RET inhibition is an emerging precision medicine approach. We present a case of durable benefit achieved from RET inhibition lasting for over two years. We illustrate the ability of repeat profiling to identify actionable resistance mutations to RET inhibition and extend clinical benefit of these strategies. Our disclosures are listed here. RET fusion events are associated with adenocarcinoma histology, which predicts response to certain therapies such as pemetrexib. However, the advent of RET-specific kinase inhibitors is evolving the standard of care toward one that focuses on targeting these fusion events. We now have two FDA-approved RET-specific inhibitors, selprocatinib and pralsetinib, both demonstrating overall response rates greater than 60%, robust CNS responses, and both are well-tolerated. Here, we present the case of a 58-year-old male who was diagnosed in October of 2016. His cancer progressed despite heavy pretreatment with standard chemotherapy. He was treated for four months with a multikinase inhibitor, and upon progression, he was then treated on trial with selprocatinib and had a durable partial response, which lasted for 23 months. Repeat genomic testing revealed a MET amplification, and he was started on the combination of selprocatinib and crizotinib and has derived a clinical benefit with decreased bone pain. In the wake of RET-specific kinase inhibitors, both on and off target alterations have been described. Notably, TPX0046 was designed to work against solvent-front mutations and is currently being investigated. In the setting of MET amplification following selprocatinib, as was the case with our patient, a small case series was recently published demonstrating responses with the combination of selprocatinib and crizotinib. This case illustrates the value of targeting RET fusion events in adenocarcinomas with the fusion and underscores the need for repeat genomic profiling, which can yield actionable information on therapy resistance and enable logical combination therapy strategies to extend clinical benefit.

precision medicine

RET inhibition

cancer treatment

actionable resistance mutations

combination therapy strategies