Tagrisso, known scientifically as osimertinib, is a targeted therapy for a specific type of non-small cell lung cancer (NSCLC) in patients whose cancer cells have mutations in the epidermal growth factor receptor (EGFR) gene. While this medication is effective, a significant challenge is acquired resistance, where the cancer begins to grow again despite ongoing treatment. This development necessitates a shift in therapeutic strategies for managing EGFR-mutated NSCLC.
Tagrisso’s Mechanism and Initial Success
Tagrisso is a tyrosine kinase inhibitor (TKI) that works by blocking signals from mutated EGFR proteins that tell cancer cells to grow and divide. It is effective against common EGFR mutations, like exon 19 deletions and the L858R mutation. A primary advantage is its ability to also target the T790M resistance mutation, a common reason older-generation EGFR inhibitors stop working.
Clinical trials have demonstrated Tagrisso’s superiority over earlier EGFR TKIs, showing improved progression-free survival (the length of time a patient lives with the disease without it worsening). The FLAURA trial, for instance, showed first-line treatment with osimertinib resulted in a median progression-free survival of 18.9 months, compared to 10.2 months with older TKIs. Its ability to cross the blood-brain barrier also makes it effective against brain metastases, a common issue in this type of lung cancer.
Defining Tagrisso Resistance
Tagrisso resistance is when the cancer, after a period of being controlled by the drug, starts to grow or spread again. Resistance develops after a median of 10 to 20 months of treatment, although this can vary widely among individuals. The first signs are often detected through routine imaging scans, like CT or PET scans, which may show that existing tumors are getting larger or that new tumors have appeared.
A patient might also notice a return or worsening of symptoms, such as increased coughing, shortness of breath, or pain, which can prompt further investigation. Oncologists then use standardized criteria to assess tumor response and confirm progression.
Biological Drivers of Acquired Resistance
Resistance to Tagrisso results from cancer cells evolving at a genetic level, which can be categorized into two main types: on-target and off-target. On-target resistance involves further mutations within the EGFR gene itself. The most documented of these is the C797S mutation, which alters the part of the EGFR protein where Tagrisso binds, preventing the drug from working effectively.
Off-target resistance occurs when cancer cells find new signaling pathways to fuel their growth, creating a bypass around the EGFR blockade. Common off-target mechanisms include:
- MET amplification, where the cancer cells produce many copies of the MET gene
- Amplification of the HER2 gene
- Development of mutations in other cancer-related genes like BRAF or KRAS
- Histological transformation, where the cancer changes its appearance, for example, into small cell lung cancer
Strategies After Tagrisso Resistance
Once Tagrisso resistance is confirmed, the next step is to determine the underlying biological cause, as this guides subsequent treatment decisions. This often involves a re-biopsy of the tumor, which can be a traditional tissue biopsy or a liquid biopsy that analyzes circulating tumor DNA (ctDNA) in the blood. Identifying the specific resistance mechanism allows for a more personalized treatment approach.
Treatment decisions are based on the biopsy findings. Common strategies include:
- Switching to or adding another targeted therapy if a specific alteration like MET amplification is found
- Using platinum-based chemotherapy when a clear target is not identified
- Continuing Tagrisso while treating limited progressing areas with local therapies like radiation
- Enrolling in clinical trials to access novel drugs and treatment combinations
Research in Overcoming Resistance
The scientific community is actively working to develop new ways to overcome Tagrisso resistance. A primary focus of this research is the creation of fourth-generation EGFR TKIs. These new drugs are being designed to inhibit EGFR even when it has developed resistance mutations like C797S. Several of these next-generation inhibitors are currently being evaluated in early-phase clinical trials.
Another area of research is combination therapy. Studies are exploring the effectiveness of combining Tagrisso with other drugs from the outset to prevent or delay the development of resistance. This includes combinations with MET inhibitors, chemotherapy, and other targeted agents. For example, the FLAURA2 and MARIPOSA trials have shown that combining osimertinib with chemotherapy or using a combination of amivantamab and lazertinib can improve outcomes.
Novel therapeutic approaches are also showing promise in clinical trials for patients who have progressed on Tagrisso. One example is antibody-drug conjugates (ADCs), which deliver a potent anti-cancer agent directly to tumor cells.