We thus prospectively explored the neoadjuvant use of selpercatinib, a highly selective and potent rearrangement during transfection (RET) kinase inhibitor with central nervous system activity approved in multiple countries for the treatment of RET-altered advanced or metastatic lung or thyroid cancers. Neoadjuvant anaplastic lymphoma kinase TKI therapy was likewise found to be active in anaplastic lymphoma kinase fusion-positive NSCLC, including in patients for whom pathologic complete response (pCR) was achieved ( 2). In trials randomizing epidermal growth factor receptor ( EGFR)-mutant NSCLC to targeted therapy versus chemotherapy, neoadjuvant EGFR tyrosine kinase inhibitor (TKI) achieved high objective response rates (42%–62%), major pathologic response (MPR 8%–24%), and prolonged progression-free survival ( 1). The activity of prospective preoperative selpercatinib in this case establishes proof of concept of the potential utility of RET inhibitor therapy in early-stage RET fusion-positive NSCLC.Īlthough cytotoxic chemotherapy and immunotherapy remain cornerstones of perioperative therapy in non-small cell lung cancer (NSCLC), many patients experience recurrent disease and limited survival. Neoadjuvant selpercatinib was well-tolerated with only low-grade treatment-emergent adverse events. This consensus assessment by three independent pathologists was aided by RET fluorescence in situ hybridization testing of a reactive pneumocyte proliferation showing no rearrangement. While moderate regression in the primary tumor (stable disease, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1) was observed radiologically, assessment via an Independent Pathologic Review Committee revealed a pathologic complete response (0% viable tumor). A patient with a stage IB (cT2aN0M0) KIF5B-RET fusion-positive NSCLC received 8 weeks of neoadjuvant selpercatinib at 160 mg twice daily followed by surgery. A cohort that included neoadjuvant and adjuvant selpercatinib was opened on LIBRETTO-001 for early-stage RET fusion-positive NSCLC with the primary endpoint of major pathologic response.
#PATHOLOGICAL COMPLETE RESPONSE TRIAL#
The LIBRETTO-001 trial demonstrated the activity of the selective rearrangement during transfection (RET) inhibitor selpercatinib in advanced RET fusion-positive non-small cell lung cancer (NSCLC) and resulted in the drug’s approval for this indication.
Murciano-Goroff 4, Ravi Rajaram 5, Sylwia Szymczak 6, Anna M.
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