Amivantamab represents a significant advancement in targeted cancer therapy, particularly for certain types of lung cancer. This medication operates by specifically interacting with molecular pathways that drive tumor growth and survival. Understanding how amivantamab works at a detailed molecular level reveals its unique approach to combating cancer cells.
The Targets: EGFR and MET
Epidermal Growth Factor Receptor (EGFR) and Mesenchymal-Epithelial Transition (MET) are proteins found on the surface of cells. In healthy cells, EGFR and MET regulate normal cellular processes like growth, division, and repair. When natural growth factors bind to these receptors, they activate signaling pathways inside the cell, promoting controlled cell activity.
However, in many cancers, these receptors can become overactive or mutated, leading to uncontrolled cell growth and proliferation. For instance, certain mutations in the EGFR gene, such as exon 20 insertion mutations, are frequently found in non-small cell lung cancer (NSCLC). These specific mutations cause the EGFR protein to be constantly “on,” driving cancer progression even without external growth signals. Similarly, MET can become abnormally activated through gene amplification or overexpression, contributing to tumor growth and spread.
When cancer cells develop resistance to therapies that target only EGFR, they may activate alternative pathways, such as the MET pathway, to continue growing. This highlights the interconnectedness of these pathways in cancer development and resistance. Understanding these roles provides a foundation for appreciating why a therapy targeting both EGFR and MET is a promising strategy.
How Amivantamab Works
Amivantamab is designed as a bispecific antibody, meaning it has two “arms” that can each bind to a different target: one arm binds to EGFR, and the other binds to MET. This dual-targeting capability allows it to interfere with cancer cell signaling in multiple ways. The drug’s structure also includes a modified “Fc” region, which enhances its ability to engage immune cells.
One way amivantamab works is through ligand blocking. It physically prevents natural growth factors, such as epidermal growth factor (EGF) from binding to EGFR and hepatocyte growth factor (HGF) from binding to MET. By blocking these binding sites, amivantamab stops the activation of growth-promoting signals that would otherwise tell cancer cells to multiply. This action directly interrupts the abnormal communication pathways that fuel tumor growth.
Beyond blocking, amivantamab also induces receptor degradation. Once amivantamab binds to both EGFR and MET on the cell surface, it triggers the internalization of these receptors into the cell. Inside the cell, the receptors are then broken down, effectively reducing the number of these cancer-driving proteins available on the cell surface. This mechanism helps to further dampen the uncontrolled signaling that characterizes cancer cells.
Amivantamab also leverages the body’s own immune system through Antibody-Dependent Cellular Cytotoxicity (ADCC). Its modified Fc region allows it to bind more effectively to receptors on immune cells, such as Natural Killer (NK) cells. These NK cells then recognize the antibody-bound cancer cells and initiate their destruction.
Another immune-mediated mechanism is trogocytosis, where amivantamab mediates the transfer of membrane fragments and associated receptors from tumor cells to immune effector cells. This process can contribute to the reduction of receptors on the tumor cell surface and may also influence immune responses.
Why This Mechanism Matters in Cancer Treatment
The dual targeting of both EGFR and MET by amivantamab offers a distinct advantage in cancer treatment, particularly for patients with non-small cell lung cancer (NSCLC) harboring specific genetic alterations. Patients with EGFR exon 20 insertion mutations, for example, often respond poorly to traditional EGFR-targeted therapies, which are small molecule inhibitors. Amivantamab’s unique extracellular binding and dual activity against EGFR and MET allows it to bypass some of the resistance mechanisms that make these mutations difficult to treat.
The combination of blocking growth signals, degrading receptors, and recruiting immune cells provides a multi-faceted attack on cancer cells. This comprehensive approach can help overcome resistance pathways that often develop when cancer cells are targeted by single-mechanism drugs. For instance, if cancer cells develop resistance to EGFR inhibition by activating the MET pathway, amivantamab can simultaneously address both pathways. This dual inhibition can hinder cancer cells from finding alternative routes for growth and survival, making it harder for them to develop resistance and continue spreading.
Clinical trials have shown that amivantamab provides meaningful benefits for patients with EGFR exon 20 insertion-mutated NSCLC whose disease has progressed after platinum-based chemotherapy. The objective response rate observed in these patients was approximately 40%, with a median duration of response lasting around 11.1 months. This demonstrates the effectiveness of its unique mechanism in a patient population with limited treatment options. The ability to combine direct signal blocking with immune-mediated cell killing and receptor degradation provides a more robust and sustained anti-tumor effect, ultimately improving outcomes for these patients.