Investigators Present Primary Results of PALOMA-3 Study Comparing Subcutaneous, IV Administration of Amivantamab

Subcutaneous (SC) amivantamab plus lazertinib demonstrated longer overall survival (OS) and progression-free survival (PFS) times than intravenous (IV) amivantamab plus lazertinib in patients with refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC) in the phase 3 PALOMA-3 trial.

This result, which arose “unexpectedly,” suggests that the “route of administration or formulation may affect outcomes,” according to the study investigators, led by Natasha B. Leighl, MD, FASCO, of the Princess Margaret Cancer Centre and the University of Toronto.

Dr. Leighl presented results from the study during an oral abstract session held Friday, May 31 at the 2024 American Society of Clinical Oncology Annual Meeting.

The combination of amivantamab plus lazertinib has shown antitumor activity in EGFR-mutated advanced NSCLC. SC administration of amivantamab is an option that “takes ≤7 minutes and has low infusion-related reaction (IRR) rates,” according to the PALOMA-2 investigators, who compared SC amivantamab plus lazertinib versus IV amivantamab plus lazertinib.

The study evaluated the pharmacokinetics, efficacy, and safety of SC versus IV administration in 418 patients with EGFR Ex19del- or L858R-mutated advanced NSCLC who had disease progression on osimertinib and platinum-based chemotherapy. The median patient age was 61 years, 67% were female, and 61% were Asian. Patients had a median of 2 prior lines of therapy.

The patients were randomized to receive manual injections of SC amivantamab 1600 mg (2240 mg for those ≥80 kg) weekly for the first 4 weeks, then every 2 weeks (n=206), or IV amivantamab at the approved dose of 1050 mg (1400 mg for those ≥80 kg; n=212). All patients also received oral doses of lazertinib 240 mg daily. Prophylactic anticoagulation was recommended for the first 4 months of treatment.

The co-primary pharmacokinetic noninferiority end points were trough concentration (Ctrough on cycle [C] 2 day [D] 1 or C4D1) and the C2 area under the curve (AUCD1-D15). Key secondary end points of PALOMA were the objective response rate (ORR) and PFS, with OS as a predefined exploratory end point.

PALOMA-3 met both co-primary end points of Ctrough and the cycle 2 area under the curve at a median follow-up of 7 months.

The geometric mean ratios (GMRs) comparing SC versus IV for Ctrough were 1.15 (90% CI, 1.04-1.26) for C2D1 and 0.43 (90% CI, 1.27-1.61) for C4D1. The GMR for C2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09).

The ORR was 30.1% (95% CI, 24%-37%) in patients receiving SC administration and 32.5% (95% CI, 26%-39%) for those receiving IV administration (relative risk, 0.92; P= .001), which was “meeting the noninferiority criteria,” according to the study authors.

Among patients with confirmed responses, the median duration of response was 11.2 months in those who received SC administration, longer than the median of 8.3 months among those receiving IV administration. The study also showed a “favorable PFS trend” in patients receiving SC administration, with a median PFS of 6.1 months, compared with 4.3 months in those receiving IV administration. The OS was “notably longer” in patients receiving SC than in those receiving IV (hazard ratio, 0.62; 95% CI, 0.42-0.92; nominal P=.017), according to the study authors.

At 12 months, 65% of patients receiving SC administration were alive, compared with 51% of those receiving IV administration. In addition, IRRs were around 5 times lower in the patients receiving SC administration (13%) than in those receiving IV administration (66%). The IRRs were “primarily grade 1-2,” Dr. Leighl and colleagues noted.

Most (81%) patients received prophylactic anticoagulants, with venous thromboembolism (VTE) reported in 9% of those receiving SC administration compared with 14% in those receiving IV administration. Across SC and IV administration routes, the VTE incidence rate was lower (10%) in those who received prophylactic anticoagulants than in those who did not (21%), and the risk of severe bleeding “was low among all patients” receiving prophylactic anticoagulants, according to the investigators.

Dr. Leighl and colleagues concluded by reflecting on the results, noting that SC administration showed noninferior pharmacokinetics and ORR compared with IV administration.

“Unexpectedly, [duration of response], PFS, and OS were longer in the SC arm versus IV, suggesting that the route of administration or formulation may affect outcomes,” Dr. Leighl and colleagues explained. “The safety profile was improved for SC [amivantamab], with lower IRR and VTE rates. Prophylactic anticoagulation can be safely implemented and reduces VTE risk.”

Reference

Leighl NB, Hiroaki 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. Presented at the 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, Illinois.