{"product_id":"a-patients-guide-to-ret-targeted-treatment-for-thyroid-cancer-what-the-latest-research-means-for-you","title":"A Patient's Guide to RET-Targeted Treatment for Thyroid Cancer — What the Latest Research Means for You","description":"\u003cp\u003eThis review explains how changes (called \"alterations\") in a specific gene known as RET drive many types of thyroid cancer, and how newer targeted medications — particularly two drugs called selpercatinib and pralsetinib — are transforming the way these cancers are treated. The key finding is that these newer, highly selective \"RET inhibitor\" drugs are substantially more effective and much better tolerated than older multi-kinase inhibitors, making them the new preferred first-line treatment for advanced RET-altered medullary thyroid cancer. However, these treatments are not yet curative, and patients who progress on therapy often develop mutations that make the drugs less effective. Researchers are continuing to study resistance mechanisms and new therapeutic strategies to improve long-term outcomes.\u003c\/p\u003e\n\n\u003ch1\u003eA Patient's Guide to RET-Targeted Treatment for Thyroid Cancer — What the Latest Research Means for You\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#understanding-ret\"\u003eUnderstanding the RET Gene and Its Role in Thyroid Cancer\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ret-mutations\"\u003eHow RET Mutations Cause Medullary Thyroid Cancer (MTC)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ret-fusions\"\u003eHow RET Fusions Cause Papillary Thyroid Cancer (PTC)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#testing\"\u003eTesting for RET Alterations — Who Should Be Tested and How\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#mki\"\u003eTreatment With Multi-Kinase Inhibitors (MKIs) — The Older Approach\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#mki-cabozantinib\"\u003eCabozantinib (EXAM Trial)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#mki-vandetanib\"\u003eVandetanib (ZETA Trial)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#mki-limitations\"\u003eWhy Multi-Kinase Inhibitors Have Limits\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#selective-ret\"\u003eThe New Generation: Selective RET Inhibitors\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#selpercatinib\"\u003eSelpercatinib (LOXO-292) — The Evidence\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#pralsetinib\"\u003ePralsetinib (BLU-667) — The Evidence\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#head-to-head\"\u003eThe Head-to-Head Trial: LIBRETTO-531\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#key-findings\"\u003eKey Findings at a Glance — Efficacy Data\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#resistance\"\u003eResistance: Why the Drugs Stop Working Over Time\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eClinical Implications — What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Current Research\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#future\"\u003eFuture Directions — What's on the Horizon\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003ePractical Recommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eRET gene mutations drive most medullary thyroid cancers; RET fusions drive 5–10% of papillary thyroid cancers.\u003c\/li\u003e\n\u003cli\u003eGenetic testing for RET alterations is recommended for all new medullary thyroid cancer diagnoses, using blood or tumor tissue.\u003c\/li\u003e\n\u003cli\u003eOlder multi-kinase inhibitors like cabozantinib and vandetanib have significant side effects and limited activity against some RET mutations.\u003c\/li\u003e\n\u003cli\u003eSelective RET inhibitors selpercatinib and pralsetinib show higher response rates, better tolerability, and longer progression-free survival in trials.\u003c\/li\u003e\n\u003cli\u003eIn the LIBRETTO-531 trial, first-line selpercatinib improved 24-month progression-free survival to 76.4% vs 37.2% with older drugs, with fewer side effects.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eThyroid cancer is one of the most common types of cancer, and while many cases are curable with surgery and other standard treatments, some patients develop advanced or metastatic disease that requires systemic (whole-body) therapy. For these patients, treatment has historically been limited, with modest results and significant side effects.\u003c\/p\u003e\n\n\u003cp\u003eOver the last two decades, researchers have learned that a specific gene called \u003cstrong\u003eRET\u003c\/strong\u003e (short for \"REarranged during Transfection\") acts as a major driver in several types of thyroid cancer. When RET becomes abnormally activated through mutations or structural rearrangements (fusions), it fuels the growth and survival of cancer cells. This discovery opened the door to targeted therapies — drugs designed to specifically block RET activity.\u003c\/p\u003e\n\n\u003cp\u003eThis year marks the 30th anniversary of the discovery linking inherited (germline) mutations of the RET gene to multiple endocrine neoplasia type 2 (MEN2) syndromes. In this timely review, researchers from The University of Texas MD Anderson Cancer Center summarize what is currently known about treating RET-altered thyroid cancers, the limitations of available approaches, and where the field is heading next.\u003c\/p\u003e\n\n\u003ch2 id=\"understanding-ret\"\u003eUnderstanding the RET Gene and Its Role in Thyroid Cancer\u003c\/h2\u003e\n\n\u003cp\u003eRET is a type of protein called a \u003cstrong\u003etransmembrane glycoprotein receptor tyrosine kinase (RTK)\u003c\/strong\u003e. In plain language, it's a protein on the surface of cells that helps send growth signals from outside the cell to the inside. Under normal conditions, RET plays an important role in the health and maintenance of neural (nerve), hematopoietic (blood-forming), and neuroendocrine tissues.\u003c\/p\u003e\n\n\u003cp\u003eThe RET receptor has a specific structure:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eExtracellular domain\u003c\/strong\u003e (the part outside the cell): contains four cadherin-like repeats, a calcium-binding site, and a cysteine-rich region\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIntracellular domain\u003c\/strong\u003e (the part inside the cell): contains tyrosine kinase residues that transmit signals\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eUnlike many other receptors that bind directly to their activating molecules, RET is activated indirectly. A family of molecules called \u003cstrong\u003eGDNF family ligands\u003c\/strong\u003e (glial cell line-derived neurotrophic factors) first bind to co-receptors called \u003cstrong\u003eGFRα\u003c\/strong\u003e. This complex then causes two RET receptors to pair up (a process called homodimerization), which triggers a series of chemical reactions that activate downstream signaling pathways — most importantly the \u003cstrong\u003eMAPK\u003c\/strong\u003e and \u003cstrong\u003ePI3K\u003c\/strong\u003e pathways — that control cell proliferation and survival.\u003c\/p\u003e\n\n\u003ch2 id=\"ret-mutations\"\u003eHow RET Mutations Cause Medullary Thyroid Cancer (MTC)\u003c\/h2\u003e\n\n\u003cp\u003eRET mutations are the most frequent genetic alterations found in \u003cstrong\u003emedullary thyroid carcinoma (MTC)\u003c\/strong\u003e, a type of thyroid cancer that arises from specialized cells called parafollicular C cells. About one quarter of MTC cases are hereditary, caused by germline (inherited) mutations in RET. These inherited mutations are part of two distinct syndromes called \u003cstrong\u003emultiple endocrine neoplasia type 2A (MEN2A)\u003c\/strong\u003e and \u003cstrong\u003etype 2B (MEN2B)\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eMEN2A syndrome\u003c\/strong\u003e is characterized by MTC in virtually all patients who carry the mutation, combined with variable other manifestations including pheochromocytoma (a tumor of the adrenal gland), primary hyperparathyroidism (overactive parathyroid glands), and occasionally cutaneous lichen amyloidosis (a skin condition) and Hirschsprung disease (a bowel disorder). The way the syndrome presents varies depending on the specific genetic mutation, both in terms of how often the condition appears (penetrance) and how aggressive the MTC is. The majority of germline mutations causing MEN2A occur within the extracellular cysteine-rich domain, most commonly at a location called \u003cstrong\u003eC634 in exon 11\u003c\/strong\u003e. These mutations cause abnormal disulfide bonds to form between free cysteine residues, allowing the receptor to pair up and activate without needing its normal trigger (a process called ligand-independent dimerization).\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eMEN2B syndrome\u003c\/strong\u003e is less common, accounting for only about 5% of hereditary MTCs. However, the MTC in these patients often appears in infancy and is highly aggressive. MEN2B is almost exclusively caused by a germline mutation called \u003cstrong\u003eRET M918T\u003c\/strong\u003e in exon 16, which substitutes a methionine for a threonine in the kinase domain. This causes increased ATP-binding and autophosphorylation, leading to dimerization-independent activation of downstream signaling. Less than 5% of patients with MEN2B harbor an \u003cstrong\u003eA883F\u003c\/strong\u003e mutation in exon 15, or double mutations involving \u003cstrong\u003eV804M\u003c\/strong\u003e. In addition to MTC, hallmark features of MEN2B include pheochromocytoma, generalized ganglioneuromatosis (nerve tissue overgrowth) of the aerodigestive tract, ophthalmologic abnormalities, and skeletal malformations such as a marfanoid (tall, slender) body habitus.\u003c\/p\u003e\n\n\u003cp\u003eRET mutations are also the hallmark of \u003cstrong\u003esporadic (non-inherited) MTCs\u003c\/strong\u003e, found in about 55 to 65% of cases. The \u003cstrong\u003eM918T\u003c\/strong\u003e mutation is the most frequent somatic (acquired) mutation. Other less common point mutations can occur at locations such as \u003cstrong\u003eC634, A883, and C630\u003c\/strong\u003e. Occasionally, deletions and small insertions have also been reported.\u003c\/p\u003e\n\n\u003ch2 id=\"ret-fusions\"\u003eHow RET Fusions Cause Papillary Thyroid Cancer (PTC)\u003c\/h2\u003e\n\n\u003cp\u003eUnlike MTC, where mutations are the main culprit, \u003cstrong\u003epapillary thyroid carcinoma (PTC)\u003c\/strong\u003e — the most common type of thyroid cancer — is driven by \u003cstrong\u003eRET fusions\u003c\/strong\u003e rather than mutations. RET fusions occur when a piece of the RET gene breaks off and joins with another gene. In PTC, these fusions are found in \u003cstrong\u003e5–10% of cases\u003c\/strong\u003e and are especially common in children and in people who have been exposed to radiation.\u003c\/p\u003e\n\n\u003cp\u003eThe two most common RET fusions in thyroid cancer combine RET with either:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eCCDC6\u003c\/strong\u003e (coiled-coil domain containing 6), producing the CCDC6-RET fusion, or\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNCOA4\u003c\/strong\u003e (nuclear receptor co-activator 4), producing the NCOA4-RET fusion\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese fusions typically result from defective repair of a DNA double-strand break. RET fusions over-activate downstream signaling through two possible mechanisms: either the partner gene contributes a dimerization domain that allows the RET kinase to activate without needing its ligand, or the upstream partner gene is expressed everywhere, causing RET to be produced in cells where it normally wouldn't be.\u003c\/p\u003e\n\n\u003cp\u003eThis year — 2024 — marks three decades since researchers first connected germline RET mutations to MEN2 syndromes, highlighting just how long RET has been recognized as a meaningful driver in thyroid cancers.\u003c\/p\u003e\n\n\u003ch2 id=\"testing\"\u003eTesting for RET Alterations — Who Should Be Tested and How\u003c\/h2\u003e\n\n\u003cp\u003eBecause 1 to 7% of patients with apparently sporadic MTC actually have hereditary disease, \u003cstrong\u003egermline RET mutation testing is recommended for all patients with a new diagnosis of MTC\u003c\/strong\u003e. If no germline mutation is found, testing for somatic RET alterations is also recommended in advanced medullary and differentiated thyroid cancers when systemic therapy is being considered and molecular therapeutic targets are being sought.\u003c\/p\u003e\n\n\u003cp\u003eSeveral testing methods are available, and the choice of test depends on the type and number of alterations to screen for, as well as the quantity and quality of tissue available:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eImmunohistochemistry (IHC):\u003c\/strong\u003e Protein-based detection. Not reliable for screening RET alterations because RET protein overexpression can also be seen in benign (non-cancerous) lesions.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFluorescent in situ hybridization (FISH):\u003c\/strong\u003e Detects RET fusions with good sensitivity and specificity, but cannot identify the fusion partner and depends heavily on tissue quality.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDNA quantitative PCR (Q-PCR):\u003c\/strong\u003e Can screen selected hotspot mutations but is limited by primer availability and cannot detect fusions.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRNA-based reverse transcription PCR (RT-PCR):\u003c\/strong\u003e Can detect fusions but only identifies known partners with specific primers.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDNA-based next-generation sequencing (NGS):\u003c\/strong\u003e Can test for multiple gene alterations at once with relatively high sensitivity and specificity. Very sensitive for mutations even when tumor cells are few, but limited for detecting fusions — partly because the intronic regions that must be sequenced are very large. It also cannot tell whether the rearranged gene is actually producing a fusion protein.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRNA-based NGS:\u003c\/strong\u003e Better for detecting fusion genes because introns are spliced out, making the sequencing easier. Can also show whether the fusion is in-frame (meaning it will produce a functional protein). The downside is that RNA degrades more easily.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLiquid biopsy (cell-free DNA NGS):\u003c\/strong\u003e Tests circulating tumor DNA in the blood. Useful when no tissue specimen is available, but has biological and technical limitations. If a liquid biopsy is negative, tumor tissue testing is recommended to definitively rule out a RET alteration.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn 2021, the European Society of Medical Oncology (ESMO) issued recommendations for standard RET testing:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003eIn MTC patients, start with germline testing using Q-PCR or NGS on blood or sputum.\u003c\/li\u003e\n  \u003cli\u003eIf a familial RET mutation is already known, DNA Sanger sequencing can be performed on circulating leukocytes (white blood cells).\u003c\/li\u003e\n  \u003cli\u003eIn the absence of a germline mutation, NGS is the test of choice on formalin-fixed, paraffin-embedded (FFPE) tissue in sporadic MTC and other non-MTC cancers that may harbor RET alterations.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003ch2 id=\"mki\"\u003eTreatment With Multi-Kinase Inhibitors (MKIs) — The Older Approach\u003c\/h2\u003e\n\n\u003cp\u003eBecause RET shares similarities with other tyrosine kinase receptors, several \u003cstrong\u003emulti-kinase inhibitors (MKIs)\u003c\/strong\u003e — drugs that block multiple kinases at once — have been shown to have some anti-RET activity. Among these, \u003cstrong\u003ecabozantinib\u003c\/strong\u003e and \u003cstrong\u003evandetanib\u003c\/strong\u003e are the only two MKIs currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced, metastatic MTC, regardless of RET mutation status. Meanwhile, \u003cstrong\u003elenvatinib\u003c\/strong\u003e, \u003cstrong\u003ecabozantinib\u003c\/strong\u003e, and \u003cstrong\u003esorafenib\u003c\/strong\u003e are approved for advanced radioiodine-refractory differentiated thyroid cancers (RR-DTCs), including those with RET alterations.\u003c\/p\u003e\n\n\u003ch2 id=\"mki-cabozantinib\"\u003eCabozantinib (EXAM Trial)\u003c\/h2\u003e\n\n\u003cp\u003eCabozantinib is a tyrosine kinase inhibitor that targets several proteins: hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2 (VEGFR-2), and RET. Since MET, VEGFR-2, and VEGFR-3 are all overproduced in MTC and involved in its growth, cabozantinib was studied specifically in this tumor type.\u003c\/p\u003e\n\n\u003cp\u003eA phase I study first showed encouraging results, leading to the pivotal \u003cstrong\u003eEXAM trial\u003c\/strong\u003e, a phase III placebo-controlled study that randomized \u003cstrong\u003e330 patients with progressive metastatic MTC\u003c\/strong\u003e to receive cabozantinib or placebo (at a 2:1 ratio). The results were striking:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eProgression-free survival (PFS):\u003c\/strong\u003e 11.2 months with cabozantinib vs 4.0 months with placebo — a Hazard Ratio (HR) of 0.28 (95% Confidence Interval [CI], 0.19–0.40; P\u0026lt;0.001). This means patients on cabozantinib had a 72% lower risk of cancer progression.\u003c\/li\u003e\n  \u003cli\u003eThe PFS benefit was observed regardless of tumor burden and location, prior treatment with tyrosine kinase inhibitors, or RET mutation status.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAn interim analysis did not show a statistically significant difference in overall survival (OS) between the two arms (HR 0.98; 95% CI, 0.63–1.52). However, a subgroup analysis based on tumor genetics revealed a significant OS benefit in patients with \u003cstrong\u003eRET M918T-mutated MTC\u003c\/strong\u003e who received cabozantinib compared with placebo: \u003cstrong\u003e44.3 vs 18.9 months\u003c\/strong\u003e (HR 0.60; 95% CI, 0.38–0.94; P=0.03).\u003c\/p\u003e\n\n\u003cp\u003eSide effects were substantial. The most common side effects, each reported in more than 40% of patients treated with cabozantinib, included diarrhea, palmar-plantar erythrodysesthesia (hand-foot syndrome), decreased weight and appetite, nausea, and fatigue. \u003cstrong\u003eGrade 3 or 4 adverse events\u003c\/strong\u003e (severe or life-threatening side effects) occurred in \u003cstrong\u003e69% of patients\u003c\/strong\u003e — most commonly diarrhea (16%), palmar-plantar erythrodysesthesia (13%), and fatigue (9%). High blood pressure (hypertension) occurred in 33%, bleeding (hemorrhage) in 25%, gastrointestinal perforation in 3%, and fistula formation in 5% — effects related to cabozantinib's potent anti-angiogenic (blood vessel-blocking) activity.\u003c\/p\u003e\n\n\u003ch2 id=\"mki-vandetanib\"\u003eVandetanib (ZETA Trial)\u003c\/h2\u003e\n\n\u003cp\u003eVandetanib is another tyrosine kinase inhibitor that blocks the epidermal growth factor receptor (EGFR), VEGFR-2\/3, and RET. Like cabozantinib, it counteracts the excessive stimulation of growth-promoting pathways in MTC, though its anti-angiogenic activity is less potent than cabozantinib's.\u003c\/p\u003e\n\n\u003cp\u003eAfter two phase II trials showed acceptable safety and anti-tumor activity, the phase III \u003cstrong\u003eZETA trial\u003c\/strong\u003e compared vandetanib against placebo in patients with locally advanced or metastatic MTC. Key results:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e333 patients\u003c\/strong\u003e were randomized in a 2:1 ratio to receive vandetanib or placebo.\u003c\/li\u003e\n  \u003cli\u003eAfter a median follow-up of \u003cstrong\u003e24 months\u003c\/strong\u003e, PFS was significantly longer with vandetanib: \u003cstrong\u003e30.5 vs 19.3 months\u003c\/strong\u003e (HR 0.46; 95% CI, 0.31–0.69; P\u0026lt;0.001).\u003c\/li\u003e\n  \u003cli\u003eThe overall response rate (ORR) — the percentage of patients whose tumors shrank — was also much better: \u003cstrong\u003e45% with vandetanib vs 13% with placebo\u003c\/strong\u003e (P\u0026lt;0.001).\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eOverall survival could not be properly assessed because patients who progressed on placebo were allowed to cross over to vandetanib. The most common side effects were diarrhea, rash, and nausea. \u003cstrong\u003e24% of patients\u003c\/strong\u003e experienced grade 3 or higher adverse events, including diarrhea (11%) and hypertension (9%). The most concerning side effect was \u003cstrong\u003eQTc prolongation\u003c\/strong\u003e (an abnormality in the heart's electrical activity), reported in 19 patients (8%), though no cases of torsades de pointes (a dangerous heart rhythm disorder) occurred.\u003c\/p\u003e\n\n\u003cp\u003eOne important difference between the trials: patients were not required to have progressive disease to enter the ZETA trial, whereas progression within the previous 14 months was a requirement for the EXAM trial. This has led to some questions about whether the longer PFS seen with vandetanib might be partly due to patients with more indolent (slow-growing) disease. However, a post-hoc analysis of the ZETA trial focusing on the subgroup of patients (n=184) with progressive and symptomatic disease showed similar PFS benefits: HR 0.43 (95% CI, 0.28–0.64; P\u0026lt;0.0001).\u003c\/p\u003e\n\n\u003ch2 id=\"mki-limitations\"\u003eWhy Multi-Kinase Inhibitors Have Limits\u003c\/h2\u003e\n\n\u003cp\u003eDespite their efficacy, MKIs come with significant drawbacks:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLimited RET activity at clinical doses:\u003c\/strong\u003e Anti-VEGFR MKIs are pharmacokinetically limited in their ability to target RET compared with VEGFR-2 at drug concentrations achievable in patients.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eVariable activity against different RET mutations:\u003c\/strong\u003e For example, cabozantinib and vandetanib effectively inhibit the RET M918T mutation but have limited activity against \u003cstrong\u003eRET V804 \"gatekeeper\" mutations\u003c\/strong\u003e — the IC50 (the concentration needed to inhibit 50% of the target) is 100 to 10,000 times higher against these mutations than against normal (wild-type) RET.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eOff-target side effects:\u003c\/strong\u003e Activity against VEGFR and other kinases causes dose-limiting side effects that compromise how effectively the drug can be given.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNo complete responses, and limited duration of benefit:\u003c\/strong\u003e Most patients eventually develop resistance and their disease progresses.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eSpecific resistance mechanisms that have been identified against cabozantinib and vandetanib include \u003cstrong\u003eacquired RET V804L\/M gatekeeper mutations\u003c\/strong\u003e, which block drug access to the ATP-binding pocket of RET, and \u003cstrong\u003eS904F missense mutations\u003c\/strong\u003e, which increase autophosphorylation activity of the RET kinase.\u003c\/p\u003e\n\n\u003cp\u003eLenvatinib and sorafenib have also been studied in small cohorts of patients with advanced RET-mutated MTC, with only modest efficacy. And for RET-altered radioiodine-refractory differentiated thyroid cancers, none of the clinical trials that led to approval of lenvatinib, cabozantinib, or sorafenib (or trials exploring sunitinib or vandetanib) specifically investigated the subgroup of patients with RET fusions. However, extrapolating from data in RET-rearranged non-small cell lung cancer (NSCLC), MKIs have generally produced limited PFS prolongation and lower response rates compared with targeted therapies in other types of NSCLC with ALK or EGFR alterations — suggesting that the off-target activity of MKIs limits their effectiveness in RET-fusion-positive tumors.\u003c\/p\u003e\n\n\u003ch2 id=\"selective-ret\"\u003eThe New Generation: Selective RET Inhibitors\u003c\/h2\u003e\n\n\u003cp\u003eTo overcome the limitations of MKIs, two drugs with potent and highly selective anti-RET activity were developed: \u003cstrong\u003eselpercatinib\u003c\/strong\u003e and \u003cstrong\u003epralsetinib\u003c\/strong\u003e. These drugs are far more precise — they were designed to block RET specifically while sparing other kinases like VEGFR, resulting in better efficacy and a much more tolerable side-effect profile.\u003c\/p\u003e\n\n\u003cp\u003eFor comparison, here is how the older MKIs stack up against the newer selective RET inhibitors in terms of biochemical potency (IC50 values, measured in nanomoles per liter [nM] — lower numbers mean more potent inhibition):\u003c\/p\u003e\n\n\u003ctable\u003e\n  \u003ctr\u003e\n    \u003cth\u003eDrug\u003c\/th\u003e\n    \u003cth\u003eVEGFR2\u003c\/th\u003e\n    \u003cth\u003eRET Wild-Type\u003c\/th\u003e\n    \u003cth\u003eRET M918T\u003c\/th\u003e\n    \u003cth\u003eRET V804L\u003c\/th\u003e\n    \u003cth\u003eRET V804M\u003c\/th\u003e\n    \u003cth\u003eRET G810S\u003c\/th\u003e\n    \u003cth\u003eCCDC6-RET\u003c\/th\u003e\n  \u003c\/tr\u003e\n  \u003ctr\u003e\n    \u003ctd\u003eCabozantinib\u003c\/td\u003e\n    \u003ctd\u003e2\u003c\/td\u003e\n    \u003ctd\u003e11\u003c\/td\u003e\n    \u003ctd\u003e8\u003c\/td\u003e\n    \u003ctd\u003e45\u003c\/td\u003e\n    \u003ctd\u003e162\u003c\/td\u003e\n    \u003ctd\u003e1050\u003c\/td\u003e\n    \u003ctd\u003e34\u003c\/td\u003e\n  \u003c\/tr\u003e\n  \u003ctr\u003e\n    \u003ctd\u003eVandetanib\u003c\/td\u003e\n    \u003ctd\u003e4\u003c\/td\u003e\n    \u003ctd\u003e4\u003c\/td\u003e\n    \u003ctd\u003e7\u003c\/td\u003e\n    \u003ctd\u003e3597\u003c\/td\u003e\n    \u003ctd\u003e726\u003c\/td\u003e\n    \u003ctd\u003e5470\u003c\/td\u003e\n    \u003ctd\u003e20\u003c\/td\u003e\n  \u003c\/tr\u003e\n  \u003ctr\u003e\n    \u003ctd\u003ePralsetinib\u003c\/td\u003e\n    \u003ctd\u003e35\u003c\/td\u003e\n    \u003ctd\u003e0.4\u003c\/td\u003e\n    \u003ctd\u003e0.4\u003c\/td\u003e\n    \u003ctd\u003e1.8\u003c\/td\u003e\n    \u003ctd\u003e17\u003c\/td\u003e\n    \u003ctd\u003e391\u003c\/td\u003e\n    \u003ctd\u003e0.4\u003c\/td\u003e\n  \u003c\/tr\u003e\n  \u003ctr\u003e\n    \u003ctd\u003eSelpercatinib\u003c\/td\u003e\n    \u003ctd\u003e100\u003c\/td\u003e\n    \u003ctd\u003e0.4\u003c\/td\u003e\n    \u003ctd\u003e0.7\u003c\/td\u003e\n    \u003ctd\u003e17\u003c\/td\u003e\n    \u003ctd\u003e56\u003c\/td\u003e\n    \u003ctd\u003e880\u003c\/td\u003e\n    \u003ctd\u003e10\u003c\/td\u003e\n  \u003c\/tr\u003e\n\u003c\/table\u003e\n\n\u003cp class=\"caption\"\u003eIC50 = concentration of drug needed to inhibit 50% of the target's activity in the lab. Lower numbers indicate stronger inhibition. Notice how pralsetinib and selpercatinib are far more potent against RET alterations than against VEGFR2, whereas cabozantinib and vandetanib are much more potent against VEGFR2.\u003c\/p\u003e\n\n\u003ch2 id=\"selpercatinib\"\u003eSelpercatinib (LOXO-292) — The Evidence\u003c\/h2\u003e\n\n\u003cp\u003eSelpercatinib (formerly known as LOXO-292) is an ATP-competitive, highly selective small-molecule inhibitor of RET-altered kinases. Pre-clinical studies first demonstrated powerful anti-tumor activity in RET-altered mouse tumor models, with high selectivity for RET, activity against various RET alterations including V804 gatekeeper mutations, and even some ability to penetrate the brain (intracranial activity).\u003c\/p\u003e\n\n\u003cp\u003eThe \u003cstrong\u003eLIBRETTO-001\u003c\/strong\u003e phase I\/II trial then confirmed its clinical effectiveness in advanced RET-altered thyroid cancers. Updated results presented at the 2022 ESMO Congress included \u003cstrong\u003e142 MKI-naïve patients\u003c\/strong\u003e (those who had not previously received an MKI) and \u003cstrong\u003e151 patients previously treated with vandetanib and\/or cabozantinib\u003c\/strong\u003e. Results presented at the 2021 ASCO Annual Meeting also included \u003cstrong\u003e22 patients with RET fusion-positive thyroid cancers\u003c\/strong\u003e. The findings:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTreatment-naïve MTC:\u003c\/strong\u003e ORR of 81.0% (95% CI, 73.6–87.1)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePreviously treated MTC:\u003c\/strong\u003e ORR of 73.5% (95% CI, 65.7–80.4)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRET fusion-positive thyroid cancer:\u003c\/strong\u003e ORR of 77.3% (95% CI, 54.6–92.2)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eResponse to selpercatinib was also durable. \u003cstrong\u003e84% of responses\u003c\/strong\u003e in treatment-naïve MTC and \u003cstrong\u003e65% in previously treated MTC\u003c\/strong\u003e were still ongoing at 2 years. The median duration of response in the RET-fusion-positive group was 18.4 months.\u003c\/p\u003e\n\n\u003cp\u003eThe therapy was generally well tolerated. Only \u003cstrong\u003e7% of patients (23 out of 319)\u003c\/strong\u003e required discontinuation of treatment due to drug-related side effects. The most frequent grade 3 or higher side effects were hypertension (high blood pressure, in 22% of patients) and increased cytolytic liver enzymes (elevated ALT in 8% and elevated AST in 7%).\u003c\/p\u003e\n\n\u003cp\u003eThe favorable efficacy and safety profiles shown in this study led to \u003cstrong\u003eFDA approval of selpercatinib in 2020\u003c\/strong\u003e for the treatment of patients with RET fusion-positive differentiated thyroid cancers and RET-mutant MTC who require systemic therapy.\u003c\/p\u003e\n\n\u003ch2 id=\"pralsetinib\"\u003ePralsetinib (BLU-667) — The Evidence\u003c\/h2\u003e\n\n\u003cp\u003ePralsetinib (formerly known as BLU-667) was also designed as a potent and highly selective inhibitor of activating RET alterations. Laboratory (in vitro) studies showed that pralsetinib has \u003cstrong\u003esub-nanomolar potency (IC50 of 0.4 nmol\/L)\u003c\/strong\u003e against common oncogenic RET alterations, including V804M\/L gatekeeper mutations and various fusions. It is also at least 100-fold more selective for RET than for other kinases, with limited VEGFR-2 inhibition.\u003c\/p\u003e\n\n\u003cp\u003eThe \u003cstrong\u003eARROW\u003c\/strong\u003e phase I\/II trial confirmed the clinical efficacy and favorable toxicity profile of pralsetinib in patients with locally advanced or metastatic RET-altered thyroid cancers, including \u003cstrong\u003e134 patients with RET-mutant MTC\u003c\/strong\u003e and \u003cstrong\u003e25 previously treated patients with RET-fusion-positive thyroid cancers\u003c\/strong\u003e. Updated results showed:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePreviously treated MTC (n=67):\u003c\/strong\u003e ORR of 52.2% (95% CI, 39.7–64.6)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTreatment-naïve MTC (n=67):\u003c\/strong\u003e ORR of 71.6% (95% CI, 59.3–82.0)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRET fusion-positive thyroid cancers:\u003c\/strong\u003e ORR of 84.0% (95% CI, 63.9–95.5), including 4 complete responses (complete disappearance of all tumors) and 17 partial responses (significant tumor shrinkage)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eResponses were durable. Median PFS was \u003cstrong\u003e25.8 months\u003c\/strong\u003e (95% CI, 19.7–35.0) in previously treated MTC patients and \u003cstrong\u003e25.4 months\u003c\/strong\u003e (95% CI, 17.0–not reached) in RET-fusion-positive thyroid cancers. Median PFS was not reached in the treatment-naïve MTC cohort, but the \u003cstrong\u003e18-month PFS rate was 79.4%\u003c\/strong\u003e (95% CI, 69.4–89.5).\u003c\/p\u003e\n\n\u003cp\u003eLike selpercatinib, pralsetinib was well tolerated. The most frequent grade 3 side effects were hypertension (17% of patients) and cytopenias (low blood cell counts): neutropenia (low white blood cells) in 13%, lymphopenia (low lymphocytes) in 11%, and anemia (low red blood cells) in 10%. The most frequent serious treatment-related side effect was \u003cstrong\u003epneumonitis\u003c\/strong\u003e (lung inflammation), occurring in five patients (3%). One case of grade 5 Pneumocystis jirovecii pneumonia (a severe lung infection) occurred after 44 days on therapy.\u003c\/p\u003e\n\n\u003cp\u003eRates of dose reductions and treatment discontinuations due to side effects were low — only \u003cstrong\u003e10 out of 175 patients (6%)\u003c\/strong\u003e required stopping therapy due to drug toxicity.\u003c\/p\u003e\n\n\u003cp\u003ePralsetinib initially received FDA accelerated approval for advanced RET-altered thyroid cancers in 2020. However, the indication for RET-mutant MTC was voluntarily withdrawn by the sponsor at the end of June 2023 due to the infeasibility of completing confirmatory requirements — a reminder that regulatory status can change and patients should discuss current options with their doctors.\u003c\/p\u003e\n\n\u003ch2 id=\"head-to-head\"\u003eThe Head-to-Head Trial: LIBRETTO-531\u003c\/h2\u003e\n\n\u003cp\u003eWhile the results of LIBRETTO-001 suggested that selpercatinib was superior to the MKIs, a dedicated randomized head-to-head comparison was needed to definitively establish the best first-line treatment. Very recently, the results of the \u003cstrong\u003eLIBRETTO-531\u003c\/strong\u003e trial were published — a multicenter, randomized phase III trial comparing first-line selpercatinib with physician's choice of cabozantinib or vandetanib in \u003cstrong\u003eadvanced, MKI-naïve, RET-mutant MTC patients\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eThe results confirmed a dramatic improvement in PFS with selpercatinib over the MKIs:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eAt 24 months, PFS was \u003cstrong\u003e76.4%\u003c\/strong\u003e (95% CI, 66.5–83.8) in the selpercatinib group, compared with \u003cstrong\u003e37.2%\u003c\/strong\u003e (95% CI, 21.9–52.6) in the cabozantinib\/vandetanib group.\u003c\/li\u003e\n  \u003cli\u003eThe Hazard Ratio for disease progression or death was \u003cstrong\u003e0.28\u003c\/strong\u003e (95% CI, 0.16–0.48; P\u0026lt;0.001) — a 72% reduction in risk of progression or death.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eSelpercatinib was also better tolerated:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eSide-effect-related treatment discontinuation: \u003cstrong\u003e5% vs 27%\u003c\/strong\u003e of patients (selpercatinib vs MKIs, respectively)\u003c\/li\u003e\n  \u003cli\u003eDose reductions due to side effects: \u003cstrong\u003e39% vs 77%\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThis study confirms that \u003cstrong\u003eselpercatinib is the preferred first-line treatment in advanced and\/or metastatic RET-mutant MTC\u003c\/strong\u003e and will play a key role in approval and reimbursement of the drug in many countries.\u003c\/p\u003e\n\n\u003ch2 id=\"key-findings\"\u003eKey Findings at a Glance — Efficacy Data\u003c\/h2\u003e\n\n\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat does it mean if my thyroid cancer has a RET gene alteration?\u003c\/h3\u003e\n\u003cp\u003eRET is a gene that can become abnormally activated by a mutation or fusion, driving cancer growth. In medullary thyroid cancer, RET mutations are common; in papillary thyroid cancer, RET fusions occur in 5–10% of cases. Knowing your RET status helps doctors decide if targeted RET inhibitor drugs like selpercatinib or pralsetinib might be effective for you.\u003c\/p\u003e\n\u003ch3\u003eWho should be tested for RET alterations and how is testing done?\u003c\/h3\u003e\n\u003cp\u003eAll patients with a new diagnosis of medullary thyroid cancer should have germline RET testing, because 1–7% of apparently sporadic cases are actually hereditary. If no germline mutation is found, somatic RET testing is recommended when systemic therapy is considered. Tests include DNA or RNA next-generation sequencing, liquid biopsy, or other methods, depending on tissue availability.\u003c\/p\u003e\n\u003ch3\u003eWhat are the older multi-kinase inhibitors and what are their limitations?\u003c\/h3\u003e\n\u003cp\u003eCabozantinib and vandetanib are multi-kinase inhibitors approved for advanced medullary thyroid cancer. They block RET but also other kinases, causing significant side effects. They are less potent against certain RET mutations, such as V804 gatekeeper mutations, and most patients eventually develop resistance. No complete responses were seen, and benefit duration is limited.\u003c\/p\u003e\n\u003ch3\u003eWhat are the newer selective RET inhibitors selpercatinib and pralsetinib?\u003c\/h3\u003e\n\u003cp\u003eSelpercatinib and pralsetinib are highly selective drugs designed to block RET specifically while sparing other kinases. In trials, they produced high response rates in RET-altered thyroid cancers, including durable responses and better tolerability than older multi-kinase inhibitors. Selpercatinib is now considered the preferred first-line treatment for advanced RET-mutant medullary thyroid cancer.\u003c\/p\u003e\n\u003ch3\u003eHow do selpercatinib and pralsetinib compare to older treatments in terms of effectiveness?\u003c\/h3\u003e\n\u003cp\u003eIn the LIBRETTO-531 trial, first-line selpercatinib improved progression-free survival significantly compared with cabozantinib or vandetanib: 76.4% vs 37.2% at 24 months, with a hazard ratio of 0.28. Selpercatinib also had fewer treatment discontinuations due to side effects (5% vs 27%). Pralsetinib also showed high response rates in its ARROW trial.\u003c\/p\u003e\n\u003ch3\u003eWhat side effects can I expect from selective RET inhibitors?\u003c\/h3\u003e\n\u003cp\u003eSelective RET inhibitors are generally well tolerated. In selpercatinib trials, the most frequent grade 3 or higher side effects were hypertension (22%), elevated ALT (8%), and elevated AST (7%). With pralsetinib, common grade 3 side effects included hypertension (17%), low blood cell counts, and pneumonitis (lung inflammation) in 3%. Only 6–7% of patients discontinued due to side effects.\u003c\/p\u003e\n\u003ch3\u003eWhy might RET inhibitor drugs stop working over time?\u003c\/h3\u003e\n\u003cp\u003eResistance can develop when cancer cells acquire new mutations, such as RET V804 gatekeeper mutations or S904F mutations, which prevent the drug from binding effectively. Patients who progress on therapy often develop these resistance mechanisms. Researchers are studying new strategies to overcome resistance and improve long-term outcomes, but currently these treatments are not curative.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47457988542620,"sku":null,"price":0.0,"currency_code":"EUR","in_stock":true}],"url":"https:\/\/diagnosticdetectives.es\/products\/a-patients-guide-to-ret-targeted-treatment-for-thyroid-cancer-what-the-latest-research-means-for-you","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}