CHICAGO — Administering the bispecific antibody amivantamab (Rybrevant) subcutaneously rather than intravenously in combination with lazertinib (Leclaza) not only reduces administration times but also may offer improved outcomes in EGFR-mutated advanced non-small cell lung cancer (NSCLC), according to results from PALOMA-3.
The research was presented here May 31 at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.
Subcutaneous amivantamab plus lazertinib was not only more convenient for patients and healthcare providers than the intravenous approach, it was also associated with a significant improvement in overall survival (OS), said study presenter Natasha B. Leighl, BSc, MMSc, MD, Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Canada.
Administering the subcutaneous formulation took less than 5 minutes vs 2 to 5 hours with the intravenous approach and, at a median follow-up of 7 months, the subcutaneous formulation was associated with a 38% reduced risk of death (hazard ratio [HR], 0.62, nominal P = .02).
Jessica J. Lin, MD, of Massachusetts General Hospital, Harvard Medical School, Boston who was not involved in the study, said that, if the formulation is approved, "I would favor subcutaneous over intravenous dosing of amivantamab, as this should alleviate time and clinical toxicity, and improve outcomes for patients."
Amivantamab was granted accelerated approved by the US Food and Drug Administration in May 2021 for EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy, based on response rate data from a phase 1 clinical trial.
In 2023, three phase 3 studies — PAPILLON, MARIPOSA, and MARIPOSA-2— showed that combining the drug with either platinum-based chemotherapy or lazertinib was associated with meaningful progression-free survival benefits over standard therapy.
However, in these studies amivantamab was given as an intravenous formulation.
The issue with the intravenous formulation is that the drug "has a first administration time of over 4 hours, and the initial dose requires split dosing over 2 days," said Leighl. Moreover, it is associated with an infusion-related reaction rate of 67%.
To reduce the administration time and enhance the treatment experience, researchers developed a subcutaneous administration program.
The initial PALOMA phase 1b study assessed the feasibility of subcutaneous administration and established a recommended dose with a low infusion-related reaction rate. The current phase 3 PALOMA-3 trial compared the efficacy, safety, and pharmaco*kinetics of subcutaneous vs intravenous amivantamab plus lazertinib.
The researchers enrolled 418 patients with documented EGFR-mutated locally advanced or metastatic NSCLC and whose disease had progressed on or after osimertinib (Tagrisso) and platinum-based chemotherapy.
Study participants were randomly assigned to either the subcutaneous or intravenous formulations of the combination, both of which followed the same schedule. The patients were also recommended to have prophylactic anticoagulation for the first 4 months of treatment.
The median age of patients was 61.5 years, 67% were female, and the majority (61%) were Asian (36%-38% were White). The patients had received a median of two prior lines of therapy, and 34% had a history of brain metastases.
Treatment administration time was reduced to less than 5 minutes with subcutaneous amivantamab plus lazertinib vs 5 hours for the first infusion and 2 hours for subsequent infusions with the intravenous formulation.
At the end of the treatment period, 85% of patients given the subcutaneous version reported they found the administration method to be convenient or very convenient on the Modified Treatment Administration Satisfaction Questionnaire vs 35% in the intravenous arm.
The two co-primary pharmaco*kinetic endpoints of trough concentration levels and cycle 2 area under the curve were met, indicating that exposure to the drug was almost identical between the subcutaneous and intravenous formulations.
The overall response rate was also non-inferior between the two treatment groups, at 27% with both formulations, and the disease control rate was similar as well — 75% with the subcutaneous formation vs 71% with the intravenous version.
The disease control rate was longer in the subcutaneous arm — 11.2 vs 8.3 months in patients treated intravenously — and about twice as many subcutaneous patients had a response lasting 6 months or more — 29% vs 14%.
The subcutaneous formulation was also associated with a numerically, though not significantly, longer progression-free survival compared with the intravenous version, at a median of 6.1 months vs 4.3 months (HR, 0.84; P = .20).
In a pre-planned exploratory analysis, the researchers did find a significant overall survival benefit with subcutaneous amivantamab plus lazertinib (HR, 0.62; P = .02), with 65% of patients still alive at 12 months versus 51% in the intravenous arm.
The rates of treatment-emergent adverse events "were similar between the arms" over a median treatment duration of about 4 to 5 months, Leighl said.
Adverse events leading to death were uncommon and treatment-related discontinuation was also low, at 9% in the subcutaneous and 12% in the intravenous arm, Leighl reported.
However, as expected, the rate of infusion-related reactions was much lower in the subcutaneous arm compared to the intravenous arm, at 13% and 66% respectively.
Most adverse events occurred during the first treatment cycle. There were no incidences of infusion-related reactions leading to hospitalization with the subcutaneous formulation vs two in the intravenous arm. There were also no infusion-related reaction discontinuations in the subcutaneous arm vs four events in the intravenous arm.
The results "represent an important, clinically meaningful advance for patients and healthcare professionals," Lin commented, adding that "we need more studies like PALOMA-3 dedicated to addressing how to reduce treatment burden, while delivering effective cancer therapies to patients."
Lin also highlighted a "need to more comprehensively asses if, and mechanistically, how subcutaneous amivantamab enhances efficacy" compared with the intravenous formulation.
The study was funded by Janssen Research & Development, LLC.
Leighl declares relationships with AstraZeneca; Beigene; BMS; Janssen; MSD Oncology; Takeda; AstraZeneca Canada (Inst); Inivata/NeoGenomics (Inst); Janssen Oncology (Inst); Lilly (Inst); MSD (Inst); Novartis (Inst); and Pfizer (Inst).
Lin declares relationships with OncLive; Pfizer; Anheart Therapeutics; AstraZeneca; Bayer; Blueprint Medicines; Bristol-Myers Squibb; C4 Therapeutics; CLaiM Therapeutics; Daiichi Sankyo/AstraZeneca; Elevation Oncology; Ellipses Pharma; Genentech; Merus; Mirati Therapeutics; Novartis; Nuvalent, Inc.; Pfizer; Regeneron; Turning Point Therapeutics; Yuhan; Hengrui Therapeutics (Inst); Linnaeus Therapeutics (Inst); Neon Therapeutics (Inst); Relay Therapeutics (Inst); and Roche (Inst).
