall survival,” Natasha B Leighl, BSc, MMSc, MD, clinical investigator at the Princess Margaret Cancer Centre in Toronto, Canada, said during the presentation of the findings. “Further studies are needed to elucidate the mechanism of this effect.”

Results

The trial met both coprimary end points of area under the curve at cycle 2 (between days 1 and 15) and trough concentration (on cycle 2 day 1, or cycle 4 day 1) after a median follow-up of 7.0 months. The geometric mean ratios, when comparing subcutaneous amivantamab plus lazertinib (Leclaza) with IV amivantamab, for trough concentration was 1.15 (90% CI, 1.04-1.26) at cycle 2 day 1 and 1.03 (90% CI, 0.98-1.09) at cycle 2 between days 1 and 15. The geometric mean ratio for trough concentration at steady state (cycle 4 day 1) was 1.43 (90% CI, 1.27-1.61).

The ORR was 30% (95% CI, 24%-37%) in patients assigned subcutaneous amivantamab compared with 33% (95% CI, 26%-39%) in those assigned IV amivantamab (relative risk, 0.92; 95% CI, 0.70-1.23; P = .001), which met the noninferiority criteria. For patients who were confirmed responders, the ORR was 27% (95% CI, 21%-33%) in the subcutaneous arm and 27% (95% CI, 21%-33%) in the IV arm (relative risk, 0.99; 95% CI, 0.72-1.36; P < .001).

Among confirmed responders, patients who received subcutaneous amivantamab plus lazertinib had a longer median DOR compared with IV amivantamab (11.2 months [95% CI, 6.1-not estimable (NE) vs 8.3 months [95% CI, 5.4-NE]). The subcutaneous arm also had a favorable PFS trend (median, 6.1 months; 95% CI, 4.3-8.1) compared with the IV arm (median, 4.3 months; 95% CI, 4.1-5.7; HR, 0.84; 95% CI, 0.64-1.10; P = .20), although it was not statistically significant.

Patients assigned subcutaneous amivantamab plus lazertinib had a notably longer OS vs those assigned IV amivantamab (HR, 0.62; 95% CI, 0.42-0.92; nominal P = .02). More patients in the subcutaneous arm were alive at 12 months compared with the IV arm (65% vs 51%, respectively).

Infusion-related reactions were approximately 5-fold lower in patients assigned subcutaneous amivantamab vs IV amivantamab (13% vs 66%, respectively). There were no grade 4 or 5 infusion-related reactions, and most of these reactions occurred during cycle 1. Infusion-related reactions that led to hospitalization were not observed in the subcutaneous arm compared with 2 events in the IV arm. In addition, there were no infusion reaction-related discontinuations in the subcutaneous group compared with 4 events in the IV arm.

The majority of patients assigned either subcutaneous or IV administration of amivantamab received prophylactic anticoagulants (80% and 81%, respectively).

“PALOMA-3 is the first study to prospectively look at the impact of prophylactic anticoagulation on the risk of VTE [venous thromboembolism] in patients receiving amivantamab and lazertinib,” Leighl said during the presentation.

In all patients in the trial, VTE occurred in 9% of patients in the subcutaneous arm vs 14% of those in the IV arm. VTE was observed in 10% of patients who received prophylactic anticoagulants compared with 21% of those who did not. Of note, rates of grade 3 or higher bleeding events were uncommon in the subcutaneous and IV arms (2% and 1%, respectively) in those receiving prophylactic anticoagulation.

“We conclude that administering prophylaxis to our patients receiving amivantamab plus lazertinib does impact the rate of VTE and should be routine,” Leighl added.

Treatment administration time was reduced to less than 5 minutes for subcutaneous amivantamab, compared with 5 hours for the first infusion of IV amivantamab (and 2 hours for subsequent infusions). At the end of treatment, more patients reported that subcutaneous amivantamab was convenient or very convenient compared with IV amivantamab (85% vs 35%, respectively).

Methods

Researchers analyzed the efficacy, pharmacokinetics, and safety of subcutaneous amivantamab in patients with EGFR-mutated advanced NSCLC whose disease has progressed on or after osimertinib (Tagrisso) and platinum-based chemotherapy.

“Amivantamab is a bispecific EGFR- and MET-targeting antibody with immune cell directing activity, and it's approved for use as an intravenous formulation,” Leighl said during the presentation. “IV amivantamab has a first administration time of over 4 hours, and the initial dose requires split dosing over 2 days. And it also has an infusion related reaction rate, or IRR rate, of 67%. A subcutaneous amivantamab program was developed aiming to reduce the administration time for patients.”

In this study, 418 patients were randomized to receive amivantamab either subcutaneously (n = 206; median age, 61 years; 67% female) or intravenously (n = 212; median age, 62 years; 67% female). Both groups of patients also received lazertinib. Of the randomized patients, 416 received at least 1 dose of their assigned treatment. For the first 4 months of treatment, prophylactic anticoagulation was recommended for patients.

Regarding baseline demographics, patients in the subcutaneous and IV arms received a median of 2 prior lines of therapy, and 35% of patients in both arms had a history of brain metastases.

Subcutaneous amivantamab was given at a dose of 1600 mg (or 2240 for patients 80 kg or greater) and manually injected weekly for the first 4 weeks, followed by every 2 weeks. In contrast, IV amivantamab was given at a dose of 1050 mg (or 1400 for those 80 kg or greater). Patients from both groups received 240 mg of lazertinib orally daily.

Coprimary pharmacokinetics noninferiority end points of this trial were area under the curve at cycle 2 and trough concentration. In addition, key secondary end points included PFS, ORR, DOR, patient satisfaction, and safety. Researchers also included a predefined exploratory end point of OS.

Reference

Leighl NB, Akamatsu H, Lim SM, et al. 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. J Clin Oncol. 2024;42(suppl 17):LBA8505. doi:10.1200/JCO.2024.42.17_suppl.LBA8505