Subcutaneous (SC) is faster and easier than intravenous (IV) amivantamab plus lazertinib for refractory, EGFR-mutated advanced non-small cell lung cancer (NLCLC) with encouraging efficacy signals. The primary results of the PALOMA-3 trial found that SC administration is noninferior to IV with respect to pharmacokinetics, overall response rate (ORR), and duration of response (DoR). At the same time, SC administration is superior to IV for overall survival (OS), treatment time, the incidence of infusion related reactions (IRR) and venous thromboembolism (VTE), and ease of administration.
“Median survival has not yet been reached in either arm. However, survival was improved with the use of subcutaneous amivantamab plus lazertinib, with a hazard ratio of 0.62 in this preplanned exploratory analysis,” said Natasha Leighl, MD, Clinical Investigator at Princess Margaret Cancer Centre and Assistant Professor of Medicine, University of Toronto, Toronto, who presented the results at the 2024 American Society of Clinical Oncology Annual Meeting.
Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, is already approved as an IV formulation, but IV use has a first administration time of nearly 5 hours and requires split dosing. PALOMA-3 was designed to assess noninferiority of SC dosing for pharmacokinetics, efficacy, and safety compared to the IV formulation in combination with lazertinib.
The trial randomized 418 patients with refractory, EFGR-mutated advanced NSCLC 1:1 to SC or IV dosing of amivantamab with oral lazertinib. Baseline patient demographics and disease characteristics were well balanced between the two arms. The population received a median of two lines of prior therapy, although some were more heavily pretreated and a third of patients had brain metastases at baseline.
SC dosing met co-primary endpoints for noninferiority, trough concentration levels at cycle 2, and area under the curve, Dr. Leighl reported. ORR was also noninferior, 30% in the SC arm and 33% in the IV arm, for a relative risk of 0.92 (95% CI 0.70-1.23).
DoR was numerically longer in the SC arm, 11.2 months versus and 8.3 months in the IV arm, and the median time to response was 1.5 months in both arms. Of patients receiving SC administration, 29% have had a DoR of 6 months or longer compared to 15% in the IV arm.
At 7 months of follow up, the SC arm yielded a PFS of 6.1 months compared to 4.3 months for the IV arm, a hazard ratio of 0.84 (95% CI 064-1.10, p=0.20)
Adverse events were similar in the two arms with one notable exception, Dr. Leighl said. Investigators reported a five-fold reduction of IRR in SC arm; 13% in the SC arm compared to 66% in the IV arm. There were no adverse events leading to hospitalization or discontinuation of treatment in the SC arm with 2 and 4 events respectively in the IV arm.
Dr. Leighl noted that PALOMA-3 is the first study to explore prophylactic anticoagulation to reduce VTE in patients receiving both amivantamab and lazertinib. More than 80% of patients received prophylaxis and VTE was seen in 10% of patients receiving prophylaxis versus 21% in those not receiving prophylaxis. “We conclude that administering prophylaxis to our patients receiving amivantamab plus lazertinib does impact the rate of VTE and should be routine,” she said.
SC dosing also had a dramatic effect on first-dose administration: 5 minutes with SC versus 5 hours for IV dosing of the first dose. Subsequent IV doses require 2 hours. Most patients, 85%, reported greater convenience in SC dosing compared to IV infusions both at the end of cycle 1 and at the end of treatment.
“These findings meet the criteria required for bridging from intravenous to subcutaneous formulation,” said discussant Jessica Lin, MD, Associate Professor of Medicine at Harvard Medical School and Attending Physician at Massachusetts General Hospital Center for Thoracic Cancers and Henri and Belinda Termeer Center for Targeted Therapies. “If approved, I would favor subcutaneous over IV dosing of amivantamab as this should alleviate toxicity and improve outcomes for patients and care efficiency.”
