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.
I was very upset to learn today that my sister is not responding well to Tagrisso. She has NSCLC-EFGR lung cancer with some lesions to the brain for which she received radiology therapy. She has fluid buildup in the lungs and has been drained. What is the next step? I was relieved to learn that there are options available with the information that I read on your website.
Thank you for illuminating me.
Hello Annar,
I’m sorry to hear your sister isn’t responding well to Tagrisso. Please call our Helpline at 1-800-298-2436 or email support@go2.org so we can provide support.
Sincerely,
Miranda Goff
Senior Manager, Support Programs
I have been taking Tagrisso for two weeks. I feel better, my cough subsides, and I also have metastatic that has spread to my brain. But it’s a small, scattered spot. I’m concerned about whole-brain radiation. This may result in me experiencing brain effects such as swelling or inflammation. I may have some mental problems. I have a question. Can doctors use targeted radiology therapy. ? Although each point is small and spread out in many places, I don’t want to be affected by whole brain radiation.
Hi Pattawan,
Excellent question! There are several options for radiation, should your healthcare team elect to go that route for treatment. Radiation that affects the whole brain, also known as Whole-Brain Radiotherapy (WBRT), is just one option doctor’s have in their toolbox. There are several options that deliver a more ‘targeted’ approach that may be able to reduce potential side effects, including but not limited to:
• 3-D Conformal Radiation Therapy (3D-CRT) is the most commonly used type of external beam radiation. For 3D-CRT, the radiation oncologist first scans the tumor to create a 3-D image of the tumor and the normal tissues around it. These images are then used to aim the beam at the tumor and to protect nearby healthy tissue.
• Intensity-Modulated Radiation Therapy (IMRT) is an advanced form of 3D-CRT that focuses smaller radiation beams (known as “beamlets”) of radiation on the tumor. Using small beamlets limits how intense the radiation is at any given part of the body and can help protect the healthy tissue around the tumor.
• Particle Beam (Proton) Therapy is a type of radiation treatment that uses protons (positively charged subatomic particles) instead of x-ray radiation. At high energy, protons can kill cancer cells with much less damage to the healthy tissue near the tumor, which results in fewer side effects.
• And Stereotactic Radiotherapy (SRT) uses pinpoint radiation beams from many different angles around the body to focus radiation on one small area in the body, more precisely targeting the tumor. This means the tumor receives a very high dose of radiation while the surrounding healthy tissue receives a much lower dose of radiation, lowering the risk of potential side effects.
Knowing exactly which type of radiation is right for you should be discussed with your healthcare team. If you mention your concerns about receiving whole-brain radiation, they should take these concerns into account. If you have any further questions, you can reach out to our HelpLine by calling 1-800-298-2436 or by emailing support@go2.org.
Kindest Regards,
Matthew Reiss
Manager, precision Medicine & Navigation
Tagrisso has stopped being effective for my wife. Her oncologist said that some patients can cycle back to Tagrisso after being off it a while and doing a different treatment such as chemo. Is there any published studies on this that I can read up on? Because she’s had 3 years with Tagrisso and tolerated its side effects very well.
Good day Kris,
I am sorry to hear that the treatment has stopped being effective for your wife.
To answer your question, Tagrisso can sometimes be continued to be used after NSCLC has progressed. A retrospective analysis reported that Tagrisso can be effective in combination with other treatments after progression, as Tagrisso can continue to work on primary tumors and can be used as complementary treatment for other lesions that appear. For example, Tagrisso in combination with brain radiation to help control and shrink the metastases that have spread to the brain. How Tagrisso is administered following first-line progression is dependent on how the cancer has previously responded, if it has spread, and if there are other metastases to consider.
Treatment progression on EGFR-mutated NSCLC can involve a combination of drugs or therapies, including chemotherapy, immunotherapy combination and clinical trials. Please call our HelpLine at 1-800-298-2436 or email support@go2.org and request to speak one of our LungMATCH specialists to learn more about what other treatment may be considered or if you have any other questions.
Warmest regards,
Renee Botello
Treatment and Trial Navigator
Hello, my father has been on Giotrip since 2016, and was disease free for 6 years, a bit more than a year ago they found 2 new tumors and he went through radiation therapy, however they have come back. His Giotrip dose was increased, however he is suffering greatly from the side effects. He has been offered taking Tagrisso instead. I haven’t found anything about taking Tagrisso after Giotrip, only the other way around. They are considering radiation therapy again. He is not a good candidate for surgical removal. Any advice you could give will be much appreciated.
Good afternoon Shahar,
I am sorry to hear that your father is experiencing heavy side effects to the increase in dosage of Gilotrif. Please contact our Helpline at 1-800-298-2436 or emailing support@go2.org for support.
As per your question for Tagrisso following Gilotrif, this is a great question:
Genetic studies have shown that a T790M resistance mutation is a primary mechanism of resistance that can develop following treatment with EGFR TKIs. Tagrisso (third-generation EGFR TKI) may be considered after Gilotrif (second-generation EGFR TKI) as it was developed to selectively target the activation of the mutated EGFR, as well as the T790M resistance mutation. A retrospective study has also found that third-generation EGFR TKIs may be associated with an improved survival benefit for the sensitizing EGFR mutation and inhibition of the T790M in NSCLC treatment.
Other clinical trials and treatment options may be considered, such as radiation, immunotherapy combination, or chemotherapy. Knowing exactly what type of treatment may be considered is dependent upon the medical team’s discretion of your father’s overall health, his treatment history, and how he has responded to past treatment.
If you have any further questions or would like to discuss more about other treatments options, you can reach out to our HelpLine by calling at 1-800-298-2436 or email support@go2.org, and request to speak to one of our LungMATCH Navigators.
Warmest regards,
Renee Botello
Treatment and Trial Navigator