CNS metastasis in ROS1+ NSCLC: An urgent call to action, to understand, and to overcome.

The incidence of CNS metastasis at the time of diagnosis of and during the natural disease history of advanced ROS1+ NSCLC is largely unknown. It is generally believed that the incidence of CNS metastasis is lower in ROS1+ NSCLC than ALK+ NSCLC as ROS1 fusions are regarded as a less powerful driver mutation than ALK fusions in ALK+ NSCLC based on the longer progression-free survival of ROS1+ NSCLC patients than ALK+ NSCLC patients treated with crizotinib. Here we reviewed the incidence of CNS metastasis from prospective clinical trials and retrospective case series from primarily single institution. The incidence of CNS metastasis in ROS1+ NSCLC patients at the time of diagnosis ranged from 20% to mid 30% while the incidence of CNS metastasis can be as high as in the mid 50% range post-crizotinib indicating CNS metastasis is indeed a major morbidity for ROS1+ NSCLC patients throughout the course of treatment. To date 22 fusion partners in ROS1+ NSCLC have been reported in the literature and one report has indicated CD74-ROS1 fusion variant increased the predilection for CNS metastasis than non-CD74-ROS1 fusion variants. We reviewed reported intra-cranial activity of all preclinical and clinical development stage ROS1 TKIs and pemetrexed-based chemotherapy in ROS1+ NSCLC patients. While several ROS1 TKIs (i.e. entrectinib, cabozantinib, lorlatinib, repotrectinib) have reported intra-cranial response rates, there is no literature reporting on the intra-cranial activity of pemetrexed-based chemotherapy in ROS1+ NSCLC patients. In summary, better understanding the high incidence of CNS metastasis in ROS1+ NSCLC patients, how certain ROS1 fusion variant may increase the incidence of CNS metastasis, and any intra-cranial efficacy data of pemetrexed in ROS1+ NSCLC are all urgently needed.