Blood-Brain Barrier Penetration of Amivantamab
Amivantamab has poor blood-brain barrier (BBB) penetration due to its large molecular size as a bispecific monoclonal antibody, with expected limited CNS activity similar to other antibody-based therapeutics (typically 0.1-0.2% of injected dose reaches the brain). 1, 2
Molecular Characteristics Limiting CNS Penetration
Amivantamab is a large bispecific monoclonal antibody targeting EGFR and MET, and like other antibody-based therapeutics, faces significant barriers to crossing the BBB due to its molecular size. 1, 2
Monoclonal antibodies typically achieve only 0.1-0.2% of the injected dose in brain tissue due to the restrictive nature of the BBB, which limits passage through tight junctions between endothelial cells and restricts vesicular transport. 2
The cerebral capillaries at the BBB restrict drug entry through tight junctions, lack of intracellular fenestrations, paucity of endocytotic vesicles, and presence of multiple efflux transporters. 3
Clinical Evidence of CNS Activity
Despite poor BBB penetration, emerging clinical data suggest amivantamab may have some CNS activity through indirect mechanisms:
In the MARIPOSA-2 trial evaluating amivantamab plus chemotherapy in post-osimertinib EGFR-mutated NSCLC, intracranial PFS showed improvement (HR 0.55,95% CI 0.38-0.79), suggesting some benefit in controlling brain metastases. 3
A case report demonstrated complete resolution of leptomeningeal disease and brain metastases with amivantamab monotherapy in a patient with rare EGFR mutations (G719A and A289V), challenging assumptions about its CNS limitations. 4
In the CHRYSALIS trial of amivantamab monotherapy for EGFR exon 20 insertions, intracranial-only progression occurred in only 11% (13/114) of participants, with brain being the site of first progression in 15% overall. 5
Practical Clinical Implications
For patients with brain metastases requiring amivantamab therapy:
Amivantamab remains a Category 1, preferred first-line option when combined with carboplatin-pemetrexed for EGFR exon 20 insertions, even in patients with treated brain metastases. 6, 7
Local therapy with stereotactic radiosurgery (SRS) while continuing amivantamab is feasible and well-tolerated for isolated intracranial progression, with patients continuing treatment for a median of 4.0 months post-SRS (range 2.3-6.0 months). 5
Unlike osimertinib, which demonstrated superior CNS penetration with only 6% CNS progression events compared to 15% with first-generation EGFR TKIs, amivantamab should not be relied upon as primary therapy for active CNS disease. 3
Key Caveats
The apparent CNS activity observed in clinical trials may reflect systemic disease control reducing seeding of new brain metastases rather than direct drug penetration into the CNS. 1
Future combination strategies pairing amivantamab with brain-penetrant EGFR kinase inhibitors are being evaluated to address this limitation. 1
Patients with untreated or progressive brain metastases may benefit from upfront local CNS-directed therapy (radiation or surgery) in addition to systemic amivantamab-based regimens. 5