Background: A transmembrane tyrosine kinase gene of the insulin receptor family involved in cell proliferation. ROS1 rearrangements were first identified in patients with NSCLC in 2007 and account for 1% to 2% of NSCLC driver mutations. These mutations are the result of rearrangements of ROS1 with other genes forming fusion proteins. The most common fusion is with CD74. ROS1 fusion proteins result in constitutive ROS1 kinase activity leading to upregulation of downstream signaling pathways including MAPK, PI3K/AKT and JAK pathways known to play a role in malignant transformation. While most fusions are mutually exclusive of other oncogenic drivers, there are some instances of concurrent EGFR, MET BRAF, and KRAS mutations. ROS1 rearrangements are typically associated with a better prognosis compared with other driver mutations.
- Clinical Features Associated: younger age, minimal/no smoking history, females, adenocarcinoma histology
- Detection Methods: FISH, IHC (in combination with another detection method), RT-PCR, NGS
Most Common Alterations:
- Fusion Partners: The most common identified fusion partners include: CD74, SLC34A2, SDC4, EZR, FIG, TPM3, LRIG3, KDELR2, CCDC6, MSN, TMEM106B, TPD52L, CLTC, WNK1, MYO5C, TFG, RBPMS and LIMA1
- CD74: Most common (40% to 45%) and associated with increased risk of brain metastases and lower ORR to crizotinib.
Distribution and frequency of ROS1 fusion proteins in Non-Small Cell Lung Cancer.
Adapted from: Lin JJ, et al. J Thorac Oncol. 2017;doi:10.1016/j.jtho.2017.08.002.
Secondary Acquired Resistance Mutations: Acquired resistance to TKI therapy is an issue in patients with ROS1 rearrangements resulting in secondary mutations, including: G2032R, D2033N, S1986Y/F, L2026M and L1951R. The most frequent secondary mutation is G2032R.
FDA Approved Targeted Therapies:
- Crizotinib (Xalkori; Pfizer, EMD Serono):
- First-generation, multi-targeted ATP-competitive TKI that confers activity againstMET, ALK and ROS1 with poor blood-brain barrier penetration. FDA approval was granted in 2016 for the treatment of patients with metastatic ROS1-positive NSCLC based on the phase 1 PROFILE 1001 study of ROS1-rearranged NSCLC patients. At time of approval, an ORR of 72% was found, with a disease control rate of 90% and median PFS of 19.2 months. In 2017 NCCN guidelines recommended crizotinib for patients with NSCLC with ROS1 rearrangements. Despite initial positive responses, most patients treated with crizotinib eventually progress and often develop brain metastasis.
- Most Common Adverse Events: vision disorders, nausea, diarrhea, vomiting, swelling, constipation, elevated liver enzymes, fatigue, decreased appetite, upper respiratory infection, dizziness/numbness/tingling in the hands and/or feet
- Entrectinib (Rozlytrek, Genentech):
- Second-generation multi-kinase ATP-competitive inhibitor granted approval by the FDA in 2019 for patients with metastatic ROS1-positive rearranged NSCLC based on the integrated analysis of phase 1 STARTRK-1, phase 2 STARTRK-2, and phase 2 ALKA-372-001 trials. Combined results at the time of approval showed an ORR of 77.4% with a median duration of response of 24.6 months. Entrectinib is recommended over crizotinib for patients with CNS involvement due to the enhanced intracranial penetration. Entrectinib has not been shown effective in the following ROS1 mutations: L2026M, G2032R and D2033N.
- Most Common Adverse Events: fatigue, constipation, altered taste, swelling, dizziness, diarrhea, nausea, abnormal sensation, shortness of breath, muscle pain, cognitive impairment, increased weight, cough, vomiting, fever, joint stiffness, vision disorders
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