Subcutaneous Amivantamab Plus Lazertinib Non-Inferior to IV Dosing in NSCLC

CHICAGO — Subcutaneous amivantamab (Rybrevant) was non-inferior to IV amivantamab for pre-treated patients with refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC), with the suggestion of a possible survival benefit, according to the phase III PALOMA-3 trial.

The 418 patients in the study had disease progression after treatment with osimertinib (Tagrisso) and chemotherapy. Amivantamab was combined with the tyrosine kinase inhibitor lazertinib (Leclaza), and subcutaneous administration met the two co-primary pharmacokinetic (PK) efficacy endpoints, which was measured by amivantamab levels in the blood (C_trough and area under the serum concentration time curve from day 1 to 15), reported Natasha B. Leighl, MD, of the Princess Margaret Cancer Centre in Toronto.

In addition, overall response rates with subcutaneous and IV amivantamab also met the criteria for non-inferiority (30.1% and 32.5%, respectively, relative risk 0.92, P= 0.001).

Moreover, in results that the investigators described as unexpected, secondary endpoints of duration of response and progression-free survival (PFS), as well as the exploratory endpoint of overall survival (OS), were all longer in the subcutaneous arm. The median duration of response came in at 11.2 months in the subcutaneous arm versus 8.3 months in the IV arm.

In addition, at a median follow-up of 7 months, PFS was longer in the subcutaneous arm compared with IV dosing at a median 6.1 months versus 4.3 months (HR 0.84, P=0.20).

The exploratory analysis showed OS was significantly longer in the subcutaneous arm (HR 0.62, 95% CI 0.42-0.92, P= 0.017), with 65% of patients dosed subcutaneously alive at 12 months compared with 51% in the IV arm.

“Further studies are needed to elucidate the mechanism of this effect,” Leighl said at the American Society of Clinical Oncology (ASCO) annual meeting. “For example, does subcutaneous absorption of amivantamab via the lymphatic system enhance its immune-mediated activity?”

“The findings meet the criteria required for bridging from IV to subcutaneous formulation,” commented ASCO discussant Jessica Jiyeong Lin, MD, of Massachusetts General Hospital and Harvard Medical School in Boston. “In fact, there was an advantage in reducing certain clinically important toxicities, with an expected shortening of administration time and improvement in patient-reported convenience.”

Regarding those safety and patient convenience measures, there were fewer infusion-related reactions (IRRs) with the subcutaneous formulation (13% vs 66%) as well as fewer reports of venous thromboembolism (9% vs 14%).

In addition, administration time was substantially shorter for subcutaneous amivantamab (median less than approximately 5 minutes) compared to IV administration (up to 5 hours), with significantly more patients reporting convenience with subcutaneous administration (85% vs 35% with IV administration).

These findings from PALOMA-3 “represent an important, clinically meaningful advance for patients and healthcare providers,” Lin said. “If approved, I would favor subcutaneous over IV dosing of amivantamab as it should alleviate toxicity and improve outcomes for patients and care efficiency. Future studies are needed to more comprehensively assess if, and how, subcutaneous amivantamab enhances efficacy.”

Leighl noted that while amivantamab has been approved as an IV formulation, it has a first administration time of ≥4 hours and a high IRR rate, leading to the development of a “patient centric” subcutaneous program with the intent of reducing administration time.

The study included pre-treated patients with good performance status and advanced EGFR Ex19del- or L858R-mutant NSCLC. They were randomized to receive either subcutaneous or IV amivantamab, both in combination with lazertinib, in 28-day cycles.

About two-thirds of patients were female, with a median age of 61 in the subcutaneous arm and 62 in the IV arm. They received a median of two prior lines of therapy (some received as many as 5 prior lines). About one-third of patients had brain metastases at baseline.

Leighl also pointed out that PALOMA-3 investigators prospectively looked at the impact of prophylactic anticoagulation on the risk of VTE receiving the study drugs. Prophylaxis was administered to about 80% of patients and among all patients VTE was seen in 10% of those receiving prophylaxis compared with 21% of those who did not.

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

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