Targeting RET-mutated thyroid and lung cancer in the personalised medicine era.
Targeting RET-mutated thyroid and lung cancer in the personalised medicine era.
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DOI：
10.1016/s2213-8587(21)00152-2
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发表时间：
2021-08
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Initiatives such as The Cancer Genome Atlas and the International Cancer Genome Consortium has led to the identification of specific molecular drivers of human tumours. This in turn has led to therapy focused on targeting drivers responsible for tumour growth, irrespective of the specific histological type of cancer. Two studies published in The Lancet Diabetes and Endocrinology1 by Vivek Subbiah and colleagues and The Lancet Oncology2 by Justin F Gainor and colleagues, are great examples of such an approach. These studies are part of a multicohort, registrational, phase 1/2, open-label, clinical trial (ARROW) targeting rearranged during transfection (RET)-mutation driven malignancies (thyroid cancer and non-small cell lung cancer [NSCLC]) with the specific RET inhibitor pralsetinib.RET is a single-pass-transmembrane receptor tyrosine kinase that is highly conserved among species and is crucial for normal development and cell maturation. 3 Germline activating point mutations in RET key functional motifs cause the inherited cancer syndrome multiple endocrine neoplasia type 2, which is characterised by 100% penetrance for medullary thyroid cancer (MTC). 3 Somatic RET point mutations are also associated with sporadic MTC in about 60–90% of cases, whereas RET rearrangements associated with increased proliferation are implicated in about 20% of papillary thyroid cancers (PTCs) and 1–2% of NSCLCs. 1 Targeting RET mutations with multityrosine kinase inhibitors (TKIs), vandetanib, cabozantinib (MTC, NSCLC), sorafenib (PTC), and lenvatinib (PTC, NSCLC) has led to acceptable but suboptimal clinical outcomes, with overall non-durable response rates ranging from 32% to 46% for MTC, 12% to 65% for PTC and 16% to 47% for NSCLC. However, drug toxicity is common due to off-target effects requiring dose reduction in 35–79% of patients or treatment cessation in up to 24% of individuals. 4-8 Hence, there is a potential advantage of introducing pralsetinib as a specific RET inhibitor, characterised by 90 times higher selectivity for RET than vascular endothelial growth factor receptor, limiting off-target effects. 2 In fact, the ARROW trial shows that the treatment discontinuation rate due to severe adverse events was lower with pralsetinib than with TKIs, ranging from 4% to 6%. 1, 2 The side-effects profile of pralsetinib is milder compared with TKIs, with significantly lower prevalence of vascular endothelial
