TY - JOUR
T1 - Therapeutic strategies in RET gene rearranged non-small cell lung cancer
AU - Drusbosky, Leylah M.
AU - Rodriguez, Estelamari
AU - Dawar, Richa
AU - Ikpeazu, Chukwuemeka V.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1–2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.
AB - The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1–2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.
KW - Metastasis
KW - Non-small cell lung cancer
KW - RET gene fusions
KW - Tyrosine kinase inhibitors
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U2 - 10.1186/s13045-021-01063-9
DO - 10.1186/s13045-021-01063-9
M3 - Review article
C2 - 33771190
AN - SCOPUS:85103532028
VL - 14
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
SN - 1756-8722
IS - 1
M1 - 50
ER -