Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion-Positive Lung Cancer by Combining Selpercatinib with Crizotinib.

PURPOSE

The proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.

PATIENTS AND METHODS

We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have amplification associated with resistance to selpercatinib. We validated activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP).

RESULTS

amplification was identified in posttreatment biopsies in 4 patients with fusion-positive NSCLC treated with selpercatinib. In at least one case, amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.

CONCLUSIONS

Through the use of SPPs, we were able to offer combination therapy targeting -amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.