Therapeutic strategies in RET gene rearranged non-small cell lung cancer

Abstract

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.

Cytomorphologic features of intraductal salivary gland carcinoma: A multi‐institutional study of 13 FNA cases with histologic, molecular, and clinical correlations

“…Recent Cancer Cytopathology December 2021 clinical trials in patients with various RET fusion-positive cancers using RET inhibitors, including selpercatinib and pralsetinib, have demonstrated therapeutic responses with rates ranging from 56% to 63%. [26][27][28] Currently, rationales for molecular analysis in selected salivary neoplasias detected by FNA are useful when one is considering preoperative neoadjuvant therapy, in cases in which surgical planning would be either altered or deferred on the basis of the result, or in cases in which surgery is not an option because of the patient's clinical status. Recent studies with kinase fusion-related thyroid carcinomas 29,30 provide a useful template to apply in the context of cytologic and small biopsy specimens of kinase-fusion or kinase-mutated salivary gland malignancies such as IDC when the result would potentially affect the clinical management (Fig.…”

Deep learning-based tumor microenvironment segmentation is predictive of tumor mutations and patient survival in non-small-cell lung cancer

“…For example, both RET and PDGFRB are clinically relevant LUAD cancer genes. RET has protooncogene properties and its fusions, which occur in 1-2% of LUAD 64 , are associated with a high risk of brain metastasis 65 . However, last clinical trials indicated that they may be effectively targeted by RET tyrosine kinase inhibitors as pralsetinib, selpercatinib 64 .…”

“…RET has protooncogene properties and its fusions, which occur in 1-2% of LUAD 64 , are associated with a high risk of brain metastasis 65 . However, last clinical trials indicated that they may be effectively targeted by RET tyrosine kinase inhibitors as pralsetinib, selpercatinib 64 . PDGFRB is a member of the PDGF/PDGFR axis that is recognized as a key regulator of mesenchymal cell activity in TME 66 , and several new agents (linifanib, motesanib, olaratumab) that block the PDGFR signaling are being tested in LUAD 67 .…”

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

“…The most frequent partners occur in KIF5B and CCD6, which represent around 60% and 20% of cases, respectively [137]. Different therapeutic medications targeting RET fusions have been developed, and, to date, selpercatinib and pralsetinib medications are proposed while waiting for marketing approval by the FDA and EMA [140][141][142][143][144][145]. However, testing for these fusions will now become systematic at diagnosis for all patients presenting with advanced-stage NS-NSCLC, knowing that patients with RET fusions do not generally respond well to immune checkpoint inhibitors (ICIs) [146][147][148][149].…”