# A Patient's Guide to RET-Targeted Treatment for Thyroid Cancer — What the Latest Research Means for You

This 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.

# A Patient's Guide to RET-Targeted Treatment for Thyroid Cancer — What the Latest Research Means for You

## Table of Contents

- Key Points
- Background: Why This Research Matters
- Understanding the RET Gene and Its Role in Thyroid Cancer
- How RET Mutations Cause Medullary Thyroid Cancer (MTC)
- How RET Fusions Cause Papillary Thyroid Cancer (PTC)
- Testing for RET Alterations — Who Should Be Tested and How
- Treatment With Multi-Kinase Inhibitors (MKIs) — The Older Approach
- Cabozantinib (EXAM Trial)
- Vandetanib (ZETA Trial)
- Why Multi-Kinase Inhibitors Have Limits
- The New Generation: Selective RET Inhibitors
- Selpercatinib (LOXO-292) — The Evidence
- Pralsetinib (BLU-667) — The Evidence
- The Head-to-Head Trial: LIBRETTO-531
- Key Findings at a Glance — Efficacy Data
- Resistance: Why the Drugs Stop Working Over Time
- Clinical Implications — What This Means for Patients
- Limitations of the Current Research
- Future Directions — What's on the Horizon
- Practical Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- RET gene mutations drive most medullary thyroid cancers; RET fusions drive 5–10% of papillary thyroid cancers.
- Genetic testing for RET alterations is recommended for all new medullary thyroid cancer diagnoses, using blood or tumor tissue.
- Older multi-kinase inhibitors like cabozantinib and vandetanib have significant side effects and limited activity against some RET mutations.
- Selective RET inhibitors selpercatinib and pralsetinib show higher response rates, better tolerability, and longer progression-free survival in trials.
- In 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.

## Background: Why This Research Matters

Thyroid 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.

Over the last two decades, researchers have learned that a specific gene called **RET** (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.

This 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.

## Understanding the RET Gene and Its Role in Thyroid Cancer

RET is a type of protein called a **transmembrane glycoprotein receptor tyrosine kinase (RTK)**. 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.

The RET receptor has a specific structure:

-
**Extracellular domain** (the part outside the cell): contains four cadherin-like repeats, a calcium-binding site, and a cysteine-rich region
-
**Intracellular domain** (the part inside the cell): contains tyrosine kinase residues that transmit signals

Unlike many other receptors that bind directly to their activating molecules, RET is activated indirectly. A family of molecules called **GDNF family ligands** (glial cell line-derived neurotrophic factors) first bind to co-receptors called **GFRα**. 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 **MAPK** and **PI3K** pathways — that control cell proliferation and survival.

## How RET Mutations Cause Medullary Thyroid Cancer (MTC)

RET mutations are the most frequent genetic alterations found in **medullary thyroid carcinoma (MTC)**, 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 **multiple endocrine neoplasia type 2A (MEN2A)** and **type 2B (MEN2B)**.

**MEN2A syndrome** 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 **C634 in exon 11**. 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).

**MEN2B syndrome** 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 **RET M918T** 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 **A883F** mutation in exon 15, or double mutations involving **V804M**. 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.

RET mutations are also the hallmark of **sporadic (non-inherited) MTCs**, found in about 55 to 65% of cases. The **M918T** mutation is the most frequent somatic (acquired) mutation. Other less common point mutations can occur at locations such as **C634, A883, and C630**. Occasionally, deletions and small insertions have also been reported.

## How RET Fusions Cause Papillary Thyroid Cancer (PTC)

Unlike MTC, where mutations are the main culprit, **papillary thyroid carcinoma (PTC)** — the most common type of thyroid cancer — is driven by **RET fusions** 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 **5–10% of cases** and are especially common in children and in people who have been exposed to radiation.

The two most common RET fusions in thyroid cancer combine RET with either:

-
**CCDC6** (coiled-coil domain containing 6), producing the CCDC6-RET fusion, or
-
**NCOA4** (nuclear receptor co-activator 4), producing the NCOA4-RET fusion

These 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.

This 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.

## Testing for RET Alterations — Who Should Be Tested and How

Because 1 to 7% of patients with apparently sporadic MTC actually have hereditary disease, **germline RET mutation testing is recommended for all patients with a new diagnosis of MTC**. 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.

Several 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:

-
**Immunohistochemistry (IHC):** Protein-based detection. Not reliable for screening RET alterations because RET protein overexpression can also be seen in benign (non-cancerous) lesions.
-
**Fluorescent in situ hybridization (FISH):** Detects RET fusions with good sensitivity and specificity, but cannot identify the fusion partner and depends heavily on tissue quality.
-
**DNA quantitative PCR (Q-PCR):** Can screen selected hotspot mutations but is limited by primer availability and cannot detect fusions.
-
**RNA-based reverse transcription PCR (RT-PCR):** Can detect fusions but only identifies known partners with specific primers.
-
**DNA-based next-generation sequencing (NGS):** 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.
-
**RNA-based NGS:** 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.
-
**Liquid biopsy (cell-free DNA NGS):** 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.

In 2021, the European Society of Medical Oncology (ESMO) issued recommendations for standard RET testing:

1. In MTC patients, start with germline testing using Q-PCR or NGS on blood or sputum.
1. If a familial RET mutation is already known, DNA Sanger sequencing can be performed on circulating leukocytes (white blood cells).
1. In 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.

## Treatment With Multi-Kinase Inhibitors (MKIs) — The Older Approach

Because RET shares similarities with other tyrosine kinase receptors, several **multi-kinase inhibitors (MKIs)** — drugs that block multiple kinases at once — have been shown to have some anti-RET activity. Among these, **cabozantinib** and **vandetanib** 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, **lenvatinib**, **cabozantinib**, and **sorafenib** are approved for advanced radioiodine-refractory differentiated thyroid cancers (RR-DTCs), including those with RET alterations.

## Cabozantinib (EXAM Trial)

Cabozantinib 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.

A phase I study first showed encouraging results, leading to the pivotal **EXAM trial**, a phase III placebo-controlled study that randomized **330 patients with progressive metastatic MTC** to receive cabozantinib or placebo (at a 2:1 ratio). The results were striking:

-
**Progression-free survival (PFS):** 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<0.001). This means patients on cabozantinib had a 72% lower risk of cancer progression.
- The PFS benefit was observed regardless of tumor burden and location, prior treatment with tyrosine kinase inhibitors, or RET mutation status.

An 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 **RET M918T-mutated MTC** who received cabozantinib compared with placebo: **44.3 vs 18.9 months** (HR 0.60; 95% CI, 0.38–0.94; P=0.03).

Side 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. **Grade 3 or 4 adverse events** (severe or life-threatening side effects) occurred in **69% of patients** — 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.

## Vandetanib (ZETA Trial)

Vandetanib 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.

After two phase II trials showed acceptable safety and anti-tumor activity, the phase III **ZETA trial** compared vandetanib against placebo in patients with locally advanced or metastatic MTC. Key results:

-
**333 patients** were randomized in a 2:1 ratio to receive vandetanib or placebo.
- After a median follow-up of **24 months**, PFS was significantly longer with vandetanib: **30.5 vs 19.3 months** (HR 0.46; 95% CI, 0.31–0.69; P<0.001).
- The overall response rate (ORR) — the percentage of patients whose tumors shrank — was also much better: **45% with vandetanib vs 13% with placebo** (P<0.001).

Overall 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. **24% of patients** experienced grade 3 or higher adverse events, including diarrhea (11%) and hypertension (9%). The most concerning side effect was **QTc prolongation** (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.

One 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<0.0001).

## Why Multi-Kinase Inhibitors Have Limits

Despite their efficacy, MKIs come with significant drawbacks:

-
**Limited RET activity at clinical doses:** Anti-VEGFR MKIs are pharmacokinetically limited in their ability to target RET compared with VEGFR-2 at drug concentrations achievable in patients.
-
**Variable activity against different RET mutations:** For example, cabozantinib and vandetanib effectively inhibit the RET M918T mutation but have limited activity against **RET V804 "gatekeeper" mutations** — 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.
-
**Off-target side effects:** Activity against VEGFR and other kinases causes dose-limiting side effects that compromise how effectively the drug can be given.
-
**No complete responses, and limited duration of benefit:** Most patients eventually develop resistance and their disease progresses.

Specific resistance mechanisms that have been identified against cabozantinib and vandetanib include **acquired RET V804L/M gatekeeper mutations**, which block drug access to the ATP-binding pocket of RET, and **S904F missense mutations**, which increase autophosphorylation activity of the RET kinase.

Lenvatinib 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.

## The New Generation: Selective RET Inhibitors

To overcome the limitations of MKIs, two drugs with potent and highly selective anti-RET activity were developed: **selpercatinib** and **pralsetinib**. 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.

For 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):

Drug
VEGFR2
RET Wild-Type
RET M918T
RET V804L
RET V804M
RET G810S
CCDC6-RET

Cabozantinib
2
11
8
45
162
1050
34

Vandetanib
4
4
7
3597
726
5470
20

Pralsetinib
35
0.4
0.4
1.8
17
391
0.4

Selpercatinib
100
0.4
0.7
17
56
880
10

IC50 = 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.

## Selpercatinib (LOXO-292) — The Evidence

Selpercatinib (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).

The **LIBRETTO-001** phase I/II trial then confirmed its clinical effectiveness in advanced RET-altered thyroid cancers. Updated results presented at the 2022 ESMO Congress included **142 MKI-naïve patients** (those who had not previously received an MKI) and **151 patients previously treated with vandetanib and/or cabozantinib**. Results presented at the 2021 ASCO Annual Meeting also included **22 patients with RET fusion-positive thyroid cancers**. The findings:

-
**Treatment-naïve MTC:** ORR of 81.0% (95% CI, 73.6–87.1)
-
**Previously treated MTC:** ORR of 73.5% (95% CI, 65.7–80.4)
-
**RET fusion-positive thyroid cancer:** ORR of 77.3% (95% CI, 54.6–92.2)

Response to selpercatinib was also durable. **84% of responses** in treatment-naïve MTC and **65% in previously treated MTC** were still ongoing at 2 years. The median duration of response in the RET-fusion-positive group was 18.4 months.

The therapy was generally well tolerated. Only **7% of patients (23 out of 319)** 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%).

The favorable efficacy and safety profiles shown in this study led to **FDA approval of selpercatinib in 2020** for the treatment of patients with RET fusion-positive differentiated thyroid cancers and RET-mutant MTC who require systemic therapy.

## Pralsetinib (BLU-667) — The Evidence

Pralsetinib (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 **sub-nanomolar potency (IC50 of 0.4 nmol/L)** 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.

The **ARROW** 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 **134 patients with RET-mutant MTC** and **25 previously treated patients with RET-fusion-positive thyroid cancers**. Updated results showed:

-
**Previously treated MTC (n=67):** ORR of 52.2% (95% CI, 39.7–64.6)
-
**Treatment-naïve MTC (n=67):** ORR of 71.6% (95% CI, 59.3–82.0)
-
**RET fusion-positive thyroid cancers:** 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)

Responses were durable. Median PFS was **25.8 months** (95% CI, 19.7–35.0) in previously treated MTC patients and **25.4 months** (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 **18-month PFS rate was 79.4%** (95% CI, 69.4–89.5).

Like 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 **pneumonitis** (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.

Rates of dose reductions and treatment discontinuations due to side effects were low — only **10 out of 175 patients (6%)** required stopping therapy due to drug toxicity.

Pralsetinib 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.

## The Head-to-Head Trial: LIBRETTO-531

While 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 **LIBRETTO-531** trial were published — a multicenter, randomized phase III trial comparing first-line selpercatinib with physician's choice of cabozantinib or vandetanib in **advanced, MKI-naïve, RET-mutant MTC patients**.

The results confirmed a dramatic improvement in PFS with selpercatinib over the MKIs:

- At 24 months, PFS was **76.4%** (95% CI, 66.5–83.8) in the selpercatinib group, compared with **37.2%** (95% CI, 21.9–52.6) in the cabozantinib/vandetanib group.
- The Hazard Ratio for disease progression or death was **0.28** (95% CI, 0.16–0.48; P<0.001) — a 72% reduction in risk of progression or death.

Selpercatinib was also better tolerated:

- Side-effect-related treatment discontinuation: **5% vs 27%** of patients (selpercatinib vs MKIs, respectively)
- Dose reductions due to side effects: **39% vs 77%**

This study confirms that **selpercatinib is the preferred first-line treatment in advanced and/or metastatic RET-mutant MTC** and will play a key role in approval and reimbursement of the drug in many countries.

## Key Findings at a Glance — Efficacy Data

## Frequently Asked Questions

### What does it mean if my thyroid cancer has a RET gene alteration?

RET 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.

### Who should be tested for RET alterations and how is testing done?

All 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.

### What are the older multi-kinase inhibitors and what are their limitations?

Cabozantinib 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.

### What are the newer selective RET inhibitors selpercatinib and pralsetinib?

Selpercatinib 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.

### How do selpercatinib and pralsetinib compare to older treatments in terms of effectiveness?

In 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.

### What side effects can I expect from selective RET inhibitors?

Selective 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.

### Why might RET inhibitor drugs stop working over time?

Resistance 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.


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