Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report | Oncotarget

A 42-year-old man with stage IV CD-74-ROS1 fusion NSCLC developed resistance to lorlatinib after 6 months on therapy.

A novel RUFY1-RET fusion concomitant with the patient’s original ROS1 fusion was identified by RNA NGS on a biopsy of a progressing site.

Combination therapy targeting RET and ROS1 using pralsetinib achieved a partial response with limited durability of only four months .

At the time of progression on gemcitabine, a biopsy of an enlarging supraclavicular lymph node was sent for DNA and RNA NGS testing using a 648 -gene Tempus xT assay.

The patient responded, though he experienced oligoprogression after 6 months and was treated with local radiation therapy.

Entrectinib treatment continued for 10 months , but unfortunately a new lesion of the left thalamus was identified and growth of a cervical spinal lesion occurred.

After 6 months of disease control on lorlatinib, progression occurred in a cervical lymph node and retrosternal mass, though the CNS disease remained stable.

A patient with advanced CD74-ROS1 fusion NSCLC who acquired resistance to lorlatinib concurrent with developing a novel RUFY1-RET fusion was reported in the recent expanded access selpercatinib plus osimertinib study, with that individual experiencing disease progression within 2 months .

The patient experienced terminal progression in 4 months .

This case adds to the literature on bypass signaling as a mechanism of resistance.