Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient with ROS1-rearranged lung adenocarcinoma

Patients with ROS1-rearranged non-small cell lung cancer (NSCLC) inevitably relapse after first-line targeted therapy with tyrosine kinase inhibitors. Efficacy of checkpoint inhibitor-based therapy on ROS1-positive NSCLC in second-line setting and change of immune factors during treatment are rarely studied. We report a ROS1-rearranged stage ⅢB lung adenocarcinoma patient who was resistant to ceritinib after developing a secondary ROS1 F2004L mutation. He received eight cycles of nivolumab plus chemotherapy and had an initial partial response, but brain metastases appeared in the seventh cycle. Lorlatinib was confirmed to have activity against CD74-ROS1 with F2004L in vitro, and was administered to this patient as the third-line therapy. The patient responded well to lorlatinib and had no relapse. We explored the tumor immune microenvironment (TIME) during immune-chemotherapy by multiplex immunohistochemistry, RNA sequencing, and multiplex plasma protein immunoassay. The results show that the TIME was active and plasma inflammatory factors were increased when the patient responded to immune-chemotherapy, while the plasma inhibitory checkpoint proteins, lymphocyte-activation gene 3, B and T lymphocyte attenuator, programmed cell death ligand 1 (PD-L1), and PD-1, were increased when the disease progressed. Moreover, the PD-L1 expression on tumor tissue was upregulated during treatment, predicting the limited benefit from immune-chemotherapy. This case report suggests that lorlatinib is a better choice than immune-chemotherapy in second-line setting for patients with similar genomic characteristics, and that monitoring the immune components during immunotherapy may help to predict disease response.