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Why Did My TKI Stop Working? Targeted Therapy and Acquired Resistance

At some point, Stage IV ROS1+ Cancer patients typically find that their targeted therapy has become less effective or stopped working completely. At that point, the cancer will start growing again or will metastasize. This is why regular scans are so important to Stage IV ROS1+ patients.

When a targeted therapy stops working, the cancer has developed acquired resistance to the drug. This can happen months or years after treatment begins. Why does acquired resistance happen? What should you do when your targeted therapy stops working? We present the following information on acquired resistance based on the latest research and experiences of some of the ROS1ders to help you understand why targeted therapy stops working and what you can do about it.

Why does a ROS1 targeted therapy stop working?

There are several mechanisms that enable cancer cells to become resistant to targeted therapy drugs. For ROS1+ cancer patients, these are generally categorized in two groupings:

  1. On-target Resistance. On-target resistance is seen in about 40% of all acquired resistance. On-target resistance happens when the ROS1 protein changes in ways that interfere with the targeted therapy drug as it seeks to bind the protein.

  2. Off-target Resistance. Occurring in about 60% of cases, off-target resistance includes bypass signaling, new gene alterations or phenotypic changes (changes in gene expression). In bypass signaling, the cell manages to activate downstream signaling pathways (such as RAS, RAF, and/or MEK) despite successful ROS1 inhibition. In new gene alterations, the cell acquires new mutations or fusions in genes. Phenotypic changes–changes in gene expression rather than mutations in genes--have also occurred in off-target resistance; one example is epithelial-mesenchymal transition, which makes the cancer cell more likely to spread the cancer to other parts of the body.

What should I do after my targeted therapy stops working?

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.

The targeted therapy crizotinib may be effective in the body but still allow cancer to develop in the brain. This does not mean crizotinib has stopped working; it happens because crizotinib does not effectively treat the brain. If this happens, switch to a targeted therapy that treats the brain more effectively.

In on-target resistance, the cancer will likely respond to a second-line ROS1 targeted therapy that has been shown to overcome the resistance mutation. Off-target resistance does NOT respond to switching ROS1 targeted therapy drugs. If the resistance is off-target, radiation or ablative therapy to the site of cancer progression can often kill the new cancer growth and allow the patient to remain on targeted therapy. Chemotherapy (especially pemetrexed or pemetrexed plus carboplatin) may be effective. Combination therapy (TKI plus chemo, two TKIs targeting different biomarkers, etc.) are also being explored. Evidence to date indicates single-agent immunotherapy is unlikely to be effective in treating off-target resistance mechanisms in ROS1+ cancer.

For more information, check out this medically-reviewed treatment algorithm for ROS1+ cancer.

A ROS1ders experience: when a targeted therapy stops working

Leslie LaChance, a ROS1der, experienced acquired resistance during her treatment.

“In 2018, five months after my original diagnosis of stage 4 ROS1+ metastatic lung cancer, which we were treating with Crizotinib (aka Xalkori) I got disappointing news. My scans showed progression in the lung and lymph nodes. Crizotinib, which had kept my disease stable for a few months, had failed me completely. Not only did I have progression in my lung, the cancer had moved into my brain, where there hadn’t been any cancer before.”

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