ROS1-rearranged Stage IV lung adenocarcinoma: sequential targeted therapy and 73-month survival

What happened, in summary

This 63-year-old Chinese woman was a never-smoker who presented in September 2018 with persistent cough and sputum. Chest CT showed a left lower-lobe lung mass, multiple ground-glass nodules in the right lung, and multiple enlarged mediastinal lymph nodes, explaining her persistent respiratory symptoms. Brain MRI showed no distant metastases at baseline. Lung puncture biopsy confirmed left lower-lobe adenocarcinoma, clinically staged cT2N2M1, Stage IV. Molecular profiling found a CD74-ROS1 fusion, CTNNB1 p.Thr41Ala mutation, and APC p.Glu601fs mutation. She began first-line crizotinib and achieved near-complete remission, with a first progression-free survival of 47 months. During this period, renal cysts developed, and whole-brain radiotherapy, 30 Gy in 10 fractions, was given for brain metastases. In August 2022, dyspnea and imaging confirmed progression. Plasma ctDNA testing no longer detected the CD74-ROS1 fusion. Second-line lorlatinib produced partial remission and an 11-month progression-free treatment interval, but side effects included hypercholesterolemia and cognitive decline on formal cognitive testing. In September 2023, disease progressed again. NGS of pleural effusion showed the original CD74-ROS1 fusion plus an acquired ROS1 L2086F resistance mutation, mTOR p.E2419K mutation, and FGFR3 amplification. Cabozantinib was started to target ROS1 L2086F after the resistance profile was identified from pleural effusion. After 4 months, dyspnea improved, her condition stabilized, and chest CT showed marked reduction in pulmonary metastases. Palpitations were managed by dose reduction. She progressed after 12 months on cabozantinib despite the earlier symptomatic improvement and died on October 6, 2024, with total overall survival of 73 months from the original diagnosis.