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Treating Stage 4 ROS1+ Cancer
(For Patients)

Cancer research has developed a new type of treatment called “targeted therapy” that is more effective and has fewer side effects than traditional chemotherapy. Targeted therapy is now standard of care for patients who have metastatic (stage IV) ROS1+ non-small cell lung cancer (NSCLC) in many countries. 

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Frequently Asked Questions


Many doctors may never have met a patient with ROS1+ cancer before. If you have questions about the best next step in treating your ROS1+ cancer, you may want to seek care or a second opinion from a ROS1 Clinician or ROS1 Clinician-Researcher

What is a ROS1 targeted therapy or TKI?

ROS1 targeted therapy is a drug in pill or capsule form that “targets” ROS1 cancer cells but has little effect on healthy cells. Chemotherapy targets all fast-growing cells, whether they are cancer cells or healthy cells (like hair follicles and cells lining the gut), so chemotherapy tends to have more side effects than targeted therapy. Many ROS1+ patients find they can have relatively normal lives while taking a targeted therapy drug. Some people who have ROS1+ NSCLC have been on targeted therapies for many years with good control of their cancer. 

A TKI (tyrosine kinase inhibitor) is another name for the targeted therapy drugs that bind to a specific type of protein called tyrosine kinase. The ROS1 protein is a tyrosine kinase. ROS1 targeted therapies inhibit the ROS1 protein, so they are called TKIs (tyrosine kinase inhibitors). 

How effectively do TKIs treat ROS1+ cancer?

​Clinical trials have shown some ROS1 TKIs effectively inhibit the altered ROS1 protein in 70%-80% of patients with ROS1+ lung cancer. Some patients find a TKI will effectively control their cancer for years, and some may see their tumors disappear completely. However, every patient’s case is unique--some will find their TKI is effective only for a few months, others may find a TKI does not work at all, and some may have to stop taking their TKI due to serious side effects. Not all ROS1 TKIs are effective against ROS1+ cancer in the brain. 

Who should take a ROS1 TKI?

A ROS1 TKI  may be available for patients who have metastatic ROS1+ cancer in those countries that have approved the drug. Metastatic cancer (also called stage 4) is cancer that has spread beyond the primary tumor to other organs. Patients who have metastatic ROS1+ cancer that started in organs other than the lungs (for example, melanoma) have also responded to ROS1 targeted therapies, but thus far no ROS1 targeted therapy has been approved for cancer other than NSCLC in any country.

TKIs are not approved for ROS1+ cancer that is not metastatic because TKIs cannot cure, while other types of treatment for early-stage cancer have a proven chance of cure. Patients who have non-metastatic ROS1+ cancer (stage 1, 2, or 3) receive the same standard of care as other patients who have the same type and stage of cancer, regardless of what gene alteration may be driving their cancer.  However, ROS1 TKIs are given in some countries for ROS1+ NSCLC after curative treatment in earlier stages has been completed.


How do I know if a TKI is working?

Your doctor will usually order a CT scan approximately two to three months after you start taking a TKI.  If the TKI is working, the doctor will see significant tumor shrinkage on the very first scan.  For most people, tumor shrinkage slows after a few months. Some people will see all their tumors disappear, but don’t worry if this doesn’t happen for you.  Shrinkage may continue slowly for months, or your cancer may simply remain stable (which is a sign that your cancer is not growing). 


Can a ROS1 targeted therapy cure my metastatic cancer?

Alas, no. TKIs only inhibits the cancer for as long as you take the drug.  While they may control and shrink the cancer during therapy, they cannot kill 100% of the cancer cells and so cannot cure cancer.  When you stop taking the drug, the cancer is free to grow again.


Can I be "cancer-free" while on a TKI?

The short answer is no.  A more precise answer is, "We can't tell."

When a patient achieves a complete response to a TKI (no sign of cancer on scans), ROS1 Clinician-Researchers say the patient has "No Evidence of Disease" (NED).  This means that current technology cannot detect the presence of cancer. However, microscopic ROS1+ cancer cells may still lurk undetected in the body.  Most patients with metastatic ROS1+ cancer will see their cancer return -- their living cancer cells, however few there may be, can still develop new mutations, and that causes acquired resistance.  

Different types of scans have different abilities to detect cancer cells. A PET scan (Positron Emission Tomography) may not show any sign of cancer activity even if a tumor is still visible on a CT scan (Computerized Tomography). With TKIs, cancer cells are inhibited and so they do not consume abnormally high levels of glucose, which is what makes a PET scan light up. ROS1+ cancer cells that are being effectively inhibited by a TKI also tend to shed less circulating tumor DNA (ctDNA), so a liquid biopsy may not detect any ROS1+ cancer although ROS1+ cancer cells are still present. 

What is acquired resistance? How is it detected?  How is it treated?

Most patients find their TKI will stop working eventually, and cancer will start to grow again.  This could take months or even years. When a ROS1 TKI eventually becomes less effective (or completely ineffective) at inhibiting ROS1+ cancer, the cancer has developed acquired resistance to the drug. Sometimes the cancer is still addicted to ROS1 and will respond to a different TKI, but in over half of ROS1 patients the acquired resistance mechanism allows the cancer to grow even though a TKI is effectively inhibiting the ROS1+ cancer. The mechanism of resistance cannot always be determined.


Every case of ROS1 cancer progression is different, and a variety of factors must be considered when choosing the next treatment. It can be helpful to get a biopsy of the growing tumor and have it genomically tested to determine what is driving the cancer before selecting the next treatment option, but this might not be possible for a variety of reasons. For instance, the tumor may not be in a place that can be safely biopsied, the tumor may not be big enough to biopsy, or a tissue sample might not capture any cancer cells.  In some cases, a liquid biopsy can detect a resistance mutation from a blood sample.  The cost of a liquid biopsy might not be covered by your healthcare system or health insurance; in this case, the company that makes the liquid biopsy might be able to help cover the cost of the test. 

If the area of progression is limited in extent, it may be possible to stay on the same TKI and treat the area of progression with focused radiation or even surgery. If the resistance mechanism involves a known ROS1 TKI resistance mutation, treatment might involve switching ROS1 TKIs.  If the resistance mechanism involves a different signaling pathway, treatment options might be adding chemotherapy to the TKI (although not all experts agree on this practice), combining two different TKIs, a chemotherapy combination, or a clinical trial.  ROS1 Clinician-Researchers generally agree that immunotherapy should only be an option after all other treatment options are exhausted.

What if a ROS1 TKI is not approved in my country, or my doctor can't prescribe a TKI?

Some chemotherapy drugs or drug combinations are also effective against ROS1+ cancer. Alimta (pemetrexed) and carboplatin is a chemo combination that seems effective against many ROS1+ cancers. Alternatively, a ROS1 TKI may be available through a clinical trial or compassionate access--talk to your doctor about these options.

Where can I find Treatment Guidelines for my cancer?

The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of leading cancer centers in the USA devoted to patient care, research, and education. They publish cancer treatment guidelines both for professionals and for patients.  To access these guidelines go to and then click on your type of cancer. You will need to create a free account to see the professional guidelines.

The European Society of Medical Oncology (ESMO) has a core mission to educate doctors, cancer patients and the general public on the best practices and latest advances in oncology.  It publishes clinical guidelines for many cancers.

The American Society for Clinical Oncology (ASCO) is the leading organization for cancer clinicians in North America. You can search their site for clinical guidelines for many cancers.  The also have a guidelines specifically for Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations.

Is a TKI the same as gene therapy?

No. Gene therapy alters an abnormal gene to make it normal by changing the DNA. TKIs are not designed to alter genes or DNA in any way.

Ask Oncologist

What to Ask Your Oncologist

Whether you're dealing with a new cancer diagnosis or cancer progression, it can be hard to know which questions to ask.  Here's a suggested list to help you gather the information necessary to make informed decisions about your care.

For the Newly Diagnosed Patient
  • What TKIs are accessible to me?

  • Is there any clinical or pre-clinical evidence that this treatment might work for my cancer?

  • Does the TKI effectively treat the body AND the central nervous system?

  • What side effects can I expect?

  • What clinical trials are accessible to me? What resources do I need to participate?

  • Would I or my medical team benefit from consulting with a ROS1 Clinician-Researcher?

Additional Questions for Patients Whose Cancer Has Progressed
  • Would a rebiopsy be advisable to identify resistance mechanisms?

  • Can I donate any unneeded tissue or fluid to The ROS1+ Cancer Model Project?

  • Is a TKI available to address my resistance mechanism?

  • What is the TKI’s response rate after one previous TKI? Two? Three?

Current Treatments

Current Treatments for ROS1+ Cancer


  • Physicians who have treated many ROS1+ cancer patients recommend against using a single-agent immune checkpoint inhibitor (e.g., Opdivo, Keytruda) for ROS1+ cancer.  Immunotherapy drugs used alone are frequently ineffective for ROS1+ cancer, and sometimes cause side effects that prevent a patient from taking a TKI as the next treatment option.

  • Most ROS1 Clinician-Researchers believe patients on TKIs should not take “drug holidays" (time off from TKI cancer treatment) if the drug is effective and the patient is tolerating the drug well. TKIs only inhibit ROS1+ cancer.  Most TKIs tend to remain in your system for several days, so patients who need to stop taking them for a few days (e.g., before and after a surgery) rarely experience progression.  However, if you stop taking your TKI for longer, your cancer is no longer inhibited and may begin growing again. Some clinical trials are exploring this concept.

First Line Treatment for ROS1+ Cancer

(for patients whose cancer has not been previously treated)


Patients who have early stage ROS1+ cancer (stages 1-3)

You will receive the same first line treatment as other patients who have your type of cancer (lung, pancreatic, etc). These treatments aim to cure (targeted therapies cannot cure cancer). 


Patients who have metastatic (stage 4) ROS1+ cancer

ROS1 TKIs are approved in many countries for patients who have ROS1+ non-small cell lung cancer (NSCLC), and are the preferred first line treatment because they are more effective than chemotherapy and generally have fewer side effects. You may be able to access a ROS1 targeted therapy, also known as a tyrosine kinase inhibitor (TKI). ​ROS1+ cancer has also been found in many cancers that originated in organs other than the lungs. Patients who have metastatic ROS1+ cancer other than NSCLC have responded to ROS1 TKIs, but thus far only NSCLC has approved ROS1 TKIs.  

Available ROS1 TKIs will depend on which drugs are accessible in your country and/or clinic and other health conditions you may have (the drugs have different side effects).  Patients who have other types of metastatic (stage IV) ROS1+ cancer may be able to access these TKIs off-label (if they are approved for other cancers in your country), through a clinical trial, or via compassionate use.  If ROS1 TKIs are not available to you, some chemotherapy drugs (especially pemetrexed alone or pemetrexed plus carboplatin) can be effective against ROS1+ cancers.

ROS1 TKIs used in first-line treatment for metastatic ROS1+ cancer NSCLC

  • Xalkori (crizotinib) was approved in March 206 by the FDA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive..  It does not treat the brain effectively.

  • Rozlytrek (entrectinib) was approved in August 2019 by the FDA for adults with metastatic NSCLC whose tumors are ROS1-positive.  It does treat the brain, and is often prescribed if the patient has metastases in the brain. 

  • Augtyro (repotrectinib) was approved in November 2023 by the FDA for  locally advanced or metastatic ROS1-positive NSCLC. It does treat the brain, and is effective against several resistance mutations that develop during treatment with crizotinib or entrectinib.

  • Zykadia (ceritinib) is not approved by the FDA for ROS1+ cancer, but it is available off-label. It does treat the brain, but is not as effective for ROS1+ cancer as other first-line TKIs. However, it seems to be more available than Xalkori or Rozlytrek in some countries, and may be an alternative if Xalkori, Rozlytrek, or Augtyro are not tolerable.

  • Lobrena (lorlatinib) is not approved by the FDA for ROS1+ cancer, but is recommended by the US National Comprehensive Cancer Network (NCCN) for 2nd or 3rd line treatment of ROS1+ NSCLC.  It is sometimes used first line if the patient has many brain metastases or leptomeningeal disease (cancer in the meninges of the central nervous system) because it is particularly effective in treating the brain.

If you have cancer in the brain

About half of ROS1+ cancer patients will develop brain metastases, but many patients treated first line with crizotinib (which does not effectively treat the brain) never develop brain metastases. If the patient has significant cancer metastases in the brain, entrectinib is often chosen as the first line TKI because it's effective at treating brain metastases.  Treatment might also include stereotactic brain or whole brain radiation. In general stereotactic is preferred over whole brain radiation, but this varies by health system. However, brain radiation may not be necessary if entrectinib or another TKI that treats the brain is available.  Consult with an oncologist knowledgeable about ROS1 TKIs about the best approach for treating your brain metastases.


Treatment for blood clots (thromboembolisms)

Patients who have ROS1+ cancer are more prone to developing blood clots than people with other types of cancer.  You may be prescribed a blood thinner along with your anticancer treatment if you develop a clot. Evidence is currently lacking to support using a blood thinner to prevet a clot in patients who don’t currently have a clot.

Second Line Treatment for ROS1+ Cancer

(for patients whose cancer has progressed after their first line treatment)

For most patients, ROS1+ cancer develops acquired resistance that makes the ROS1 TKI less effective. Sometimes the resistance occurs because of changes in the abnormal ROS1 protein (this is called on-target resistance). In about half of patients, acquired resistance is driven by some other mechanism, like addition of another genomic mutation (such as RET, EGFR, MET, or ALK), or other changes in the cancer cell.  Another possibility is that a different type of cancer is forming a tumor.

The most effective treatment will depend on what is causing the cancer to grow.  A second-line ROS1 TKI like lorlatinib or a TKI in a clinical trial (like repotrectinib, taletrectinib, or NVL-520) might be effective if the tumor is driven by on-target resistance. However, switching to a different ROS1 TKI likely won't be effective if the mechanism of resistance is NOT on-target resistance. Biomarker testing or a fresh tissue biopsy at the site of progression or a liquid biopsy may be helpful in determining the mechanism of resistance.

If the progression is not driven by on-target resistance, your doctor might consider keeping you on the TKI (to continue inhibiting the ROS1+ cancer) while adding another type of treatment to address the cancer that's causing progression.  One option might be treating the area of progression with surgery or stereotactic radiosurgery--this is known as "weeding the garden" and has allowed some patients to remain on the same TKI for many years. Another option may be adding chemotherapy or a different TKI that targets a different biomarker. 

As you can see, choosing a new treatment after progressing while on a ROS1 TKI can be complicated.  If your doctor does not have a lot of experience dealing with progression in ROS1+ cancer, ask them about consulting a ROS1 Clinician-Researcher.

Some ALK TKIs Work for ROS1+ Cancer, But Others Do Not

Many TKIs developed for ALK+ cancer (ALK is another biomarker) also show activity against ROS1+ cancer. However, some ALK TKIs are not as effective than ROS1 TKIs.   Alunbrig (brigatinib) and ensartinib have some effectiveness against ROS1+ cancer, but are much less effective than crizotinib, entrectinib, or repotrectinib in first-line treatment, and have not shown effectiveness against ROS1 TKI resistance mutations. Alecensa (alectinib) does not work for ROS1 and should NEVER be used to treat ROS1+ cancer. If your doctor prescribes any of these TKIs for your ROS1+ cancer outside of a clinical trial, ask them why--you might want to get a second opinion from a ROS1 Clinician-Researcher


Clinical Trials for ROS1+ Cancer

A clinical trial may also be a good treatment option for a patient with ROS1+ cancer as first, second, or later line of treatment. A clinical trial may be attractive for patients with no access to approved ROS1 TKIs, especially if it provides access to a TKI that has been approved in other countries.  Learn more about participating in a clinical trial or see which ROS1 TKI clinical trials may be available.

Coping with Side Effects of Treatment 

More about Treating ROS1+ Cancer (with links to journal articles)

Medically reviewed by ROS1 Clinician-Researchers
Last updated 19-Feb-2022

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