A novel three-drug combination regimen—amivantamab, lazertinib, and bevacizumab—may offer effective treatment for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who experience disease progression following third-generation EGFR tyrosine kinase inhibitors (TKIs), according to results from a single-arm phase II trial.
The study reported a 33% objective response rate (ORR) at 12 weeks and a 39% best overall response rate (BORR) for the triplet therapy, meeting the predefined primary endpoint. Median progression-free survival (PFS) reached 10.9 months, with a median duration of response of 13.9 months. An updated analysis indicated a median overall survival (OS) of 19.9 months, demonstrating chemotherapy-sparing potential.
“This is the first prospective trial evaluating a biologic combination targeting EGFR, MET, and angiogenic pathways,” noted lead author Rolf A. Stahel, MD, and colleagues in Lancet Respiratory Medicine. “These preliminary findings suggest sustained antitumor activity in a subset of patients with acquired resistance to third-generation EGFR TKIs.”
Third-generation EGFR TKIs like osimertinib and lazertinib remain standard first-line therapies for advanced NSCLC with sensitizing EGFR mutations. However, resistance inevitably develops, prompting exploration of alternative strategies. The phase III MARIPOSA trial previously demonstrated that amivantamab-lazertinib improved PFS by 7 months versus osimertinib monotherapy, leading to its first-line approval. Subsequent MARIPOSA-2 data further confirmed benefits when combining amivantamab with or without lazertinib plus chemotherapy in post-osimertinib patients.
Yun Fan, MD, PhD, highlighted that the current study’s median PFS and response duration were among the longest reported in this setting, suggesting durable efficacy in some patients through simultaneous EGFR, MET, and VEGF inhibition. However, she cautioned that the modest ORR compared with prolonged PFS might stem from enrollment of lower-risk patients, and the comparator-free design limits definitive conclusions.
The ETOP 18-21 AMAZE-lung trial enrolled 61 patients across 17 European centers between March 2023 and May 2024. Most participants (82%) were white, 70% female, with a median age of 65 years. Sixty-one percent had stage IVB disease, 61% were never-smokers, and 62% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1.
Primary treatment-related adverse events (TRAEs) included infusion-related reactions (58%) and acneiform rash (50%). Severe (grade 3-4) TRAEs occurred in 43% of patients, with 20% experiencing serious adverse events. Venous thromboembolism was reported in 17% (grade 3-4: 3%), and treatment discontinuations occurred in 67% of patients, primarily due to infusion reactions (amivantamab: 10%), thrombotic events (bevacizumab: 13%), and rash (lazertinib: 5%). No treatment-related deaths were observed.
Researchers emphasized that single-arm trial limitations necessitate validation through randomized studies. This investigation marks a critical step in managing resistance to modern EGFR-targeted therapies while minimizing chemotherapy exposure.
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