Osimertinib is a targeted therapy widely used for a specific type of lung cancer known as epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). This medication has significantly improved outcomes for many patients. However, cancer cells can adapt over time, leading to resistance. This means the drug eventually stops working effectively, prompting the need for further strategies.
How Osimertinib Works
Osimertinib functions as a third-generation EGFR tyrosine kinase inhibitor (TKI), designed to target genetic alterations within cancer cells. The epidermal growth factor receptor is a protein on cell surfaces that, when mutated, signals cancer cells to grow and divide uncontrollably. Osimertinib works by irreversibly binding to specific mutated forms of this receptor, including common activating mutations like exon 19 deletions and L858R, as well as the T790M mutation, which is a common cause of resistance to earlier EGFR TKIs. This binding blocks signaling pathways that fuel cancer cell growth. The drug is also effective against lung cancer that has spread to the central nervous system, including the brain.
Why Osimertinib Stops Working
Cancer cells can develop resistance to osimertinib through various biological mechanisms. Primary resistance refers to pre-existing traits that make the cancer less responsive from the start, while acquired resistance develops during treatment as the cancer evolves. These changes allow the cancer to bypass the drug’s effects and continue growing.
One mechanism is on-target resistance, involving further mutations within the EGFR gene. The C797S mutation, occurring in exon 20 of the EGFR gene, is the most frequently identified tertiary EGFR mutation, appearing in 10-26% of cases of resistance to second-line osimertinib. This mutation interferes with osimertinib’s ability to form a covalent bond with the mutant EGFR, reducing its inhibitory effect. Other less common EGFR mutations, such as L798I, G724S, G796R/D, and L792, can also contribute.
Cancer cells can also activate alternative bypass signaling pathways, enabling growth even when EGFR is blocked. MET amplification, where the MET gene is copied multiple times, is a common resistance mechanism, observed in 9-24% of tumors progressing on second- or later-line osimertinib and 7-15% in first-line cases. This amplification can occur with or without the T790M mutation. HER2 amplification, involving another tyrosine kinase receptor, is detected in approximately 5% of second-line and 2% of first-line osimertinib resistance cases, often mutually exclusive with the T790M mutation. BRAF mutations, such as BRAF V600E, have also been reported as a resistance mechanism in about 3% of cases.
Resistance can also develop through histological transformation, where cancer cells change their type. This can involve the tumor transforming from adenocarcinoma to small cell lung cancer (SCLC) or, less commonly, to squamous cell carcinoma. This transformation occurs in 2-15% of patients who progress on osimertinib. Such changes are often linked to additional genetic alterations, including mutations in the RB1 and TP53 genes.
Identifying Osimertinib Resistance
Identifying osimertinib resistance involves clinical observation and molecular testing. Clinically, disease progression is noted through imaging scans, such as CT or PET-CT, which show an increase in tumor size or new lesions. These findings prompt further investigation into underlying biological changes.
Molecular testing pinpoints the specific genetic alterations driving resistance. Tissue biopsy, which involves obtaining a tumor sample, allows for direct genetic analysis. This method is useful for identifying histological transformations, such as a change to small cell lung cancer, which cannot be detected through blood tests.
A less invasive approach is liquid biopsy, which analyzes circulating tumor DNA (ctDNA) from a blood sample. This method can detect resistance mutations, including EGFR C797S and MET amplification, by identifying fragments of tumor DNA shed into the bloodstream. Liquid biopsies are less invasive and can be repeated more easily than tissue biopsies, allowing for ongoing monitoring. A tissue biopsy may still be considered if liquid biopsy results are inconclusive, or if there is suspicion of histological transformation.
Next Steps After Osimertinib Resistance
When cancer becomes resistant to osimertinib, subsequent treatment strategies are personalized, based on the specific resistance mechanism identified. Understanding these mechanisms guides the choice of therapies to target the cancer’s new vulnerabilities.
Traditional chemotherapy, often platinum-based, is a common option for patients whose cancer has progressed after osimertinib, especially when no other actionable mutations are found. However, chemotherapy alone can be limited, with many patients experiencing recurrence within about six months.
For patients with newly identified actionable mutations, other targeted therapies may be considered. For example, if MET amplification is found, therapies that inhibit MET, sometimes in combination with EGFR inhibitors, are being explored. The EGFR/MET bispecific antibody amivantamab, alone or combined with chemotherapy, has shown promise in some cases, particularly for MET-amplified tumors.
Immunotherapy, which harnesses the body’s immune system to fight cancer, has generally shown disappointing outcomes when used alone in EGFR-mutated NSCLC due to the tumor’s microenvironment. However, combinations of immunotherapy with chemotherapy and anti-VEGF (vascular endothelial growth factor) antibodies, such as the IMpower150 regimen, are being investigated and may offer benefit.
Participating in clinical trials is often a recommended path for patients with osimertinib-resistant disease. These trials explore novel drugs, new combinations of existing therapies, or different treatment sequences, aiming to overcome resistance and improve outcomes. The goal is to find the most effective personalized approach to manage cancer after osimertinib stops working.