ROS1 Rearranged NSCLC

ROS1 rearranged NSCLC is a rare molecular subtype defined by structural rearrangement (translocation or fusion) of the c-ROS oncogene 1 (ROS1) gene. It accounts for roughly 1-2% of NSCLC. ROS1 is a receptor tyrosine kinase from the insulin receptor family located on chromosome 6q22. Fusion partners include CD74 (44%, the most common), EZR, SLC34A2, TPM3, SDC4, and LRIG3. The typical patient profile is younger (median diagnosis under 50), never-smoker, with adenocarcinoma histology and a mild female predominance. Clinically the picture resembles ALK rearranged NSCLC, and both share a tendency for brain metastases.

Diagnostic methods: (1) FISH — fusion detection with a break-apart probe (the historical gold standard); (2) IHC — screening with the D4D6 antibody, in which positive staining is diagnostic because ROS1 is not expressed in normal lung tissue; (3) RT-PCR — for specific fusion partners; (4) NGS (RNA-based or DNA + RNA) — identifies the fusion partner and concurrent mutations and is now the gold standard. Because ROS1 and ALK kinase domains share 77% homology, many ALK inhibitors are also active against ROS1. Resistance mutations include G2032R (solvent-front mutation, resistant to crizotinib, ceritinib, and entrectinib but more sensitive to lorlatinib and repotrectinib), D2033N, S1986F/Y, and L2026M.

Treatment options: (1) Crizotinib — the first TKI approved for ROS1+ NSCLC (2016), effective in the first line with median PFS around 19 months (PROFILE 1001) and limited CNS penetration; (2) Entrectinib (Rozlytrek) — pan-tumor approval for ROS1 and NTRK with strong CNS penetration and median first-line PFS of 19 months, particularly preferred in brain metastases; (3) Lorlatinib (off-label for ROS1) — third-generation ALK inhibitor active against ROS1 and resistance mutations; (4) Repotrectinib (Augtyro) — next-generation ROS1/TRK inhibitor approved in 2023, showing superior efficacy in TKI-naive and post-crizotinib patients in TRIDENT-1 and active against G2032R; (5) Taletrectinib — under investigation, targeting G2032R. Approach: first-line entrectinib or repotrectinib (CNS efficacy plus broad resistance coverage), with crizotinib as an alternative. After resistance, NGS-guided selection of the next TKI. Immunotherapy is generally ineffective in ROS1+ NSCLC. From a pan-tumor perspective, ROS1 fusion can also occur in glioma, cholangiocarcinoma, and angiosarcoma, where the same TKIs are used.