Osimertinib, known commercially as Tagrisso, is a targeted therapy for non-small cell lung cancer (NSCLC) with specific epidermal growth factor receptor (EGFR) gene changes. It benefits patients with these EGFR mutations, especially the T790M mutation, by blocking cancer cell growth signals. However, over time, cancer cells can adapt and bypass the drug’s effects, leading to resistance, where treatment no longer controls the disease.
Understanding Tagrisso Resistance
Resistance to osimertinib develops through molecular changes within cancer cells. A common mechanism is the C797S mutation in the EGFR gene, which directly interferes with osimertinib’s binding and prevents it from blocking the EGFR pathway.
Beyond direct changes to the EGFR gene, cancer cells can develop “off-target” resistance mechanisms by activating alternative growth pathways. Examples include the amplification of other genes like MET or HER2, which provide new routes for cell proliferation that osimertinib does not block. In some cases, cancer cells may even transform into a different type of lung cancer, such as small cell lung cancer (SCLC), or develop mutations in other genes like BRAF.
Identifying resistance mechanisms involves advanced diagnostic tests. Liquid biopsy, a blood test detecting circulating tumor DNA (ctDNA), is frequently used for its minimally invasive nature. This technique reveals genetic alterations like C797S mutations or MET amplifications, providing insights into resistance. A tissue biopsy may also be performed, especially if liquid biopsy results are inconclusive or a broader genetic analysis is required.
Treatment Approaches After Resistance
Once osimertinib resistance is confirmed, treatment decisions are highly individualized, taking into account the specific resistance mechanism identified, the patient’s overall health, and their previous treatments. The goal is to select therapies addressing the adapting cancer’s new challenges.
Chemotherapy often becomes a standard treatment option after targeted therapy failure. Platinum-based regimens, sometimes combined with other agents, work by broadly targeting rapidly dividing cancer cells to control tumor growth.
For identified resistance mechanisms, other targeted therapies may be considered. If MET amplification is detected, for instance, specific MET inhibitors might be incorporated into the treatment plan, sometimes combined with osimertinib or other agents. Similarly, if other actionable mutations like BRAF or HER2 amplifications are found, drugs designed to target those specific pathways could be explored.
Immunotherapy, which harnesses the body’s immune system to fight cancer, can also play a role. While its effectiveness in EGFR-mutated NSCLC after targeted therapy is varied, it may be used, sometimes with chemotherapy, especially if the tumor has high PD-L1 expression or if no other targeted options are available.
When cancer progression is localized to a few areas, local therapies such as radiation therapy or surgery may be considered. These approaches aim to remove or destroy tumor sites causing symptoms or posing a direct threat, even if systemic treatment is ongoing for broader disease control. Participation in clinical trials also offers access to investigational new treatments and is a significant option for patients seeking advanced therapies.
Emerging Therapies and Clinical Trials
Research continues to explore new strategies to overcome osimertinib resistance, focusing on therapies targeting identified resistance mechanisms. One area involves next-generation EGFR tyrosine kinase inhibitors (TKIs) designed to be effective against mutations like C797S, which renders osimertinib ineffective. These novel agents aim to restore the ability to block the EGFR pathway.
Other investigational approaches include novel combination therapies, exploring synergistic effects of combining osimertinib with other targeted agents, chemotherapy, or immunotherapy. For example, studies are evaluating combinations of osimertinib with MET inhibitors for MET amplification, or with anti-angiogenic drugs blocking blood vessel formation in tumors. These combinations aim to hit cancer cells through multiple pathways simultaneously.
Antibody-drug conjugates (ADCs) and bispecific antibodies are additional promising avenues. ADCs deliver potent chemotherapy directly to cancer cells by linking a cytotoxic drug to an antibody targeting specific proteins on the cancer cell surface. Bispecific antibodies are designed to bind to two different targets simultaneously, potentially enhancing immune responses or blocking multiple growth signals. These innovative treatments are being evaluated in clinical trials, offering potential new options for patients with osimertinib-resistant NSCLC.