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Amivantamab approval
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Based on clinical data from the Phase 1 CHRYSALIS trial (ClinicalTrials.gov NCT02609776
), the FDA granted accelerated approval for amivantamab in May
2021 as therapy for adults with locally advanced or metastatic
NSCLC with EGFR exon 20 insertion mutations whose disease has
progressed on or after platinum-based chemotherapy16,17
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Amivantamab is being evaluated in other studies, including as
combination therapy, in various Phase 3 trials18–20
Why combine amivantamab and lazertinib?
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Preclinical and early clinical studies suggest improved inhibition
of tumor growth when both the extracellular and intracellular
catalytic domains of the EGFR receptor are simultaneously
targeted9,13,15,21–23
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Lazertinib is a mutation selective, CNS-penetrant,
third-generation EGFR TKI with intracellular
activity that targets T790M and common
EGFR mutations9
Key hypothesis
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Combining amivantamab with lazertinib may be potent against
acquired resistance, such as
EGFR
T790M-mutated tumors, while also increase blood-brain barrier
(BBB) penetration and CNS activity4,9
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Mechanistically, simultaneous treatment with amivantamab and
lazertinib provides a multi-pronged approach, with two
structurally distinct mechanisms of EGFR inhibition: the
extracellular binding of EGFR with amivantamab and the
intracellular TKI activity of lazertinib4
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The combination of amivantamab and lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations was FDA approved based on results from the Phase 3 MARIPOSA trial (ClinicalTrials.gov NCT04487080).
Amivantamab
Mechanism of action
Johnson &Johnson Innovative Medicine | 03/2024
Patients with EGFR -mutated NSCLC are often treated with
EGFR TKIs, although some more uncommon mutations are resistant to
TKI therapy.4,5
Amivantamab is a
first-in-class bispecific antibody targeting both the EGFR and MET
signaling pathways by binding the extracellular regions of the
respective receptors.3,4
Amivantamab reduces ligand-induced receptor activation by blocking
the binding of EGF to EGFR, and HGF to MET.4,13
The binding of the Fc region of amivantamab to the Fcγ receptors on
immune cells induces several effector functions through activation
of the immune cells. Of these, trogocytosis is the most prominent
activity.4,15
Amivantamab is a bispecific antibody that acts via three different
mechanisms of action and has a design tailored around higher
selectivity and specificity.3,4
The EGFR gene is a key oncogene that is mutated in
different cancer types, including NSCLC, and regulates cell
proliferation and survival.1
A majority of NSCLC tumors eventually acquire resistance to therapy
through various mechanisms, leading to disease progression.4,10–12
Amivantamab inhibits receptor activation and downstream signaling
through three separate mechanisms of action (MOA).4
Amivantamab reduces downstream signaling as a result of EGFR and MET
receptor degradation following receptor internalization.4,13
Other immune cell-directed activities include cellular cytotoxicity,
phagocytosis, and cytokine release.4,14
