The mainstay drugs for ROS1+ nonsmall cell lung cancer (NSCLC) belong to a group of drugs called tyrosine kinase inhibitors (TKIs). Drug side effects vary, but are similar amongst the various drugs. They often occur within the first few months of starting a TKI.
Crizotinib, entrectinib, and ceritinib are first line therapies. First line therapies aren’t able to control cancer after it has progressed while being treated by a TKI, with a few exceptions.
Crizotinib (Xalkori) is the standard of care for metastatic ROS1+ NSCLC in the USA. Crizotinib is effective even in patients previously treated with chemotherapy. While one case study suggests patients who develop certain lorlatinib resistance mutations might be resensitized to crizotinib, it is typically only a first line drug.
Entrectinib (Rozlytrek, RXDX-101) may become the new standard of care for ROS1+ NSCLC due to its ability to effectively treat the brain, which crizotinib doesn’t do for most patients. Entrectinib is not an effective treatment for ROS1+ cancers that have progressed on crizotinib in the body. However, patients whose cancer is controlled by crizotinib in the body were allowed to enroll in the clinical trial if they developed brain metasisis. Entrectinib is also a frequent go-to TKI when patients cannot tolerate crizotinib.
Ceritinib has demonstrated potent clinical activity (including treating the brain) in ROS1+ NSCLC patients who had previously received platinum-based chemotherapy.
TKIs only inhibit cancer cells, so they cannot cure it. Most patients treated with TKIs find their cancer eventually starts to grow again. This is due to the cancer cells developing resistance mutations. Within a few years on first-line treatment, the drug often stops working. Second line drugs are drugs that are given when initial treatment (first-line therapy) doesn't work, or stops working. The two most commonly used second line TKI drugs for ROS1+ cancer are lorlatinib and repotrectinib.
Lorlatinib (Lorbrena, PF-06463922) can overcome certain resistance mutations that develop during treatment with crizotinib.. Lorlatinib is typically available off label for ROS1+ NSCLC, and some ROS1 NSCLC patients in the USA have been able to obtain insurance coverage with their 3 1st and 2nd line drugs used for ROS1 mutations oncologist’s assistance. It is available to ROS1+ NSCLC patients in other countries via expanded access and compassionate use. The 11/06/2019 NCCN Guidelines for NSCLC list lorlatinib as a treatment option for ROS1+ metastatic NSCLC after progression on crizotinib or ceritinib. Many oncologists will use it if you have progression on entrectinib, as well.
Repotrectinib (TPX-0005) was designed by Dr. Jean Cui, the Pfizer lead chemist who helped design crizotinib and lorlatinib. Repotrectinib is the most potent ROS1 inhibitor against the major resistant mechanism developed after crizotinib treatment. Like entrectinib and lorlatinib, this drug can treat brain mets.
A few notes about other drugs: Not all TKIs that effectively treat ALK patients are effective for ROS1. Preclinical tests show alectinib is not effective against ROS1 mutations. Brigatinib has not been clinically shown to be effective for ROS1 patients.