Author: GO2 for Lung Cancer Treatment and Trials Navigator, Renee Botello MSc

Tagrisso (osimertinib) has been the treatment of choice and effective standard of care option for the treatment of EGFR+ non-small cell lung cancer (NSCLC) since its FDA approval in 2018 as a first-line treatment for EGFR+ NSCLC. It’s a tyrosine kinase inhibitor (TKI) that works by targeting the mutated or abnormal change in the EGFR protein, blocking the growth and spread of the cancer cells. Although many people will respond well to Tagrisso, resistance is something that many may eventually experience during their lung cancer treatment path.

Why does Tagrisso resistance happen?

It depends on many factors that vary from person to person. Current research is trying to better understand how changes in the cell cycle, the continued activation of EGFR through new mutations in the cancer cells, and abnormalities in the cell signaling pathways may affect treatment interaction and ultimately lead to Tagrisso resistance.

What happens next?

We understand that this can be an uncertain time and scary outcome after previously responding well to treatment. Although there is not one answer for what is best after Tagrisso resistance, there are some common next steps to consider.

Repeat biomarker testing

If you have not already, we recommend repeating comprehensive biomarker testing to find out if new biomarkers are present. When a cancer stops responding to treatment, it is often because there is a new mutation. Repeating biomarker testing can let you and your oncologist know of any new mutations. It may tell us if a new targeted therapy is an option or if you qualify for a clinical trial. Sometimes, EGFR-targeted therapies are used in combination with Tagrisso depending on the mutations present when disease progression happens. For instance, other EGFR mutations, including exon 19 deletion or L858R, are associated with having a good response with other EGFR-targeted therapies, such as Gilotrif (afatinib). In this case, a combination of Tagrisso and Gilotrif may be the next step in treatment.

Understanding metastases and progression of the cancer

How the cancer has progressed and where it has spread are also especially important when considering the next steps in your treatment. In many cases, Tagrisso continues to work in the primary tumors and may be used as adjuvant or complementary therapy when targeting the metastases, or distant lesions, that have surfaced. An example includes a combination of Tagrisso with brain radiation if the smaller metastases have spread to the brain. Tagrisso has been shown to effectively cross the bloo­­d-brain barrier, which can help shrink and control the lesions. If the cancer has spread to other areas but the lesions are considered minimal, local therapy such as targeted radiation or surgery, if possible, may be used while the primary cancer still responds to Tagrisso treatment.

Post-Tagrisso resistance treatment options

In the instance that cancer has spread to multiple spots and Tagrisso is no longer effective, there are some treatment options available.

Use of systemic therapy or immunotherapy combinations

The Impower150 clinical trial has provided evidence that some people with EGFR+ NSCLC who have progressed on EGFR-targeted therapies, such as Tagrisso, may benefit from immunotherapy combinations. Immunotherapy works by helping one’s own immune system fight cancer by identifying the cancer cells and targeting them without damaging the healthy cells in the body. One of these combinations is platinum doublet chemotherapy combined with a type of immunotherapy called a PD-L1 inhibitor. An example of this treatment regimen is Paraplatin (carboplatin)+Alimta (pemetrexed)+Keytruda (pembrolizumab). Doctors may consider this option based on the person’s health status, past response to treatments, and if they have a high level of PD-L1 expression (if the cancer has more of this protein on the cell surface, then the drug could be more effective). Other systemic therapies include a combination of chemotherapy with a VEGF inhibitor, to stop the growth of new blood vessels in tumor cells. Examples of this treatment regimen, including Taxotere (docetaxel)+Cyramza (ramucirumab), have shown potential and are being studied as possible treatments following Tagrisso resistance.

Clinical trials

Clinical trials are another option when a person experiences treatment progression and wants to look at the different available treatments. Enrollment in clinical trials depends on several factors, some of which include how many and what types of treatment you have had, your medical history, where the cancer has spread to, where you are located and/or are able to receive care, and your latest biomarker tests results, among other considerations. Each clinical trial sets its slate of inclusion and exclusion criteria that will determine if you are eligible to join. The scope of clinical trials varies, with some studies exploring the next generation of EGFR inhibitors focused on overcoming the resistance observed with Tagrisso treatment, combination therapies, or the potential of immunotherapy as a treatment for EGFR+ NSCLC.

If you are experiencing progression after Tagrisso treatment for EGFR+ NSCLC, talking with your oncologist about these options and others can help you find the best next step in treatment. You can also contact our LungMATCH team. LungMATCH navigators offer one-on-one personalized clinical trial and treatment navigation services. To speak with one of our LungMATCH specialists, please call 1-800-298-2436 or email support@go2.org.