Amivantamab-vmjw is a first-in-class, fully human bispecific antibody that targets epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET). It represents one of the most significant therapeutic advances for patients with EGFR-driven non–small cell lung cancer (NSCLC), particularly those with tumors harboring EGFR exon 20 insertion mutations, a population historically characterized by aggressive disease biology and resistance to conventional EGFR tyrosine kinase inhibitors (TKIs). Since its accelerated FDA approval in 2021, amivantamab has rapidly expanded its clinical footprint, supported by robust data from multiple landmark trials, including CHRYSALIS, PAPILLON, and MARIPOSA.
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Mechanism of Action: Dual Targeting of EGFR and MET
Amivantamab is a bispecific IgG1 antibody engineered to bind the extracellular domains of both EGFR and MET. By doing so, it simultaneously blocks ligand-dependent signaling in both pathways, induces receptor degradation, and engages immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC) (Park et al., 2021). The dual inhibition is critical, because MET amplification and MET-dependent bypass signaling frequently mediate resistance to EGFR TKIs, particularly osimertinib. Amivantamab’s ability to target both receptors allows it to counteract multiple mechanisms of primary and acquired resistance.
Structural studies demonstrate that amivantamab uniquely binds to the extracellular portion of EGFR, unlike TKIs that interact with the intracellular kinase domain (Yun et al., 2023). This extracellular binding enables activity against EGFR exon 20 insertions, where steric hindrance limits TKI efficacy.
Clinical Evidence Supporting Amivantamab
CHRYSALIS: First Evidence Leading to FDA Approval
The CHRYSALIS Phase I study established amivantamab as the first approved therapy specifically for EGFR exon 20 insertion–positive NSCLC. In 81 patients previously treated with platinum chemotherapy, amivantamab demonstrated an overall response rate (ORR) of 40%, with a median duration of response (mDOR) of 11.1 months, and a median progression-free survival (mPFS) of 8.3 months (Park et al., 2021). These outcomes significantly exceeded historical data for standard chemotherapy and single-agent TKIs in this population, where ORRs typically ranged from 3% to 12%.
Infusion-related reactions (IRRs) occurred in approximately 66% of patients, almost exclusively during the first infusion, and were manageable with premedication and split dosing. Other common adverse events included rash, paronychia, and hypoalbuminemia.
CHRYSALIS-2: Activity After Osimertinib and Chemotherapy
CHRYSALIS-2 extended the evidence base to patients previously treated with both osimertinib and platinum chemotherapy—one of the most difficult groups to treat. The study reported a 37% ORR, a median PFS of 4.9 months, and durable responses in a heavily pretreated cohort (Johnson et al., 2023). These findings supported amivantamab’s potential role in post-TKI, post-chemotherapy resistance settings.
PAPILLON: Amivantamab + Chemotherapy in First-Line EGFR Exon 20 Insertion NSCLC
The PAPILLON Phase III trial changed the treatment landscape by demonstrating significant benefit for amivantamab combined with carboplatin-pemetrexed in the first-line setting. The combination produced a median PFS of 11.4 months, nearly doubling outcomes compared with chemotherapy alone (6.7 months), with a hazard ratio for progression or death of 0.40 (Sabari et al., 2023). The ORR also improved substantially, confirming the synergistic effect of antibody-targeted inhibition with cytotoxic chemotherapy.
These results position amivantamab-based regimens as the preferred first-line therapy for EGFR exon 20 insertion NSCLC in major treatment guidelines (NCCN, 2024).
MARIPOSA: Amivantamab + Lazertinib vs Osimertinib
The MARIPOSA Phase III trial evaluated the combination of amivantamab with lazertinib, a third-generation EGFR TKI, in treatment-naïve common EGFR-mutated NSCLC (ex19del or L858R). The study demonstrated superior PFS of 23.7 months versus 16.6 months with osimertinib, with a hazard ratio of 0.70 (Johnson et al., 2024). Importantly, intracranial activity was preserved, and the combination reduced the emergence of MET-driven resistance.
This is the first trial to outperform osimertinib in the first-line setting, marking the beginning of a new era in EGFR-mutant NSCLC.
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MARIPOSA-2: Post-Osimertinib Setting
MARIPOSA-2 evaluated two combinations—amivantamab plus lazertinib, and amivantamab plus chemotherapy—in patients who progressed on first-line osimertinib. Both regimens significantly improved PFS compared with chemotherapy alone. The amivantamab + chemotherapy regimen achieved PFS of ~8.3 months versus 4.2 months with chemotherapy alone, cutting the risk of progression by ~50%. This is a population for whom historical options were limited to single-agent chemotherapy with poor outcomes.
Safety Profile
Amivantamab’s safety profile is consistent across trials. IRRs, skin toxicity (acneiform rash, paronychia), hypoalbuminemia, and peripheral edema are the most frequent adverse events. These reflect EGFR and MET pathway inhibition. Discontinuation rates remain low, underscoring its tolerability even when combined with chemotherapy or TKIs.
Future Directions and Ongoing Research
Amivantamab is currently being studied in:
- Combination regimens with lazertinib (MARIPOSA-3)
- Neoadjuvant and adjuvant therapy for early-stage NSCLC
- Combinations with antibody-drug conjugates (ADCs) to deepen response rates
- Trials targeting resistance mechanisms after osimertinib and amivantamab failure
Preclinical data suggest amivantamab may sensitize tumors to MET-TKIs and ADCs, offering opportunities for rational next-line strategies.
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Conclusion
Amivantamab has emerged as one of the most important therapeutic innovations in EGFR-driven NSCLC. Its dual EGFR/MET inhibition mechanism addresses key resistance pathways, and clinical results across multiple Phase I–III studies consistently demonstrate meaningful, durable responses—even in historically refractory subgroups. With ongoing expansion into earlier lines of therapy and combinations with next-generation TKIs, amivantamab is reshaping the treatment landscape and may soon become foundational in EGFR-mutant lung cancer care.
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Written by Armen Gevorgyan, MD