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Off-Label Targeted Therapy Drugs for ROS1

Physicians are legally permitted to prescribe drugs approved for one type of cancer to treat a different kind of cancer. This is called off-label use. Many targeted therapy drugs developed for ALK+ non-small cell lung cancer (NSCLC) or other cancers have been shown to have activity against ROS1+ NSCLC, but have not yet been approved for treating ROS1+ cancer by the FDA or other regulatory agencies.

Some off-label ROS1 targeted therapies are more effective than others. Also, some insurance plans and national healthcare systems may not provide coverage for off-label targeted therapies.

The following provides a description of several off-label targeted therapies and what we know about their effectiveness for treating ROS1+ cancer. None of these drugs have received regulatory approval for ROS1+ NSCLC.


Ceritinib is approved in several countries for treating ALK+ NSCLC, and is recommended by the National Comprehensive Cancer Network (NCCN) as a first-line treatment for ROS1+ NSCLC. It is less effective and often less tolerable than crizotinib or entrectinib (approved first-line targeted therapy drugs), but it may be more accessible in some countries. It is not effective at treating resistance mutations that arise after treatment with crizotinib.

In a Korean phase II study (2016), 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with ceritinib. The overall response rate was 63%, with 1 complete response and 19 partial responses. Of 5 patients with retrospectively confirmed brain metastases, intracranial disease control was reported in 4 patients (80%).


Lorlatinib is approved in several countries for ALK+ NSCLC, and is recommended by the US NCCN for 2nd or 3rd line treatment of ROS1+ NSCLC. It is sometimes used as a first-line TKI if the patient has brain metastases or leptomeningeal disease (cancer in the meninges of the central nervous system, or CNS) because it seems more effective than other first-line ROS1 targeted therapies in treating the brain.

A phase 1-2 trial of lorlatinib (2019) included 69 patients with ROS1+ NSCLC, of which 58% had previously received crizotinib as their only targeted therapy drug, and 12% had previously received either one non-crizotinib ROS1 targeted therapy or two or more ROS1 targeted therapies. The study concluded that “Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent.”


Cabozantinib is approved in various countries for treating kidney, thyroid, and liver cancers. It has shown ability in the lab to overcome acquired crizotinib resistance in ROS1+ cancer, particularly the G2032R on-target resistance mutation. However, the dosage required to treat ROS1 effectively makes the drug difficult to tolerate. A study of 4 patients (2018) who were treated with cabozantinib after developing resistance to ceritinib reported all patients achieved stable disease with progression free survival of 4.9 to 13.8 months.


Brigatinib is approved in several countries for treating ALK+ NSCLC. Preclinical data showed it has modest activity against ROS1+ cancer that has not developed resistance to first-line ROS1 targeted therapies. A small unpublished study of three ROS1+ NSCLC patients showed 1 partial response in a TKI naive patient, and no responses in patients previously treated with crizotinib (one had stable disease, and one had progressive disease). In a Israeli retrospective study (2020) of 8 ROS1+ cancer patients treated with Brigatinib, 3 patients had a partial response.


Ensartinib (approved for treating ALK+ NSCLC in China) has a modest efficacy for ROS1+ cancer. In a Chinese study (2021) of 59 patients treated with ensartinib, 10 patients had partial response, and duration of response ranged from 1.8 to 10.8 months. Of the 4 patients who had brain metastasis, 3 experienced disease control in the brain.


Alectinib is approved for treating ALK+ NSCLC in many countries. However, preclinical studies show it does not inhibit ROS1. ALECTINIB SHOULD NEVER BE USED TO TREAT ROS1+ CANCER.

Alternatives to Off Label Drugs

Fortunately, there are several experimental ROS1 targeted therapy drugs in clinical trials, such as repotrectinb, taletrectinib and NVL-520. Preliminary clinical trial data indicate these may be better options for ROS1+ cancer than off-label targeted therapies. Learn more about treatment options for ROS1+ cancer at

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