Stage IV lung adenocarcinoma: ROS1 fusion detected after immunotherapy resistance and partial response to entrectinib

What happened, in summary

This 66-year-old Chinese woman was admitted in February 2022 after 6 months of mild cough and sputum. She had no smoking history and no relevant family history. Chest-enhanced CT showed diffuse nodular shadows in both lungs and multiple enlarged mediastinal lymph nodes. Lung biopsy confirmed adenocarcinoma. Brain MRI showed multiple enhancing brain lesions, and the cancer was staged T4N2M1, Stage IV. Tumor staining supported lung adenocarcinoma, with CK7, TTF-1, Napsin A, and SP-A positivity, P40 negativity, Ki-67 of 5%, and PD-L1 expression below 1%. Because next-generation sequencing was not yet available, she first received pemetrexed plus carboplatin. Initial sequencing found no therapeutic target, so treatment moved to pembrolizumab, carboplatin, and pemetrexed for 5 cycles, followed by pembrolizumab plus pemetrexed for 18 cycles. Imaging in February and March 2023 showed no brain progression and a much smaller lung mass. Pemetrexed was later stopped because of moderate facial edema, while pembrolizumab continued for 10 cycles. In April 2024, chest CT and brain MRI showed slow progression. Repeat sequencing then found a CD74-ROS1 fusion. Because of brain metastases, she started entrectinib 600 mg daily. By June 2024, CT showed partial response by RECIST 1.1, brain MRI showed regression of brain metastases, and tumor markers CEA and CA153 decreased. As of December 2024, she remained stable and continued treatment. The key change in her course was the shift from an initially driver-negative profile to a later ROS1-driven resistance pattern, which created a new targeted-therapy option after immunotherapy resistance. This later result changed her treatment direction from immunotherapy maintenance to ROS1-targeted therapy.