Registrational results of LOXO-292 in patients with RET-altered thyroid cancers

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

“…The highly selective RET inhibitor selpercatinib is well tolerated and induces significant and durable tumor responses in heavily pretreated patients with diverse tumor histologic diagnoses and RET alterations, in particular RET-rearranged NSCLC and RET-mutant MTC. 13,14 However, as has been seen with other selective tyrosine kinases, the emergence of acquired resistance may limit long-term efficacy. In this study, we report recurrent, acquired RET solvent front mutations causing selective RET inhibitor resistance in cancers driven by oncogenic RET alterations.…”

“… 7 - 12 Recently, registrational results of the phase 1 and 2 study of selpercatinib (LOXO-292, NCT03157128 ), a highly selective anti-RET tyrosine kinase inhibitor (TKI), reported durable responses in various tumor histologic diagnoses, against diverse RET gene alterations, after prior MKIs, and in the setting of the RET V804 “gatekeeper” mutation. 13 , 14 Activity has also been seen with another selective anti-RET TKI, pralsetinib (BLU-667). 15 , 16 Although rare, RET mutation-mediated resistance to MKIs has been previously reported in single patients (e.g., RET V804M gatekeeper mutations and RET S904F), mechanisms underlying resistance to selective RET TKIs remain unknown.…”

Activity of the Highly Specific RET Inhibitor Selpercatinib (LOXO-292) in Pediatric Patients With Tumors Harboring RET Gene Alterations

“… 18 , 19 Preliminary results for selpercatinib in a phase I/II trial (LIBRETTO-001; ClinicalTrials.gov identifier: NCT03157128 ) are highly encouraging, showing that it is generally well tolerated and has marked antitumor activity in adolescent and adult patients with RET -altered cancers, including those with brain metastases and those with tumors resistant to previous multitargeted kinase inhibitors. 20 , 21 We report the clinical activity of selpercatinib in five pediatric patients with tumors harboring RET alterations, four of whom were ineligible for the selpercatinib clinical trial open at the time their treatment was started because of their young age (younger than 12 years).…”

Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy

“…RET inhibitors in MTC have also shown spectacular antitumor activity leading to the approval of selpercatinib by the FDA for the treatment of RET-mutated MTC [106]. This drug was analyzed in a cohort of RET-mutated MTC patients in the phase I/II LIBRETTO-001 trial, achieving an ORR of 69% with a DCR of 95% in pretreated patients and an ORR of 73% with a DCR of 95% in treatment naïve patients [104].…”