Treatment process of ALK and ROS1 double-rearranged lung adenocarcinoma cell carcinoma: a case report

Anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) rearrangements are vital oncogenic drivers in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (LUAD), with positivity rates of 2.6% and 1.4% respectively, and are critical prognostic and predictive markers. These two rearrangements are mutually exclusive in most cases, and their co-occurrence is exceptionally rare in existing literature. Therefore, the clinical behavior, therapeutic responses, and optimal treatment strategies for this dual-rearranged subtype are poorly characterized. This case report aims to explore the efficacy of chemotherapy in this rare subtype.

A 47-year-old never-smoker woman presented with a persistent dry cough and dyspnea. Imaging and biopsy confirmed stage IV (cT2N2M1b) poorly differentiated LUAD with metastases to the mediastinal lymph nodes, pleura, and orbit. Comprehensive molecular profiling identified concurrent ALK and ROS1 rearrangements. The patient received first-line chemotherapy with pemetrexed (820 mg on day 1) plus cisplatin (40 mg on days 1-3) every 21 days and achieved a remarkable progression-free survival (PFS) of 48 months. Upon disease progression at four years, with new pulmonary and cerebral lesions, DNA-based next-generation sequencing (NGS) revealed an echinoderm microtubule-associated protein-like 4 (EML4) exon 13-ALK exon 20 fusion with a variant frequency of 10.33%. She was subsequently treated with ensartinib (225 mg once daily), yielding a favorable response. Treatment remains ongoing.

This case highlights that first-line pemetrexed-cisplatin chemotherapy can yield prolonged disease control in NSCLC harboring dual ALK/ROS1 rearrangements, followed effectively by targeted therapy. It underscores the importance of high-precision molecular profiling to guide sequential treatment strategies. Although tyrosine kinase inhibitors remain the cornerstone for ALK- or ROS1-positive NSCLC, the ideal initial approach for concurrent ALK/ROS1 fusions is yet to be established. Unless there are studies with large cohorts clarifying the case, an individualized regimen-potentially starting with chemotherapy and transitioning to targeted agents-may be justified. Further clinical experience and collaborative research are essential to develop evidence-based guidelines for this exceptionally rare subset.