Of the various types of non-small cell lung cancer (NSCLC), one of the most difficult to treat is Rearranged during Transfection (RET)-rearranged NSCLC. RET-rearrangement occurs in about 1% to 2% of adenocarcinoma NSCLC. Patients with this type of NSCLC are typically younger, female, and light or never smokers.

But what is RET and what is the significance of RET-rearrangement? RET is a gene that has been identified as an oncogenic driver in NSCLC. RET tyrosine kinase is a transmembrane glycoprotein that does not bind directly to a receptor ligand, but instead functions in concert with a coreceptor, the Glial-derived neurotrophic factor ligands (GFL)-Glial–derived neurotropic factor family receptors (GFRα).

Under nonpathological circumstances, the GFL-GFRα complex facilitates RET homodimerization and autophosphorylation of the intracellular domain of the tyrosine kinase. In RET-rearranged NSCLC, there is a chromosomal rearrangement that produces an RET fusion protein. There are several genes that partner with the RET gene, including KIF5B, CCDC6, and NCOA4; the most common is KIF5B, which accounts for 70% of RET-rearranged NSCLC cases.

A recent review article discussed current management of RET- rearranged NSCLC, providing an update on drug therapy and diagnostic testing. When vendetanib, caboxantinib, lenvatinib, RXDX-105, and alectinib—multitargeted tyrosine kinase inhibitors (TKIs) with activity against the vascular endothelial growth factor (VEGF) receptors and/or epidermal growth factor receptor (EGFR)—have been used to manage RET-arranged NSCLC, they have been found to offer limited benefit in progression-free survival (PFS) and overall survival (OS) and their use has been marred by the occurrence of Grade 3 and 4 adverse events. VEGF inhibitors are associated with severe hypertension, while EGFR inhibitors are associated with serious dermatological toxicity and significant diarrhea. Median PFS has ranged from 3.4 to 7.3 months and median OS was 9.9 to 11.6 months with the use of the multitargeted TKIs.

Data are very limited on the use of chemotherapy and chemotherapy with immunotherapy combinations in RET-rearranged NSCLC as these trials often did not gather information on RET status prior to patient enrollment. Another class of agents mentioned in this article are the next generation RET TKIs, such as selpercatinib and pralsetinib, which offer the advantage of avoiding off-target adverse events.

On September 4, 2020, the FDA granted pralsetinib accelerated approval for use in adults with metastatic RET fusion-positive NSCLC. This approval was based on results of the ARROW study, a phase I/II, multicenter, open-label, multicohort clinical trial that found an overall response rate (ORR) of 57% in patients who had previously been treated with a platinum-based regimen and an ORR of 70% in those who were treatment-naïve. The duration of response was 6 months or longer in 80% and 58% of patients, respectively. The most common adverse reactions, occurring in ≥25% of study patients, were constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea.

The most common Grade 3 to 4 laboratory abnormalities, which occurred in ≥2% of the study population, were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium (corrected), decreased sodium, increased aspartate aminotransferase, increased alanine aminotransferase, decreased platelets, and increased alkaline phosphatase.

The FDA also approved Oncomine DX Target Test as a companion diagnostic to detect the presence of RET rearrangement.

Pharmacists should be aware of advances in the management of RET-rearranged NSCLC as the arrival of pralsetinib and other not-yet-approved, next-generation RET TKIs has the potential to change the standard of care for patients with RET-rearranged NSCLC, who up to now have had limited treatment options.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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