What is the chromosomal rearrangement of the ROS1 gene?

ROS1 is a gene that codes for a receptor tyrosine kinase. Due to random chance, a part of the ROS1 gene (the portion with tyrosine kinase activity) can detach and join another gene. The result is the formation of a new gene that can give rise to lung adenocarcinoma development. To date, 14 fusion partners have been identified with which the 3’ end of ROS1 can fuse to. Among these, the most frequent rearrangement occurs with CD74.

The ROS1 gene rearrangement is observed in approximately 1-2% of patients diagnosed with non-small cell lung cancer mainly of an adenocarcinoma histology. They are generally seen in nonsmokers and young patients (<40 years old).

The tyrosine kinase domain of the ROS1 gene is 49% homologous with that of the ALK gene. In addition, the ATP binding domain of the ROS1 gene shares 77% of the amino acids that are found in the ALK gene. Therefore, some ALK inhibitors are also effective in patients with ROS1 gene rearrangements.

Treatment of lung cancer patients with ROS1 rearrangement – 1st line therapy

To date, the only treatment approved for patients with ROS1 rearrangements is crizotinib. Evidence for crizotinib effectiveness in ROS1 positive patients was first observed in the expansion phase of the phase I/II PROFILE 1001 study, which was initially designed to only include ALK positive patients. In the 50 ROS1 positive patients enrolled, crizotinib provided a 72% objective response rate with a progression-free-survival of about 19 months.

Based on these results, in March 2016, crizotinib was approved by the U.S. Food and Drug Administration (FDA) for treatment of non-small cell lung cancer patients carrying a ROS1 gene rearrangement.

In subsequent years, several phase II studies confirmed the effectiveness of crizotinib in this subset of patients. These also include the Italian METROS study, in which 26 patients were enrolled. The results showed an objective response rate of 65% with a progression-free-survival of about 22 months.

With regards to Italy, starting from May 23rd, 2018, crizotinib may also be administered in patients with non-small cell lung cancer carrying ROS1 gene rearrangements.

To learn more about the side effects of crizotinib, go to the side effects section.

What to do when crizotinib stops working

We are currently learning more about the resistance mechanisms that develop in patients who no longer benefit from crizotinib. Secondary mutations have been identified that develop during therapy with crizotinib, which block the drug’s binding to the receptor or inactivate the drug altogether.

To date, there are no drugs registered for second-line treatment, but there are ongoing trials that patients may enroll in.

In December 2019, results of a phase I/II study were published that assessed the effectiveness of lorlatinib in ROS1 positive patients. In the study, 69 patients were enrolled (58% had previously received crizotinib, 12% received other ROS1 inhibitors, and about 30% were not previously treated). The percentage of objective responses in previously untreated patients was 62%, while for patients who had progressed from previous therapies, the objective response was 35%.

Currently in Italy, patients may receive lorlatinib at time of progression after crizotinib if requested on a personal basis.

New hopes – Entrectinib

Entrectinib is a drug initially developed as a tropomyosin receptor kinase (TRK) inhibitor but with activity against ROS1. Entrectinib has been tested in 3 phase I/II clinical trials, in which 53 ROS1 positive patients (not previously treated with crizotinib) were enrolled. The results of the study were published in Lancet in December 2019. 38% of the enrolled patients had brain lesions. An objective response of 77% was observed with a progression-free survival of about 24 months as well as a 55% cerebral response. Thus, entrectinib represents a possibly new therapeutic option for these patients.