AMIVANTAMAB (AMI) is an EGFR-MET bispecific antibody with an immune mechanism of action including ligand blocking, receptor degradation, and engagement of immune effector cells, given its bispecific nature. The combination of AMI and chemotherapy significantly improved progression-free survival (PFS) compared with chemotherapy alone in patients with NSCLC after progression on osimertinib.
LASERTINIB (LS) is a highly selective, CNS-penetrating, third-generation EGFR TKI that is active in NSCLC with EGFR mutations, including the T790M mutation.
In the phase III LASER301 trial, first-line LS therapy improved PFS compared with gefitinib in patients with EGFR-mutated NSCLC.
In the second line, AMI+LZ demonstrated significant clinical activity in patients with EGFR-mutated NSCLC who experienced disease progression on osimertinib.
The first article we mention here is the international randomized phase III MARIPOSA trial comparing AMI+LZ with osimertinib, a first-line treatment for EGFR-mutated advanced NSCLC, which was published in The New England Journal of Medicine, and the results were amazing! PFS was significantly longer in the AMI+LZ group than in the osimertinib group (23.7 vs. 16.6 months; HR, 0.70).
The second article we review here presents results from the same MARIPOSA study with a secondary analysis in patients with high-risk disease for progression as determined by circulating tumor DNA (ctDNA) at baseline and still present at cycle 3 of treatment , or with a TP53 gene mutation, or liver metastases. Once again, the results of this secondary analysis were impressive. AMI+LZ significantly prolonged PFS in patients who did not undergo ctDNA clearance compared with osimertinib, resulting in a median PFS of 16.5 versus 9.1 months, with a hazard ratio of 0.49. Similarly, in patients with a TP53 mutation, PFS was 18.2 months versus 12.9 months in favor of combination treatment, with a hazard ratio of 0.65.
Together, these two articles provide us with a truly new therapeutic approach to treating EGFR-mutated lung cancer. The EGFR–MET bispecific antibody amivantamab (with a novel mechanism of action) in combination with lasertinib is superior to osimertinib in patients with advanced NSCLC. In addition, patients with disease at high risk of progression may also experience superior results with this combination.
The AMI–LZ combination is currently approved by the FDA as second-line therapy for EGFR-mutated non-small cell lung cancer; It is reasonable that the findings will help elevate this combination to first-line status if these results are confirmed by other studies.
Amivantamab plus Lasertinib versus Osimertinib for first-line treatment of EGFR-mutated advanced NSCLC.
Activating mutations in the EGFR gene occur in 15–50% of cases of non-squamous non-small cell lung cancer (NSCLC). These are usually deletions of exon 19 or substitutions of exon 21 (for example, the L858R mutation). Third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, have been most effective in this patient population, including activity against the T790M mutation when present. However, all patients eventually develop resistance to this approach.