Details

Autor(en) / Beteiligte

• Lin, J.J.
• Liu, S.V.
• McCoach, C.E.
• Zhu, V.W.
• Tan, A.C.
• Yoda, S.
• Peterson, J.
• Do, A.
• Prutisto-Chang, K.
• Dagogo-Jack, I.
• Sequist, L.V.
• Wirth, L.J.
• Lennerz, J.K.
• Hata, A.N.
• Mino-Kenudson, M.
• Nardi, V.
• Ou, S.-H.I.
• Tan, D.S.-W.
• Gainor, J.F.

Titel

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

Ist Teil von

• Annals of oncology, 2020-12, Vol.31 (12), p.1725-1733

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH. We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6–10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients. •Resistance is a major challenge in RET fusion-positive lung cancer treated with RET tyrosine kinase inhibitors (TKIs).•RET mutations involving the solvent front residue G810 are a recurrent yet infrequent mechanism of resistance to RET TKIs.•The majority of resistance to selective RET inhibition is driven by RET-independent resistance, such as MET amplification.•RET TKIs with potency against RET solvent front mutations and combination strategies are needed to overcome resistance.